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AJR 2005; 185:622-626
© American Roentgen Ray Society

Clinical Observations

Pulmonary Cryptococcosis in Immunocompetent Patients: CT Findings in 12 Patients

Danial L. Fox1 and Nestor L. Müller1,2

1 Department of Radiology, Vancouver General Hospital, 899 W 12th Ave., Vancouver, BC V5Z 1M9, Canada.
2 Department of Radiology, The University of British Columbia, 3350-950 W 10th Ave., Vancouver, BC V5Z 4E3, Canada.

Received July 22, 2004; accepted after revision October 6, 2004.

 
Address correspondence to N. L. Müller.


Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
OBJECTIVE. The aim of our study was to review the CT findings of pulmonary cryptococcosis in 12 immunocompetent patients.

CONCLUSION. The CT manifestations of pulmonary cryptococcosis consist of pulmonary nodules or masses measuring 5-52 mm in diameter and focal areas of consolidation. The nodules and masses have a predominantly peripheral distribution in 80% of the cases. Cavitation of nodules or consolidation is seen in approximately 40% of the cases. The infection can be due to Cryptococcus neoformans var gattii or var neoformans.


Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cryptococcus neoformans is a ubiquitous encapsulated yeastlike fungus with a predilection for the central nervous system in humans and animals. Inhalation is the usual portal of entry of infection [1]. The organism may cause isolated pulmonary infection or may progress to disseminated disease, particularly in patients with AIDS or other causes of impaired T cell-mediated immunity [2, 3]. Pulmonary cryptococcosis in the immunocompetent host is rare and may be asymptomatic [2, 4].

The most common radiographic manifestations of pulmonary cryptococcosis consist of single or multiple pulmonary nodules, segmental or lobar consolidation, or a reticulonodular pattern of opacities [3, 5-7]. Associated features include cavitation, lymphadenopathy, and pleural effusion. To our knowledge, the CT findings have been reported in 53 immunocompromised patients, including five case series [8-12] and three case reports [13-15]. The description of the CT findings in immunocompetent patients has been limited to 18 patients, including three case series [8, 12, 16] and three case reports [17-19]; the largest of the case series [8] focused on the clinical findings and only gave a brief summary of the CT findings with no illustrations. The aim of our study was to review the CT findings of pulmonary cryptococcosis in immunocompetent patients.


Materials and Methods
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 Abstract
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 Materials and Methods
Results
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This retrospective study included 12 immunocompetent patients with proven pulmonary cryptococcosis who had attended our institution and who had undergone chest CT between 2000 and 2004. Eight patients were men and four were women; the patients ranged in age from 21 to 74 years (mean age, 42.8 years). Approval for this study was obtained from our institutional clinical research ethics board.

Scans were acquired on a variety of single-detector (n = 7) and multidetector (n = 5) scanners. Pitch, milliampere-second, and peak kilovoltage settings varied among the scanners. Helical scans were obtained in 11 patients. For those examinations, scanning collimation was 1 (n = 1), 5 (n = 4), 7 (n = 4), 7.5 (n = 1), or 10 (n = 1) mm. One patient underwent thin-section CT with 1.25-collimation images acquired at 10-mm intervals. All but two examinations were performed without IV contrast material. Information about each patient's clinical symptoms, immune status, diagnostic test results, and treatment was obtained from reviewing the case notes.

Two fellowship-trained chest radiologists who reached a decision by consensus reviewed the CT findings. Scans were reviewed either on a dedicated monitor (n = 6) or on film (n = 6). All images were viewed using window settings appropriate for lung parenchyma (width, 1,000-1,500 H; level, -600 to -700 H) and soft tissues (width, 300-450 H; level, 30-50 H). The observers assessed the scans for the presence of nodules, masses, consolidation, ground-glass attenuation, and interlobular septal thickening and categorized the abnormalities according to laterality, lobe, and location, with peripheral defined as being located in the outer third of the lung and central defined as inner two thirds of the lung. If appropriate, nodules were also categorized according to location within the secondary pulmonary lobule (i.e., centrilobular, perilymphatic, or random).



