Introduction

In human immunodeficiency virus (HIV)-negative patients, pulmonary cryptococcosis (PC) has been extensively studied and nodular masses are the most common radiological manifestations [1–4]. However, PC in HIV-infected is less well defined. Knowledge of HIV-associated PC are largely based on studies performed about 2 decades ago which reported that the most common findings on chest radiograph were diffuse interstitial infiltrates [5–7]. In those HIV-infected immunocompromised patients, PC was thought to be an important contributor to fetal respiratory failure [5]. Although computed tomography (CT) has been widely applied in evaluating pulmonary lesions, few studies on the CT findings of HIV-associated PC are available. In our previous study, we evaluated 11 HIV-infected patients with pulmonary abnormalities on chest CT scan and confirmed cryptococcal diseases outside of the lung. Interestingly, 9 patients had solitary pulmonary nodules that could be clinically related to cryptococcal infection [8]. This finding is inconsistent with the dominant perception of HIV-associated PC and necessitates further investigation. Here, we extend our previous study to expand the understanding of CT findings of HIV-associated PC.

Patients and methods

Results

Findings on chest CT scan

Chest CT scans demonstrated nodular lesions in 93.3% (56/60) of the studied patients (Fig 1), and solitary nodule accounted for the majority of the cases (69.6%, 39/56). These nodular lesions were usually cavitated with a cavitation rate of 78.6% (44/56). Pleural effusions occurred in 11.6% (7/60) of the studied patients, and 71.4% (5/7) of the patients with pleural effusions had co-existing nodular lesions. Pneumonic infiltrates occurred in 31.7% (19/60) of the patients; of which, 68.4% (13/19) were diffuse pneumonic infiltrates (all diffuse ground-glass opacities), 21.1% (4/19) were focal pneumonic infiltrates and 10.5% (2/19) were multi-focal pneumonic infiltrates. Of these 19 patients with pneumonic infiltrates, 89.5% (17/19) had co-existing nodular lesions.

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Fig 1. Chest CT findings of HIV-infected patients with cryptococcal infection and pulmonary abnormalities.

SN, solitary nodule; MN, multiple nodules; PE, pleural effusions; PI, pneumonic infiltrates.

https://doi.org/10.1371/journal.pone.0173858.g001

Etiologies of pulmonary lesions

76.8% (43/56) of the nodular lesions could be demonstrated a relationship with PC that 12.5% (7 /56) of the nodular lesions were “laboratory-confirmed” cases, 48.2% (27/56) were “clinically confirmed” cases and 16.1% (9/56) were “clinically probable” cases (Table 1). Of the 7 “laboratory-confirmed” cases of PC with nodular lesions, 5 were confirmed by lung needle biopsies that revealed cryptococcal elements (Fig 2, S1 File) and culture of the biopsy specimens grew Cryptococcus spp.; the other 2 “laboratory-confirmed” cases of PC fulfill the criteria of “clinically confirmed” cases and culture of the sputum grew Cryptococcusspp. (S1 File). All the above mentioned 9 “clinically probable” cases of PC also had pneumonic infiltrates that anti-cryptococcal drugs and other antibiotics were used to achieve an improvement of pulmonary lesions(S1 File). Finally, it was difficult to deduce the etiologies of the nodular lesions in 23.2% (13/56) of the patients because follow-up chest CT scans to define clinical responses were unavailable(S1 File).

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Fig 2. A representative case of laboratory-confirmed pulmonary cryptococcosis.

A 49-years-old man presented to hospital with Lymphadenopathy for 3 months and fever for 1 month. He had HIV infection with a CD4 count of 108 cells/μL. Serum cryptococcal antigen titer was 1:40. Serum galactomannan assay was negative. Chest CT scan demonstrated multiple pulmonary nodules (A, arrow). Lung biopsy showed encapsulated yeast-like fungal cells consistent with cryptococcal infection(arrows in B, alcian blue stain).

https://doi.org/10.1371/journal.pone.0173858.g002

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Table 1. Etiologies of pulmonary lesions.

https://doi.org/10.1371/journal.pone.0173858.t001

85.7% (6/7) of the pleural effusions were “clinically confirmed” cases of PC, and the remaining one was undefined due to lack of follow-up chest CT scan. For the 19 cases of pneumonic infiltrates, one with solitary cavitary nodule and multi-focal pneumonia fulfill the criteria of “clinically confirmed” case and culture of the sputum grew Cryptococcus spp., therefore was considered “laboratory-confirmed” PC. Of the 13 cases of diffuse pneumonic infiltrates, 53.8% (7/13) were "clinical probable" cases of PC as additional drugs, aside from anti-cryptococcal drugs, were used to achieve pulmonary improvement (those 7 cases also received anti-PCP therapy therefore PCP could not be excluded); 38.5% (5/13) were unlikely to related to PC (Fig 3, a representative case of clinically deducing the etiology of pulmonary lesion) but were perhaps clinically attributed to PCP. Etiology of diffuse pneumonic infiltrates was undefined in 1 case due to lack of follow-up chest CT scan.

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Fig 3. A representative case of clinical deduction of pulmonary cryptococcosis.

