Lung (2012) 190:339–346 DOI 10.1007/s00408-011-9362-8
RESPIRATORY INFECTIONS
Retrospective Analysis of 76 Immunocompetent Patients with Primary Pulmonary Cryptococcosis Feng Ye • Jia-xing Xie • Qing-si Zeng • Guo-qin Chen • Shu-qing Zhong • Nan-shan Zhong
Received: 19 July 2011 / Accepted: 19 December 2011 / Published online: 14 January 2012 Ó Springer Science+Business Media, LLC 2012
Abstract Background Pulmonary cryptococcosis typically occurs in immunocompromised patients, but it can also occur in immunocompetent patients. Our objective was to describe the clinical manifestations, diagnosis, and management of primary pulmonary cryptococcosis in immunocompetent patients. Methods We retrospectively reviewed the clinical data of 76 patients with primary pulmonary cryptococcosis who were admitted to our hospital from 1995 to 2010. Results Pulmonary cryptococcosis was pathologically proven in all patients. Mean patient age was 42.5 years and 55 patients (72%) were male. The major clinical manifestations were cough (47 pts, 62%), expectoration (29 pts, 38%), fever (16 pts, 21%), chest pain (15 pts, 20%), dyspnea (17 pts, 22%), and emaciation (10 pts, 13%). Eighteen patients (24%) were asymptomatic. Most patients were admitted due to shadows on chest X-rays. Lesions were more common in the lower lung (60 pts, 78.9%) than in the upper lung (25 pts, 32.9%). More lesions (28 pts,
F. Ye (&) J. Xie S. Zhong N. Zhong Guangzhou Institute of Respiratory Diseases, First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 151 Yan Jiang Road, Guangzhou, People’s Republic of China e-mail:
[email protected];
[email protected];
[email protected] Q. Zeng Department of Radiology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China G. Chen Department of Pathology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China
37%) were characterized by patchy consolidations. Pulmonary cryptococcosis was confirmed histologically among all patients. Surgical removal of lesions or treatment with fluconazole and other antifungal agents for complete courses led to favorable outcomes for most patients. Conclusions Primary pulmonary cryptococcosis was found mainly in immunocompetent patients aged\50 years without preexisting lung disease. Shadow on the chest X-ray is the predominant feature. Treatment with a complete course of fluconazole and/or other antifungal agents can achieve favorable outcome. Keywords Pulmonary cryptococcosis Immunocompetent Symptom Treatment Cryptococcus
Introduction Cryptococcosis, which occurs sporadically worldwide, is a potentially serious fungal disease that is typically caused by inhalation of Cryptococcus neoformans or Cryptococcus gattii, which tend to form aerosol [1]. Cryptococcus sp. has a high affinity for the central nervous system, followed by the skin and lungs. Many pulmonary cryptococcosis (PC) patients have lung involvement alone [1]. Cryptococcosis typically occurs in immunocompromised patients such as those with HIV/AIDS, and the presence of pulmonary Cryptococcus sp. in HIV/AIDS patients is associated with high mortality [2]. Patients who are given long-term treatment with immunosuppressants, recipients of organ transplantation, those with malignancies, diabetes mellitus, and chronic pulmonary diseases are also susceptible to Cryptococcus infection [3]. In recent years, with the widespread use of broad-spectrum antibiotics, immunosuppressants, glucocorticoids, and chemotherapeutics, and with advances in the
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diagnosis and treatment of diseases, the incidence of pulmonary cryptococcosis (PC) has increased [4, 5]. Cryptococcosis also occurs in immunocompetent patients [2]. Cryptococcus infection has been reported in China, in immunocompetent hosts, including non-AIDS patients [6] and children [7]. In the present study, we retrospectively analyzed the data of 76 immunocompetent patients with PC who were admitted to our medical center from January 1995 to August 2010 and describe the characteristics and correlates of CP and the treatments in these patients.
