Journal of Respiratory and Lung Diseases

A Study of 19 Pulmonary Cryptococcosis Cases

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Published Date: September 18, 2017

A Study of 19 Pulmonary Cryptococcosis Cases

Feng-Li Zhou*, Jia-Xin Zhu, Xiao-Ling Zou, Ding-Yun Feng, and Tian-Tuo Zhang

Department of Respiratory Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

*Corresponding author: Feng-Li Zhou, Department of Respiratory Medicine, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, China, Tel: +86-1392-2165-519; Fax: +86-20-8525-2874; E-mail: zhoufenglizfl@126.com

Citation: Feng-Li Zhou, Jia-Xin Zhu, Xiao-Ling Zou, Ding-Yun Feng, Tian-Tuo Zhang (2017) A Study of 19 Pulmonary Cryptococcosis Cases. J Resp Dis 1(1): 110.

 

Abstract

 

Background: Pulmonary cryptococcosis (PC) has recently become more frequent.

Methods: We collected and analyzed data from 19 cryptococcal pneumonia cases that had been treated in our hospital over the past 10 years and analyzed of the clinical features, underlying diseases, past medication and auxiliary examinations of the patients.

Results: The patients demonstrated various symptoms and underlying diseases, but most of the latter involved diseases associated with immune deficiency. More than half of the patients had no history of exposure to bird droppings or soil. Chest computed tomography scans of the 19 patients revealed single or multiple pulmonary nodular shadows in 11 subjects. Initial misdiagnosis was common. Because of the long course of treatment for PC and the high costs of fluconazole and itraconazole; as long as the renal functions in these patients are normal, the more cost-effective drug amphotericin B can be used as an alternative treatment for PC.

Conclusions: This study provides a summary of the characteristics of pulmonary cryptococcosis as a basis for future clinical diagnosis and treatment of pulmonary cryptococcosis.

Keywords: Acquired immune deficiency syndrome; Cryptococcus neoformans; Diagnosis; Disseminated cryptococcal infection; Imaging; Pathology; Pulmonary cryptococcosis

 

Introduction

 

Pulmonary cryptococcosis (PC) is a subacute or chronic visceral fungal disease caused by Cryptococcus neoformans infection [1]. In recent years, the incidence of cryptococcal infection has shown an apparent upward trend [2,3]. Because of the atypical clinical manifestations of pulmonary cryptococcosis, clinical diagnosis is difficult, we have collected 19 cryptococcal pneumonia cases that had been treated in our hospital over the past 10 years, and analyzed the corresponding data. We hope to help clinicians improve their understanding of pulmonary cryptococcosis.

 

Materials and Methods

 

Source of Subjects

From January 1, 2006, to December 31, 2015, 19 patients in total were diagnosed with cryptococcal pneumonia in our hospital, and pertinent information, including general information, medical history, laboratory data, and treatments were collected, analyzed, and summarized. The study was approved by the Ethics Committee of Clinical Medical Research at The Third Affiliated Hospital, Sun Yat-sen University (Approval No. [2016]2-114). The requirement for obtained informed consent was waived by the committee due to the retrospective nature of the study.

Diagnostic Criteria [5]

Pathogenic examination: Traditional microscopy and culture methods were used to identify C. neoformans from the patients’ phlegm, broncho-alveolar lavage fluid (BALF), or cerebrospinal fluid (CSF). The strains of Cryptococcus neoformans were identified using RapID Yeast Plus System [6].

Pathologic diagnosis: The pathological tissues of the patient were collected by different ways, such as by lung needle biopsy or fine-needle aspiration, or by bronchoscopic-protected brushing. C. neoformans can be found by different staining.

Cryptococcal antigen: The latex agglutination test was used to detect the capsular polysaccharide antigen of C. neoformans from patients’ serum, BALF, or excessive pleural fluid.

 

Results

 

General Information

Of the 19 patients, 11 were male and 8 were female. Patients’ age ranged from 26 to 81 years, with a median age of 51.5 years.

Patients’ Medical History

Symptoms: Seven were asymptomatic (36.8%), 8 subjects had a cough and expulsion of phlegm (42.1%), 9 had chest pain (47.4%), 3 had a fever (15.8%), and 3 had dyspnea and hypoxemia (15.8%). Ten subjects had fatigue and weight loss (52.6%), 4 subjects had hemoptysis (21.1%), 3 had a pleural effusion (15.8%), and 1 subject had concurrent cryptococcal meningitis (5.3%).