A 47-year-old woman presented to hospital with fever, cough and shortness of breath. She was confirmed of HIV infection with a CD4 count of 60 cells/μL. The serum cryptococcal antigen titer was 1:16. Lumbar puncture was performed and there was no evidence of cryptococcal meningitis. A chest CT scan showed diffuse ground-glass opacities (DGO). Also on the Chest CT, there was a small nodule (A, arrow). She was given empirical treatment with co-trimoxazole (1440 mg, every eight hours) for pneumocystis pneumonia, and methylprednisolone as an adjunctive therapy. A chest CT scan after 3 weeks showed nearly complete resolution of the DGO; however, the nodular lesion progressed(B, arrow). The patient then received secondary prophylaxis for pneumocystis pneumonia with co-trimoxazole(960 mg/d) and treated with fluconazole (400mg/d). A follow-up CT scan after seventeen days of fluconazole treatment showed partial resolution of the nodule (C, arrow). Taken together, the nodule lesion was attributed to pulmonary cryptpcoccosis, while the DGO were related to pneumocystis pneumonia.

https://doi.org/10.1371/journal.pone.0173858.g003

Discussion

In this study, 82.5% (66/80) of the HIV-infected patients with confirmed cryptococcal infection had pulmonary lesions. On one hand, those lesions could be related to cryptococcal infection, but on the other hand those lesions may be caused by other pathogens or tumors. Due to immunodeficiency, mixed infection should not beunderestimated, especially in patients with multiple forms of pulmonary lesions. The initial identification of possible cases of PC excluded 4 cases of pulmonary tuberculosis and 2 cases of Kaposi’s sarcoma. Intriguingly, 56 out of the 60 remaining cases showed pulmonary nodules which usually cavitated and solitary nodule was the most common form. Based on the available patients' data, at least 76.8% (43/56) of the nodular lesions could be demonstrated a relationship with PC. Those findings were closely consistent with our previous observation which suggested that solitary cavitary pulmonary nodule may be a common CT finding in HIV-associated PC[8]. Nevertheless, pulmonary nodular lesions with or without cavitation, although reported in other studies, were not recognized as common manifestations of HIV-associated PC [6, 7, 10]. More recently, Lin et al reported that PC contributed to about 17% of the cavitary pulmonary lesions in HIV-infected patients [11].

The high frequency of diffuse interstitial infiltrates, attribute to HIV-associated PC in other studies [6, 7], was not seen in our study. Diffuse pneumonic infiltrates, specifically diffuse ground-glass opacities, were only present in 21.7% of (13/60) the patients and almost always co-existed with pulmonary nodules. Of note, at least some of those diffuse pneumonic infiltrates may be related to PCP (Table 1, Fig 3). It is therefore better to include anti-cryptococcal therapy as well as anti-PCP drugs in empirical treatment for patients with confirmed cryptococcal infection (for example CM) and diffuse pneumonic infiltrates. Aside from PCP, it is also necessary to exclude other causes of diffuse pneumonic infiltrates in HIV-infected immunocompromised persons, such as cytomegalovirus pneumonia and mycobacteriosis[12, 13]. This is important as diffuse pneumonic infiltrates, unlike nodular lesion, would result in severe respiratory symptoms, and may quickly progress to respiratory failure if left untreated.

Although pleural effusions were less frequently seen in our study, the presence of pleural effusions was suggestive of PC in our patients. Of note, pleural effusions could be caused by multiple common conditions in HIV-infected patients, such as tuberculosis and Kaposi sarcoma [13, 14]. Extensive laboratory evaluation of pleural effusions was required torule out those comorbidities, especially when pleural effusions did not respond to anti-cryptococcal therapy.

As discussed above, cryptococcal infection seems likely to cause localized pulmonary lesions in HIV-infected patients similar with that in HIV-negative patients [1–4], although cavitation of the nodules seems to be more common in HIV-infected patients. The imaging modality of Chest CT scan used in our study is more sensitive to reveal pulmonary lesions [15]. As shown in Fig 3, the small nodular lesion was surrounded with diffuse pneumonic infiltrates which may be very difficult to be revealed by chest radiograph. It is possible that nodular lesions were underestimated in former studies of HIV-associated PC[5–7]. Moreover, as shown in our study and others’ case report[10], pulmonary nodules without pneumonic infiltrates or pleural effusions did not often cause respiratory symptoms, while former studies on HIV-associated PC generally included patients with respiratory symptoms [5–7]. All the above mentioned factors may lead to the low prevalence of pulmonary nodules in HIV-associated PC in other studies. Nevertheless, as our study was conducted in Chinese population, different host-pathogen interactions may exist and contribute to the discrepancy.

There are limitations to our study. Only a minority of the cases of PC were laboratory-confirmed, and most cases were diagnosed by clinical deduction. Response of pulmonary lesions to anti-cryptococcal treatment is suggestive of PC, however other fungal infections, such as aspergillosis, penicilliosismarneffei and histoplasmosis that could cause similar lesions [16–18], should also be excluded. Nevertheless, the clinically confirmed cases of PC were less likely to be associated with aspergillosis, penicilliosismarneffei or histoplasmosis, as anti-cryptococcal treatments used in our study were not optimal therapies for the above mentioned diseases[19]. Also, penicilliosis was unlikely considered because our patients were not from an endemic area and did not have skin lesions or blood culture results consistent with penicilliosis. Aside from fungal infections, pulmonary nodules could also be caused by many other reasons, such as mycobacteria infection and malignancy [11, 13, 20–22], and those etiologies should be included in the differential diagnosis.

In conclusion, our study suggested that pulmonary nodules but not diffuse pneumonia are the most common radiological characteristics of HIV-associated PC. HIV-infected patients with pulmonary nodules on chest CT should particularly be screened for cryptococcal infection.

Supporting information

Acknowledgments

We thank Dr. Danielle Minkoulou at Southeast University for assistance with editing the manuscript.