Lung (2012) 190:339–346 Table 1 Demographic and clinical characteristics of immunocompetent patients with primary pulmonary cryptococcosis (n = 76) Variablesa
All patients (N = 76)
Demographics Age (years)
42.54 ± 11.33
Gender Female
21 (27.63%)
Male
55 (72.37%)
Smoking
15 (19.74%)
Drinking Disease history
11 (14.47%) 25 (32.89%)
Symptoms
Methods Patient Enrollment From January 1995 to August 2010, immunocompetent patients with a diagnosis of pulmonary cryptococcosis at the First Affiliated Hospital of Guangzhou Medical College were retrospectively reviewed by a computer-assisted search of medical records. The following data were abstracted from the medical records: age, sex, host immune status, presenting symptoms, clinical features, results of radiology, antifungal and surgical therapy; follow-up and final outcome. Our Institutional Review Board approved our retrospective study, waiving the informed consent from each patient. Those patients with HIV infection, organ transplantation, hematological malignancy, and other immunocompromising conditions were excluded from the study. In addition, subjects with a history of cancer, those who died from coronary heart disease, those who were untreated, or those who were discharged against medical advice were excluded after the review of their medical records. Finally, the records of 76 patients were considered for this retrospective analysis. The Diagnosis of Cryptococcus neoformans Respiratory tract specimens submitted to the microbiology laboratory for fungal culture were inoculated onto Sabouraud dextrose agar. The cultures were incubated at 35°C and examined daily for 1 week to confirm species identification. The diagnosis of pulmonary cryptococcosis was made with the histopathologic presence of the organism on a lung biopsy specimen or by detection of capsular polysaccharide antigens of C. neoformans from blood using CryptoTrol (Bio-Rad Laboratories, Hercules CA, USA). The cytologic or histologic identification of C. neoformans was obtained by transbronchial lung biopsy (TBLB, 33 pts, 43%), videoassisted thoracoscopic surgery (VATS, 25 pts, 33%), percutaneous translung biopsy (5 pts, 6.6%), or open lung biopsy (15 pts, 20%) (Table 1). For pathologic diagnosis,
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No symptom
18 (23.68%)
Cough
47 (61.84%)
Spit phlegm
29 (38.16%)
Dyspnea
17 (22.37%)
Fever
16 (21.05%)
Chest pain
15 (19.74%)
Emaciation
10 (13.16%)
Hemoptysis
4 (5.26%)
Diagnosis by TBLB
33 (43.42%)
VATS
25 (32.89%)
Open lung biopsy
15 (19.74%)
Percutaneous translung biopsy
5 (6.58%)
a Age indicated as mean ± SD and categorical data are presented as counts (percentages)
TBLB transbronchial lung biopsy, VATS video-assisted thoracoscopic surgery
all specimens were managed with periodic acid Schiff (PAS) stain, Gomori methenamine silver (GMS) stain, and Mucin stain and examined by an experienced pathologist. Statistical Analysis Patient age had a normal distribution and is presented as the mean and standard deviation (SD). The number of in-hospital days had a non-normal distribution and is presented as median and interquartile range (IQR). All categorical variables are presented as counts and percentages. Statistical analyses were performed with SAS 9.1 (SAS Institute Inc., Cary, NC).
Results Patient Demographics We examined the records of 76 immunocompetent patients who were admitted to our institute with a diagnosis of primary PC from January 1995 to August 2010 (Table 1). In
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all cases, the diagnosis was confirmed histologically by the presence of Cryptococcus in lung tissues. A total of 55 males (72%) and 21 females (28%) were included. The mean age of all patients was 42.5 ± 11.3 years (range = 20–69 years) (40.6 ± 10.6 for females and 43.3 ± 11.6 for males; insignificant difference). There were 15 patients (20%) who smoked and 11 patients (14%) who drank alcohol. Disease history, clinical characteristics, chest X-ray data, and method of diagnosis were recorded for all patients. All patients were given appropriate treatment and follow-up.
