Retrospective Analysis of 76 Immunocompetent Patientswith Primary Pulmonary Cryptococcosis

Lung (2012) 190:339–346

Guangzhou Institute of Respiratory Diseases, First AffiliatedHospital of Guangzhou Medical University, State KeyLaboratory of Respiratory Disease, Guangzhou Medical University

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.

Abstract

Methods

We retrospectively reviewed the clinical data of 76 patients with primary pulmonary cryptococcosis who were admitted to our hospital from 1995 to 2010.

Abstract

Results Pulmonary cryptococcosis was pathologicall

y 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,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.

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 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.

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.

Methods ： 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℃ 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).

TBLB transbronchial lung biopsy, VATS video-assisted thoracoscopic surgery

Diagnosis by

TBLB 33 (43.42%)

VATS 25 (32.89%)

Open lung biopsy 15 (19.74%)

Percutaneous translung biopsy 5 (6.58%)

For pathologic diagnosis, all specimens were managed with periodic acid Schiff (PAS) stain, Gomori methenamine silver (GMS) stain, and Mucin stain and examined by an experienced pathologist.

Methods ： 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 all cases, the diagnosis was confirmed histologically by the presence of cryptococcus in lung tissues.

Table 1 ： Demographic and clinical characteristics of immunocompetent patients with primary pulmonary cryptococcosis (n = 76)

Variablesa All patients (N = 76)DemographicsAge (years) 42.54 ± 11.33GenderFemale 21 (27.63%)Male 55 (72.37%)Smoking 15 (19.74%)Drinking 11 (14.47%)Disease history 25 (32.89%)

SymptomsNo 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%)

Results ： Clinical Manifestations

Results ： Disease History

Among the 76 patients, 51 patients (67%) were previously healthy and 25 patients (33%) had a history of previous diseases.

hypertension (3 pts), hepatitis (5 pts), gastritis (2 pts), diabetes mellitus (2 pts), hyperthyroidism (2 pts), coronary heart disease, arrhythmia,cholecystitis, kidne

y stones and gastric disease, and anaphylactic nephritis with allergic purpura (1 pt each),

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).

25 patients (33%) had a history of previous diseases

Results ： Chest Radiography

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 13 (17.11%)Enlarged mediastinal lymph node 11 (14.47%)Pleural effusion 11 (14.47%)Lobulated in shape 7 (9.21%)Inconsistency of frontal and lateral 2 (2.63%)

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 23 (30.26%)

Combination 24 (31.58%)

No lesion 1 (1.32%)

Lesion area (upper/middle/lower)Upper lung 10 (13.16%)Middle lung 3 (3.95%)Lower lung 44 (57.89%)Combination 16 (21.05%)No lesion 3 (3.95%)Physical examination findingsRales 12 (15.79%)Diminution of breath sound 12 (15.79%)Dullness on percussion 6 (7.89%)

F 52y was hospitalized due to enlargedcervical lymph nodes for 2 months and left chest pain for 1 month. subpleural nodular opacity in upper area of left lung, with adjacent pleural adhesion indicated by the arrow

Fig. 1

M 61Y was hospitalized due to cough,expectoration, fever for 3 months, dyspnea for 1 day, and left chest pain. 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

Fig. 2

Results ： 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 patients, and serological analysis of C. neoformans antigens.

TreatmentNo 1 (1.32%)Surgery 9 (11.84%)Medicine 40 (52.63%)Both 26 (34.21%)In-hospital days (day) 27 (17.39)PrognosisCured 70(92.11%)Improved 1(1.32%)Ongoing treatment 1 (1.32%)Lost to follow-up 3 (3.95%)Died by recurrence 1 (1.32%)

Results ： Treatment 、 Prognosis

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.

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.

In this study, most patients presented with respiratory symptoms typical of PC, including cough, expectoration, fever, chest pain, dyspnea, and hemoptysis . One patient presented with pneumothorax.

As in other studies, not all patients were symptomatic . Cryptococcus infection can be associated with other symptoms. For example, patients can have meningitis which can present with headache and fever.

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. [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 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).

A Granuloma forms and vesicular Cryptococcus spores were present in the cytoplasm of multinucleated giant cells (H&E staining, X200).

B Cryptococcus spores in cytosol and interstitial spaces (PAS staining, X400)

C Cryptococcus spores in granuloma (GMS staining,X400).

D Alcian blue staining of Cryptococcus capsular polysaccharide (X400)

1. 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.

Once PC is confirmed, it is necessary to assess the immune status of the infected patient

2. For an immunocompetent patient with symptoms, if the 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].

3.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]

4.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 cou

rse 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 foll

owing 3–6 months of standard antifungal treatment,

when the symptoms and signs are uncontrollable, when the lesions are difficult to differentiate from tu

mors. Lai et al. [35] studied 36 PC patients whose lesions were su

rgically 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.

Thanks!