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  		Fig. 1A —57-year-old man with pulmonary cryptococcosis. CT image obtained with 1-mm collimation shows spiculated nodule (arrow) in right lower lobe is abutting major fissure.

 



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  		Fig. 1B —57-year-old man with pulmonary cryptococcosis. CT image obtained with 1-mm collimation at same level as A 6 weeks after treatment with fluconazole shows spiculated nodule (arrow) is reduced in size. Diagnosis was confirmed on surgical wedge resection of 17-mm spiculated nodule in anterobasal segment of right lower lobe. Subtyping confirmed var gattii.

 
Consolidation, ground-glass attenuation, and interlobular septal thickening were defined according to the recommendations of the Nomenclature Committee of the Fleischner Society [20]. Nodules and masses were defined as rounded opacities that were at least moderately well marginated and less or greater than 3 cm in maximum diameter, respectively. Nodules and masses were further categorized according to size (1-5, 6-10, 11-30, 31-50, > 50 mm, or variable), number (1, 2-4, 5-10, or > 10), and margin (smooth, lobulated, or spiculated). Scans were also assessed for the presence of pleural abnormality and lymphadenopathy. Lymph nodes were considered enlarged if their short-axis diameter was greater than 10 mm.



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  		Fig. 2A —32-year-man with pulmonary cryptococcosis. CT image obtained with 1.25-mm collimation shows two smoothly marginated nodules (arrows) in left upper lobe.

 



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  		Fig. 2B —32-year-man with pulmonary cryptococcosis. CT image at more caudal level than A shows 8-mm thin-walled cavity (arrow) in right lower lobe. Diagnosis was confirmed on bronchoalveolar lavage and sputum culture. Subtyping confirmed var neoformans.

 
Eleven of the 12 patients presented with limited pulmonary disease. Of these patients, seven were asymptomatic; three presented with cough, fever, and weight loss; and one presented with cough alone. The remaining patient presented with pulmonary disease and meningitis. The diagnosis was proven at surgical resection in five patients, CT-guided fine-needle aspiration in four patients, bronchoalveolar lavage in two patients, and both sputum and bronchoalveolar lavage in one patient. In all the patients, the diagnosis of C. neoformans infection was based on the characteristic appearance of the fungus on the surgical resection, biopsy, or bronchoalveolar lavage specimens. Culture subtyping was performed in five of the 12 patients, yielding C. neoformans var gattii in three of the five patients and var neoformans in two patients.

Treatment consisted of surgical resection alone (n = 4) or antifungal therapy (n = 7). The remaining patient declined antifungal therapy and self-medicated with an herbal remedy. Radiologic follow-up of 1-11 months from diagnosis was available in nine of the 12 patients and consisted of CT in six patients and chest radiography in three.


Results
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Discussion
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Nodules and masses were present in 10 (83%) of the 12 cases. The number of nodules and masses in each case was one (n =4), two to four (n = 3), five to 10 (n = 1), and more than 10 (n = 2). Size in each case was 6-10 mm (n = 3), 11-30 mm (n = 4), and greater than 50 mm (n = 1). In two cases, the size varied from 2 to 52 mm and from 3 to 40 mm, respectively. The margin in each case was smooth (n = 6), spiculated (n = 2) (Figs. 1A, and 1B), or variable (n = 2). Cavitation was a feature in three cases (Figs. 2A, and 2B). The location of the nodules and masses was predominately peripheral (n = 8), central (n = 1), or random (n = 1). One patient with nodules and masses had associated centrilobular nodularity, focal ground-glass attenuation, and mild interlobular septal thickening (Fig. 3), and another patient had associated air-space consolidation.



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  		Fig. 3 —30-year-old man with pulmonary cryptococcosis. CT image obtained with 5-mm collimation shows multiple predominantly ill-defined nodules in periphery of both lower lobes. Also noted are areas of ground-glass opacification. Diagnosis was confirmed on bronchoalveolar lavage. Subtyping confirmed var neoformans.