341 Table 2 Radiographic and physical signs and treatments for immunocompetent patients with primary pulmonary cryptococcosis (n = 76) Variablesa
All patients (N = 76)
Lesion area (right/left) Right lung
28 (36.84%)
Left lung Combination
23 (30.26%) 24 (31.58%)
No lesion
1 (1.32%)
Lesion area (upper/middle/lower)
Disease History
Upper lung Middle lung
3 (3.95%)
Among the 76 patients, 51 patients (67%) were previously healthy and 25 patients (33%) had a history of previous diseases (Table 1), including hypertension (3 pts), hepatitis (5 pts), gastritis (2 pts), diabetes mellitus (2 pts), hyperthyroidism (2 pts), coronary heart disease, arrhythmia, cholecystitis, kidney stones and gastric disease, and anaphylactic nephritis with allergic purpura (1 pt each), and underlying lung diseases (3 pts, one with pulmonary, nasopharyngeal, and lymphatic tuberculosis, hepatitis B and uterine myoma; one with chronic bronchitis; and one with bilateral interstitial pneumonia and polymyositis).
Lower lung
44 (57.89%)
Combination
16 (21.05%)
No lesion Patchy consolidation opacity
28 (36.84%)
Solitary pulmonary mass opacity
22 (28.95%)
Mass conjunction tendency
20 (26.32%)
Cavitation
15 (19.74%)
Patchy shadows ? nodular shadows
15 (19.74%)
Multinodular opacity Enlarged mediastinal lymph node
13 (17.11%) 11 (14.47%)
Pleural effusion
11 (14.47%)
Lobulated in shape
7 (9.21%)
Inconsistency of frontal and lateral
2 (2.63%)
Physical examination findings Rales
12 (15.79%)
Diminution of breath sound
12 (15.79%)
Dullness on percussion
6 (7.89%)
Treatment No Surgery Medicine Both In-hospital days (day)
1 (1.32%) 9 (11.84%) 40 (52.63%) 26 (34.21%) 27 (17.39)
Prognosis Cured Improved
Chest Radiography
Ongoing treatment
Chest radiography indicated that 28 patients (37%) had lesions in the right lung, 23 patients (30%) had lesions in the left lung, 24 patients (32%) had lesions in both lungs, and one patient had no lesions in the left or the right lung. Lesions were more frequent in the lower lung (44 pts, 57.9%) than in the upper lung (10 pts, 13.2%) and middle lung (3 pts, 4.0%). The radiographs were classified as patchy consolidation opacity (28 pts, 37%), solitary pulmonary mass opacity (22 pts, 29%), mass conjunction (20 pts, 26%), cavitation (15 pts, 20%), combined patchy and nodular shadows (15 pts, 20%), multinodular opacity (13 pts, 17%), enlarged mediastinal lymph node (11 pts,
3 (3.95%)
Chest X-ray results
Clinical Manifestations A total of 47 patients (62%) had coughs and 29 patients (38%) spat up phlegm (thick yellow-white phlegm in 8 pts, white foam phlegm in 9 pts, and blood-stained phlegm in 1 pt). Other symptoms included fever (16 pts, 21%), chest pain (15 pts, 20%), dyspnea (17 pts, 22%), emaciation (10 pts, 13%), and hemoptysis (4 pts, 5.3%). Eighteen patients (24%) had no symptoms but were admitted due to detection of radiographic shadows during chest X-rays at checkup. Physical examinations indicated the presence of rales (12 pts, 16%), diminution of breath sounds (12 pts, 16%), and dullness on percussion (6 pts, 7.9%) (Table 2).