Underlying diseases: Five with no underlying diseases (26.3%),  3 subjects with AIDS (15.8%), 2 subjects with diabetes (10.5%), 4 subjects with tuberculosis (21.1%), 2 subjects who had undergone organ transplantation (10.5%), 1 subject with rheumatic autoimmune disease (5.3%), and 2 subjects with tumors (10.5%).

Exposure history: Two patients (10.5%) had a history of raising chickens, 4 patients (21.1%) had a history of soil exposure, and the remaining patients (68.4%) were not occupationally exposed to bird droppings and/or soil.

Previous medication history: Five subjects without underlying disease and 3 subjects with AIDS had no medication history; the 2 subjects who had undergone organ transplantation had a 0.5- to 3-year history of taking anti-rejection drugs; 1 subject with rheumatic autoimmune diseases had a history of long-term glucocorticoid intake; 2 cancer subjects had received more than 2 courses of chemotherapy.

Hematology

No patients underwent galactomannan testing, as it was not yet available in our hospital at the time of the study. We detected CD3 and CD4 in the blood of all patients (Table 1).

Imaging (CT)

19 patients revealed single or multiple pulmonary nodular shadows in 11 subjects (57.9%), of which 7 cases had cavity formation and 5 subjects had a “halo sign.” Lung patchy shadows were found in 5 subjects (26.3%), 2 subjects (10.5%) had diffuse miliary shadows, and 1 subject (5.3%) had acute interstitial pneumonia. Mild mediastinal lymph node enlargement was observed in 12 subjects. Localized foci were generally found in the lower lobes of the lung (Figure1–6, foci indicated by arrows).

Pathology

The diagnoses of the 19 patients were confirmed by pathological examinations. C. neoformans was found in 15 subjects using CT-guided percutaneous needle biopsy of the lung, in 3 subjects by using thoracoscopic lung biopsy, and in 1 subject using bronchoscopic lung biopsy. Granuloma formation (Figure 7) or jelly-like lesions (Figure 8) were observed under low magnification. C. neoformans with capsules could be observed inside macrophages at high magnification (indicated by the arrows in Figures 9–13) [7].

Etiology

Culture and smear: Among the 19 patients, C. neoformans was isolated from only 6 subjects. One subject had a positive CSF direct ink smear, while BALF culture and culture of the secretions collected using bronchoscopic-protected brushing were positive in the other 4 and 1 subjects, respectively. The smear and culture results of C. neoformans are shown in figures 14-19.

Identification of strains: C. neoformans were identified using RapID Yeast Plus System. (Figures 20, 21)

Diagnosis and Treatment

All 19 patients were diagnosed with C. neoformans infection. All patients had received some form of misdiagnosis. Four patients were misdiagnosed with tuberculosis, and diagnostic anti-tuberculosis treatment that had been administered for 2-4 weeks was ineffective. Five subjects were misdiagnosed with lung cancer and were subsequently diagnosed with C. neoformans infection based on CT-guided percutaneous needle biopsy of the lung. Three subjects with patchy shadows in their chest CT scans were misdiagnosed with pneumonia, and a 2-week antibiotic treatment was ineffective. Three subjects with underlying diseases (AIDS) were misdiagnosed with viral infection or Pneumocystis carinii infection, because the bilateral lung lesions involved diffuse pulmonary infiltrates, and a 2-week ganciclovir or caspofungin therapy was not effective.

After receiving the correct diagnosis, 16 patients with localized PC were administered fluconazole (0.4 g/day) intravenously for 2-4 weeks and were then given fluconazole (0.4 g/day) orally for 3-6 consecutive months. One patient who also had central nervous system infection received fluconazole (0.4 g/day) orally for 12 months. The 3 subjects with underlying diseases (AIDS) had disseminated cryptococcosis; for these patients, amphotericin B was administered for 6-8 weeks (starting from 5 mg/day, and gradually increasing to the maintenance dose of 0.6 mg/kg per day), co-administered with flucytosine (100 mg/kg per day) for the first 2 weeks. After 8 weeks, fluconazole 0.4 g/day was given orally for 6-12 consecutive months. The treatments for all subjects followed the Clinical Practice Guidelines for the Management of Cryptococcal Disease [8].

Outcome

All 16 non-AIDS patients completed the course of treatment, and the corresponding clinical symptoms disappeared. Chest CT lung scans were performed again and revealed that the pulmonary foci had been absorbed, and the patients were cured or in a stable condition for more than 3 months. Of the 3 subjects with underlying diseases (AIDS), 1 died after 4 weeks of treatment due to the deteriorating condition associated with AIDS. For another of these subjects, amphotericin B was switched to oral fluconazole due to the impaired renal function, and the subject had a worsening lung infection after 2 weeks and died of respiratory failure. The remaining subject with AIDS was treated for 12 months; the pulmonary foci were absorbed, and the subject was cured of the cryptococcal infection and is still alive.