 

In two patients, the sole parenchymal finding was nonsegmental consolidation with associated cavitation (Fig. 4). In one of these patients, the consolidation had progressed from a 30-mm spiculated nodule since CT was performed 6 weeks earlier.



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  		Fig. 4 —36-year-old man with pulmonary cryptococcosis. CT image obtained with 7-mm collimation shows dense consolidation in right upper lobe with area of cavitation (arrow). Diagnosis was confirmed on bronchoalveolar lavage. No subtyping of organism was performed.

 

The distribution of parenchymal changes was predominately lower lobe (n = 7), upper lobe (n = 2), right middle lobe (n = 1), or mixed (n = 2). Parenchymal changes were right-sided (n = 5), left-sided (n = 2), or bilateral (n =5).

All patients older than the median age of 44 years (n = 6) showed only one or two peripheral nodules. In this group, a total of nine nodules were identified, seven of which were well marginated and eight of which were located in the lower lobes. Histopathology was available in five of these patients and showed well-defined granulomata in four patients with well-defined nodules on CT and a poorly defined granuloma with reactive fibrosis in the fifth patient with spiculated nodules on CT. By contrast, all patients presenting with cavitary disease, consolidation, or more than two nodules (n = 6) were younger than the median age of 44 years.

Lymphadenopathy was present in two patients. One had ipsilateral hilar lymphadenopathy in association with extensive consolidation, and the other had paraesophageal lymphadenopathy adjacent to a 20-mm peripheral nodule (Figs. 5A, 5B, 5C, and 5D). None of the cases exhibited pleural abnormality.



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  		Fig. 5A —59-year-old man with pulmonary cryptococcosis. CT image obtained with 7.5-mm collimation shows two peripheral lower lobe pulmonary nodules (arrows).

 


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  		Fig. 5B —59-year-old man with pulmonary cryptococcosis. CT image obtained at more caudal level than A shows right lower lobe nodule (straight arrow) with adjacent enlarged paraesophageal lymph node (curved arrow).

 


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  		Fig. 5C —59-year-old man with pulmonary cryptococcosis. CT image obtained 11 months after A and B shows left lower lobe nodule (arrow) is reduced in size.

 


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  		Fig. 5D —59-year-old man with pulmonary cryptococcosis. CT image obtained 11 months after A and B shows paraesophageal lymph node (arrow) is reduced in size. No subtyping of organism was performed.

 
Follow-up imaging showed a reduction in the size of the parenchymal abnormalities in six patients on antifungal therapy, including resolution of cavitation in five patients. Follow-up CT performed after 6 weeks of antifungal therapy in one patient showed reduction in size of multiple nodules and masses, but also revealed interval cavitation of several of the masses and larger nodules. Follow-up CT in the patient who refused antifungal therapy showed reduction in the size of the pulmonary nodules and paraesophageal lymphadenopathy (Figs. 5A, 5B, 5C, and 5D).


Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
To our knowledge, this study is the largest to address the CT findings of pulmonary cryptococcosis in the nonimmunocompromised host. In one previous study, investigators commented on limited CT findings in three immunocompetent patients [16]. In another study, researchers commented on limited CT findings in a cohort of variable immunologic competence [8]. Two studies have focused on CT findings in cohorts of predominantly immunocompromised individuals [11, 12]. Several studies in the literature have focused on radiographic findings in immunocompetent cohorts [21, 22] or cohorts with variable immunologic competence [6, 7].

The radiographic features of pulmonary cryptococcosis can be broadly categorized into pulmonary nodules or masses with well- or ill-defined margins, segmental or lobar consolidation, and small nodular or reticulonodular opacities [5-7, 22]. Miliary disease, cavitation, pleural effusions, and lymphadenopathy are also recognized features, but are seen more commonly in immunocompromised patients [5-7, 9]. Lacomis et al. [11] reported that CT provided additional information about the character or extent of disease in 23 (92%) of 25 cases. Nunez et al. [16] reported four cases of pulmonary cryptococcosis in nonimmunocompromised hosts, three of whom had undergone chest CT. Two of the three patients had multiple bilateral nodules on CT and one had dense consolidation.