10 (13.16%)
70 (92.11%) 1 (1.32%) 1 (1.32%)
Lost to follow-up
3 (3.95%)
Died by recurrence
1 (1.32%)
a
Categorical data are presented as counts (percentages); in-hospital days are presented as medians (IQRs)
14%), pleural effusion (11 pts, 14%), lobulated lesions (7 pts, 9.2%), and inconsistency of frontal and lateral X-ray images (2 pts, 2.6%) (Table 2). The diameter of the radiographic shadow was less than 2 cm in 6 cases, 2–7 cm in 13 cases, and greater than 7 cm in 3 cases. In addition,
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chest CT scans were performed. Figures 1 and 2 show chest CT scans of two representative patients. Detection of C. neoformans The presence of C. neoformans was detected by three different analyses: microbiological culture using sputum, histological analysis using lung biopsy specimen from
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patients, and serological analysis of C. neoformans antigens. C. neoformans was recovered from sputum cultures of four patients (6.1%). C. neoformans was identified in one patient by a sputum smear and India ink staining. Other cultures obtained at the time of PC diagnosis did not yield any additional pathogen. Figure 3 shows the histological results of one representative patient with H&E, PAS, and GMS staining. The presence of Cryptococcus was assessed in 24 patients using ELISA against a cryptococcal antigen in serum. Sixteen patients were positive, 2 were weakly positive, and 6 were negative. Treatment
Fig. 1 Subpleural nodular opacity revealed in lung by chest CT scan. A female patient (aged 52 years) was hospitalized due to enlarged cervical lymph nodes for 2 months and left chest pain for 1 month. A chest CT scan revealed the presence of subpleural nodular opacity in the upper area of left lung, with adjacent pleural adhesion indicated by the arrow
A total of 75 patients (99%) were given treatment for primary PC. The median (IQR) of the in-hospital stay was 27 days (range = 17–39) (Table 2). Treatments were categorized as surgery, medication, or both. Nine patients (12%) were treated with surgery alone, 26 patients (34%) were treated with surgery and postsurgical medication, and 40 patients (53%) were treated with medication alone. The medication regimens were fluconazole alone (51 pts); fluconazole and 5-fluorocytosine (12 pts); and fluconazole, 5-fluorocytosine, and amphotericin B (2 pts) for 3–18 months. The patient with purpura nephritis developed PC following long-term treatment with prednisone; this patient was treated with itraconazole, fluconazole, 5-fluorocytosine, and amphotericin B liposomes but had an unfavorable outcome. Finally, this patient was given voriconazole for 16 months and the lesions in both lungs reduced remarkably. Prognosis
Fig. 2 Subpleural patchy opacity revealed in lung by chest CT scan. A male patient (aged 61 years) was hospitalized due to cough, expectoration, fever for 3 months, dyspnea for 1 day, and left chest pain. A chest CT scan revealed the presence of subpleural patchy opacity or consolidation in the upper area of the left lung, with partially unclear borderline and multiple small cavities as indicated by the arrow; subpleural nodular opacity with surrounding small punctual opacity was observed in the upper area of the right lung as indicated by the arrow
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A total of 70 patients (92%) were completely cured after treatment. Two patients were not cured (one was still in follow-up and one showed some improvement), three patients were lost to follow-up, and one patient died of recurrence. None of the other patients experienced recurrence, but cord-like shadows or nodular calcified foci were still evident in some patients (n = 12) based on high-resolution CT. Of the two patients who died, one was treated with fluconazole for 3 months (IV infusion for the first 2 months). The lesion’s diameter shrunk *50%, the patient became asymptomatic, and he discontinued medication on his own. Two months later he developed a cough, headache, and impaired vision and increased radiographic shadows on the lung. Although he was treated with amphotericin B and 5-fluorocytosine, Cryptococcus infection metastasized intracerebrally and the patient became blind and eventually died. Another patient underwent surgical intervention in the absence of a pathological examination at another hospital before admission to our institute. However, the diagnosis of
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this patient was not confirmed due to the atypical morphology of the pathogens; this delayed antifungal treatment and this patient eventually developed cryptococcal meningitis from which he died. For the 35 patients who underwent surgery at our hospital, antifungal medications were applied and the patients were closely followed for complications. No serious complications occurred.