 

Discussion

 

C. neoformans can invade various organs. The lungs are the main entrance for C. neoformans invasion [9]. Generally, PC patients are asymptomatic or show mild symptoms; the main manifestations are cough, an expulsion of phlegm, and dull chest pain, and there is usually a large amount of bacteria in the phlegm [10,11]. The 19 patients presented in the present study had similar clinical symptoms as those described in the literature.

The imaging findings of PC are non-specific [12]. Among the 19 patients presented in this paper, those with solitary or multiple mass shadows or nodular shadows, lung patchy shadows, diffuse miliary shadows, and acute interstitial pneumonia in their chest CT scans were present in 57.9%, 26.3%, 10.5%, and 5.3%, respectively. Localized foci were generally found in the lower lobes of the lung, which was consistent with the report by Ye et al. [13]. The non-specificity in the imaging finding of PC is one of the leading causes for the clinical misdiagnosis of PC.

The pathological type of C. neoformans is Jelly-like lesions or noncaseating granulomatous lesions and C. neoformans with capsules can be observed inside macrophages under high magnification [5]. C. neoformans was found in the lung biopsy specimens obtained from the 19 patients of this paper, and currently, pathological diagnosis is the main approach for the diagnosis of PC.

Among the 19 patients in this paper, C. neoformans was cultured from the CSF, BALF, or the secretions collected using bronchoscopic-protected brushing in 31.6% of patients, only 1 patient showed the positive result in the CSF cryptococcal capsular polysaccharide antigen test, and C. neoformans could not be isolated from 63.2% of patients. This result is related to minimal or absent phlegm in most patients and the localized nature of the foci.

Because of diversified imaging findings of PC, clinical misdiagnosis is common [14]. Most of the 19 PC cases collected in this paper were first misdiagnosed, and the average time from the onset to diagnosis was 21 days. Based on our experience, we suggest that for patients with a lung mass or nodular lesions, the possibility of PC should be considered, and corresponding diagnostic tests should be conducted. For patients with pulmonary inflammation or with disseminated disease, the possibility of C. neoformans infection should be considered when antimicrobial therapy is not efficacious, particularly in patients with immunodeficiency or those receiving immunosuppressive therapy. Early percutaneous lung biopsy, transbronchial lung biopsy, or even surgical thoracoscopic lung biopsy is the key to accurate diagnosis of PC.

C. neoformans infects both AIDS patients [15,16] and non-AIDS patients [17,18], and infects both adults and children [19]. Among the 19 PC cases collected in this study, there were 3 AIDS patients?15.7%), non-AIDS patients accounted for 84.3%. Among them, 1 patient with rheumatic autoimmune diseases and 2 patients who underwent organ transplantation and had received continuous glucocorticoid or immunosuppressive therapy, which causes impaired cellular immune function, which in turn is the root cause for C. neoformans infection. Three patients with malignant tumors received earlier induction chemotherapy, and their humoral and cellular immune functions were suppressed, which is also related to C. neoformans infection. The primary diseases in the 2 diabetic patients and 4 tuberculosis patients were not well controlled and they had a long-term medication history, and the changes in their own immune function are one of the causes for C. neoformans infection. The reason for the C. neoformans infection in the other 5 PC patients without underlying diseases was not clear, but the CD4+ and CD8+ T lymphocyte counts were low. This indicated that, despite the absence of underlying disease in these patients, their cellular immune functions decreased, which is probably the main reason for their susceptibility.

In this study, 15 non-AIDS patients with localized PC were treated with fluconazole and cured, but treatment needs 5-10 weeks. For the 3 subjects with underlying AIDS, the pulmonary manifestation involved disseminated cryptococcosis; amphotericin B treatment was administered for 6-8 weeks, fluconazole was given orally for 6-12 consecutive months. The mortality rate was only 10.5%, and the cure rate was 89.5%. All patients were followed up for 2 years, without recurrence. Our treatment can be replicated.

As long as the renal functions in these patients are normal, the more cost-effective drug amphotericin B can be used as an alternative treatment for PC.

 

Acknowledgment

 

This study was funded as a social development project of the Science and Technology Department of Guangdong province (Grant No. 2014A020212531).

 

Conflict of Interest

 

Authors declare no conflict of interest.

 

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Copyright: © 2017 Feng-Li Zhou, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.