In agreement with previous radiographic [3, 5, 6] and CT [12] studies, the most common CT manifestation of pulmonary cryptococcosis in our study was the presence of solitary or multiple pulmonary nodules or masses, seen in 10 (83%) of the 12 patients. The nodules ranged from 5 to 52 mm in diameter and from one to more than 10 in number. The remaining two patients had focal areas of consolidation.

Cavitation was evident on CT in five (42%) of the 12 patients, including cavitating nodules in three patients and cavitating consolidation in two. This finding contrasts with those of previous studies [6, 11, 12, 21], which found cavitation to be rare. Although this discrepancy may in part be due to the greater sensitivity of CT, cavitation also has been rarely reported in the CT literature, especially in patients who did not have HIV.

The parenchymal abnormalities in our study involved predominantly the lower lobes in 58% of the cases. This is in agreement with early radiographic series [23, 24] but contrasts with more recent radiographic and CT series that found no significant lobar predilection [7, 11, 12, 22] or an upper lobe predilection [5]. The nodules and masses were peripherally located in 80% of the cases, in agreement with the study by Lacomis et al. [11].

None of our 12 patients had pleural effusion, and only two had lymphadenopathy evident on CT. These results are in agreement with those of several previous studies based on radiographic or CT findings [6, 7, 9, 10, 12]. It should be noted that pleural effusion and lymphadenopathy are relatively common in immunocompromised patients [2, 6].

In our study, CT manifestations and clinical presentation were influenced by patient age. All six patients who were older than the median age of 44 years presented with only one or two peripheral nodules and were asymptomatic. All patients with multiple nodules, consolidation, or cavitation were younger than the median age. Of these, five were symptomatic and one was asymptomatic. The reason for the different presentations is unclear.

There are two varieties of C. neoformans: var neoformans and var gattii. The C. neoformans var neoformans is ubiquitous, whereas the var gattii occurs mainly in tropical and subtropical climates [25], probably because of its strong association with certain species of the Eucalyptus tree [26]. Recently an out-break of var gattii was documented in the temperate climate of Vancouver Island, with 59 documented cases between January 1999 and July 2002 [27]. Five of the 12 patients in this study either had visited (n = 3) or were a resident of (n = 2) Vancouver Island. Of these, var gattii was isolated in one patient and was suspected in another because of a travel history to the endemic area of Vancouver Island. Subtyping was not performed in the remaining three patients. No travel history to Vancouver Island was elicited in the remaining seven patients, in whom var gattii was isolated in two patients and var neoformans in two patients.

To our knowledge, our study constitutes the first report of the CT findings of var gattii. Var neoformans occurs more commonly in immunocompromised hosts, including those with HIV infection, and var gattii occurs mainly in immunocompetent hosts [22, 28]. Previous studies have reported a tendency for var neoformans to cause extensive pulmonary involvement associated with disseminated disease, particularly in immunocompromised patients, and for var gattii to cause more focal pulmonary and cerebral disease [22, 28]. The numbers of patients in our study were too small to be able to discern differences in CT findings between the two subtypes of C. neoformans.

Our study has several limitations. It is retrospective and includes a small number of patients and a wide range of CT techniques. However, to our knowledge, it is the largest series on the CT findings of cryptococcal pulmonary infection in immunocompetent patients. Further studies are required to examine the imaging characteristics of var neoformans and var gattii, which may differ, and the imaging features in patients of different ages.

In conclusion, the CT manifestations of pulmonary cryptococcosis in immunocompetent patients consist of pulmonary nodules or masses measuring 5-52 mm in diameter or focal areas of consolidation. Cavitation of nodules or consolidation is seen in approximately 40% of the cases. Older patients are more likely to present with one or two nodules and younger patients, with multiple nodules or consolidation and with cavitation. Also, in our study, the older patients were asymptomatic and the younger patients were symptomatic.


References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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