Discussion PC is an acute or subacute pulmonary fungal disease caused by C. neoformans. Our results indicate that clinical manifestations, imaging, and pathology can vary significantly among immunocompetent individuals with PC. Immunocompetent PC patients can have mild symptoms or be asymptomatic. In the present study, PC was diagnosed in 20 patients during routine physical examinations, indicating that PC may be present even in healthy subjects with no symptoms. A previous study of neonates indicated that symptoms of Cryptococcus infection can occur after birth from an asymptomatic mother, possibly indicating that placental infection can lead to a potentially serious condition [8]. There are two main human pathogenetic species of Cryptococcus—C. neoformans and C. gattii—and both are associated with Cryptococcus infection in immunocompetent people [9, 10]. C. neoformans occurs worldwide and is a common cause of infections in immunocompromised people, while C. gattii is localized to northern Australia, Papua New Guinea, and Vancouver Island and is associated with infecting immunocompetent populations [1, 9, 10]. The Vancouver Island strain is highly virulent, a characteristic that may be derived from having different molecular mechanisms for infection compared with other strains [9–11]. In this study, most patients presented with respiratory symptoms typical of PC, including cough, expectoration, fever, chest pain, dyspnea, and hemoptysis [6, 12–15]. One patient presented with pneumothorax. As in other studies, not all patients were symptomatic [12–14, 16]. Cryptococcus infection can be associated with other symptoms. For example, patients can have meningitis which can present with headache and fever [6, 17]. No patients in the current study presented with meningitis. In children, Cryptococcus infection can be associated with the abdominal lymph nodes, lung, and spleen [7]. Chang et al. [18] reported an immunocompetent patient with Cryptococcosis-induced pulmonary empyema accompanied by rib osteomyelitis. Compared to immunocompetent patients, the symptoms of Cryptococcosis infection in immunocompromised patients are more obvious, and concomitant adult respiratory distress syndrome (ARDS) is frequently observed, resulting in
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an extremely high mortality rate during hospitalization [12, 19]. Eriguchi et al. [20] reported that a patient undergoing hemodialysis died of abrupt dyspnea 6 days after admission; the dyspnea was due to disseminated cryptococcosis accompanied by secondary pulmonary capillary embolism. The manifestations of PC on chest CT can be diverse. In the present study, radiography indicated that most patients (37%) had multiple patchy consolidations and solitary pulmonary mass opacity (29%) and single and multiple nodules. The high frequency of these lesions is consistent with other studies [6, 12–14, 21]. Other findings included mass conjunction, cavitation, and combined patchy and nodular shadows, which have also been noted in other studies [6, 12–14, 21–24]. In most patients we found lesions mainly in subpleural areas and more frequently in the lower lung than in the upper lung. Enlargement of small mediastinal lymph nodes and pleural effusion or even chest involvement can occur, but this appears to be more likely in immunocompromised patients [22–24]. Other studies have also found nodular lesions in the bronchial mucosa [23, 25]. The diagnosis of PC is based on serological, etiological, and histological results. A test for cryptococcal capsular polysaccharide antigen in the blood and cerebral spinal fluid is an important tool for early diagnosis [12, 23]. In patients with cryptococcal meningitis, the positive rate of cryptococcal capsular polysaccharide antigen is as high as 92% in the cerebral spinal fluid and 75% in the serum, but the positive rate in the serum of infected patients without meningitis is about 20–50% [24]. For immunocompromised patients or those treated with immunosuppressants, granulomas are rare and interstitial infection and massive lung involvement are common [26]. Cryptococcus appears colorless and difficult to identify in H&E staining (Fig. 3a), but can be identified by PAS staining (Fig. 3b), MC staining, GMS staining (Fig. 3c), and Ashley Alcian Blue (AB) staining (Fig. 3d). Campbell et al. [27] studied 101 patients with PC. A total of 62 underwent thoracotomy for biopsy and an autopsy was performed on nine patients, but positive fungal cultures were noted in only 19 patients. Transbronchial lung biopsy is critical for the diagnosis of PC and can be performed in patients suspected of PC. Once PC is confirmed by transbronchial lung biopsy, thoracotomy for biopsy is avoided. Percutaneous lung biopsy can be performed in patients with lesions near the pleura. Once PC is confirmed, it is necessary to assess the immune status of the infected patient. For immunocompetent patients without symptoms, PC may resolve spontaneously [13], so immediate treatment is often not required. When the lesions enlarge and symptoms develop during the follow-up period, timely treatment is needed. For an immunocompetent patient with symptoms, if the
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Fig. 3 Representative histological staining of the biopsy of an immunocompetent patient with primary pulmonary cryptococcosis. a Granuloma forms and vesicular Cryptococcus spores were present in the cytoplasm of multinucleated giant cells (H&E staining, 9200).
b Cryptococcus spores in cytosol and interstitial spaces (PAS staining, 9400). c Cryptococcus spores in granuloma (GMS staining, 9400). d Alcian blue staining of Cryptococcus capsular polysaccharide (9400)
chest radiograph shows multiple nodular shadows or diffuse infiltration or if the patient is positive for serum cryptococcal antigen, then treatment with fluconazole (200–400 mg/day) is recommended for 3–6 months, with dose adjustment performed as needed [28, 29]. For an immunocompromised patient with severe symptoms, central nervous system involvement, or disseminated infection, treatment with amphotericin B (0.5–1 mg/kg/day) and 5-Fc (100 mg/kg/ day) is preferred; after intensive treatment for 2 weeks, fluconazole or itraconazole (400–800 mg/day) is recommended for 6–10 weeks for consolidation, and maintenance treatment is fluconazole (200–400 mg/day) for 6–12 months [28]. For HIV-infected patients, long-term treatment with low-dose fluconazole (200 mg/day) is recommended to prevent recurrence or dissemination [28]. For patients with refractory infection, voriconazole is an alternative [29]. Several previous studies have indicated that voriconazole is superior to other antifungal drugs in the treatment of C. neoformans, and they have confirmed the effectiveness of voriconazole in the treatment of PC and cerebral
cryptococcosis [30–33]. Based on our experience, we recommend individualized regimens for the treatment of cryptococcosis and a complete treatment course is necessary. In particular, the disappearance of initial symptoms and a decrease in lesion size should not be used as indications for the discontinuation of treatment; medication should be administered for about 1 year or until the lesion disappears completely, is fiberized, or is calcified. In the present study, one patient discontinued treatment prematurely due to improvement of symptoms and he ultimately died due to intracranial spread of PC. A previous study that employed Southern blotting of C. neoformans in patients with initial and recurrent PC showed that recurrence was due to the presence of residual fungus, not reinfection [34]. Surgical intervention should be considered when the lung lesions remain stable or enlarge following 3–6 months of standard antifungal treatment, when the symptoms and signs (hemoptysis, abscess, sinus, and empyema) are uncontrollable, or when the lesions are difficult to differentiate from tumors. Lai et al. [35] studied 36 PC patients
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whose lesions were surgically removed and reported that 7 patients developed postoperative cryptococcal meningitis and 2 of these patients died. Therefore, surgical procedures should be gentle and compression of lesions should be avoided. Postoperative antifungal treatment is necessary and should be sufficient to prevent systemic dissemination. Moreover, we suggest postsurgical follow-up once every 3 months for at least 6 months. Cryptococcus infection is frequently found in young and middle-aged males. This susceptible population has a hobby of using sauna baths, although infection due to a humid climate cannot be ruled out. PC patients have no history of lung disease and may present with no symptoms. In these patients, patchy consolidation is a common radiographic result. PC can be asymptomatic, so misdiagnosis or neglect is possible. We suggest that clinicians consider PC in susceptible patients and that transbronchial lung biopsy be performed in patients suspected of PC so that timely treatment can be implemented. Disclosure
The authors have no conflicts of interest to disclose.
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