Mycopathologia DOI 10.1007/s11046-016-9999-1
Pulmonary Fungal Diseases in Immunocompetent Hosts: A Single-Center Retrospective Analysis of 35 Subjects XiaoPei Yan . Feng Zong . Hui Kong . YanLi Wang . XinYun Zhao . WenRui Liu . ZaiLiang Wang . WeiPing Xie
Received: 1 March 2015 / Accepted: 8 March 2016 Ó Springer Science+Business Media Dordrecht 2016
Abstract Background Pulmonary fungal disease is an emerging issue in immunocompetent patients, for whom the characteristics are only partially understood. Methods We conducted a single-center retrospective study of histologically verified pulmonary fungal disease in Eastern China from 2006 to 2014 to understand the demographics, clinical manifestations, therapeutic approaches, and factors associated with prognosis in this population. All cases were diagnosed according to the 2008 European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infection Diseases Mycoses Study Group definition criteria.
XiaoPei Yan and Feng Zong have contributed equally to this article. X. Yan Department of Respirology, First People’s Hospital of Changzhou, Changzhou 213000, China F. Zong Department of Geriatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China H. Kong Y. Wang X. Zhao W. Liu Z. Wang W. Xie (&) Department of Respirology, First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Road, Nanjing 210029, China e-mail:
[email protected]
Results A total of 112 cases of pulmonary fungal diseases were enrolled (35 proven, 16 probable, 61 possible), and we analyzed the 35 patients with histologically proven pulmonary fungal diseases in this study. The main fungal species identified were Aspergillus (51.4 %), Cryptococcus (22.9 %), and Mucor (2.4 %). Treatment consisted of antifungal therapeutic agents (54.3 %), surgery and postsurgical agents (25.7 %), or surgery alone (14.3 %). The overall crude mortality rate was 14.3 %, and the mortality due to pulmonary fungal infections was 2.9 %. Significant predictors of mortality by univariate analysis were hypoalbuminemia (P = 0.005), cancer (P = 0.008), and positive culture (P = 0.044). Additionally, hypoalbuminemia was the only risk factor for mortality by multivariate analysis (RR = 7.56, 95 % CI 1.38–41.46). Conclusion Pulmonary fungal disease in immunocompetent patients, with Aspergillus as the most common identified species, had a prognosis that was influenced by the level of serum albumin. Keywords Pulmonary fungal disease Immunocompetent Mortality
Introduction Pulmonary fungal disease is an opportunistic infection that mainly invades immunocompromised patients, especially those undergoing hematopoietic stem cell
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transplantation (HSCT), solid-organ transplantation (SOT), and those presenting with HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome). Therefore, most of the large-scale studies [1–5] often focused on these specific populations. However, with the widespread use of broad-spectrum antibiotics, glucocorticoids, and chemotherapeutics, pulmonary fungal disease is no longer a rare event in immunocompetent patients [6], which have drawn increased attention since the 1990s. Cases have been reported in the USA, Spain, Germany, France, India, Korea, and Taiwan [7–14]. Unlike immunocompromised patients, pulmonary fungal disease in immunocompetent patients can be easily misdiagnosed due to the absence of the specific clinical and imaging manifestation, as well as a lack of recognition. For this reason, some patients may receive unnecessary antibiotic therapy or pulmonary lobectomy. Therefore, it is important to expound the epidemiology, clinical characteristics, and predisposing factors for pulmonary fungal disease in immunocompetent patients. Pulmonary fungal disease in immunocompetent hosts is not rare in China [15, 16]. However, few studies have compared the characteristics between different species in immunocompetent patients [17]. Since autopsy is not widely available, the epidemiology of proven pulmonary fungal disease in immunocompetent patients is deficient. Therefore, we conducted a retrospective study of immunocompetent patients with histologically verified invasive pulmonary fungal disease over a period of 9 years (2006–2014) at a university teaching hospital with the aim of investigating the epidemiology, clinical and radiological characteristics, and treatment of pulmonary fungal disease.
Methods Data Collection Cases were collected on a standardized form through the hospital’s computerized medical records database, including demographic, clinical, radiographic, cultural, and serological records, in addition to diagnostic data, information on antifungal therapy, immunosuppressive medications, and clinical outcome. The Ethical Review Committee of the First Affiliated Hospital of Nanjing Medical University approved the study.
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Patients We retrospectively reviewed all cases of pulmonary fungal diseases diagnosed in the First Affiliated Hospital of Nanjing Medical University from January 1, 2006, to December 31, 2014, and analyzed 35 patients with histologically proven pulmonary diseases. Informed consent was obtained from all individual participants included in this study. Inclusion Criteria Patients from the Department of Medicine and Surgery were included if they had proven invasive pulmonary fungal infection. This diagnosis was based on the Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infection Diseases Mycoses Study Group (EORTC/MSG) [18]. Exclusion Criteria Patients defined as immunocompromised according to the following immune function evaluation criteria were excluded from this study. Immune Function Evaluation Patients with at least one of the following factors were considered immunocompromised: (1) a history of immunosuppressive drugs (including corticosteroids), (2) sever diabetes mellitus with associated organ damage, (3) HIV infection, (4) organ transplantation or hematopoietic stem cell transplantation, (5) malignant cancer being on chemotherapy or radiotherapy, and (6) peripheral absolute lymphocyte count of \1000 cell lL-1 or absolute neutrophil count of \2000 cell lL-1. Otherwise, the patients without any of these factors were defined as immunocompetent. Outcome Assessments Every participant was observed for 2 years by telephone and physical clinical follow-up. The outcome was evaluated based on the criteria originally proposed by Walsh [19], which divided the clinical
Mycopathologia
outcomes into three levels: complete response, partial response, and a lack of response.
gas (14.3 %), and diabetes mellitus (5.7 %). Thirteen patients (37.1 %) were without any significant predisposing conditions.
Statistical Analysis Clinical Manifestations Qualitative variables were compared using the Chisquare test or Fisher’s exact test when appropriate. Quantitative variables were tested using one-way ANOVA when normality and homogeneity were satisfied; otherwise, the Kruskal–Wallis K sample test was applied. Relationships between characteristics and survival were examined by Kaplan–Meier analysis. The Cox proportional hazards model was used to assess the effects of potentially confounding variables on risk of any-cause mortality. Statistical analysis was executed with SPSS version 13.0 statistical analysis software (SPSS Inc, Chicago, IL, USA). All tests used were two-tailed, and statistical significance was defined as a P value \0.05.
In this group, 30 (85.7 %) patients had a variety of symptoms, as presented in Table 1. The average time from first symptoms to diagnosis for aspergillosis, cryptococcosis, and mucormycosis was 123 (4–500) days, 37 (7–150) days, and 22 (13–30) days, respectively. The chief clinical symptoms were cough (n = 27, 77.1 %), hemoptysis (n = 17, 48.6 %), moist crackles (n = 7, 20.0 %), and fever (n = 5, 14.3 %). Hemoptysis was more common in pulmonary aspergillosis (P = 0.017, 1 - b = 0.7399). In addition, 5 patients (14.3 %) had no symptoms and were admitted due to detection of radiographic shadows during chest X-rays at checkup, and this situation was more inclined to present in pulmonary cryptococcosis (P = 0.033, 1 - b = 0.7399).
Results Radiological Findings Patient Characteristics A total of 112 patients met the EORTC/MSG criteria of pulmonary fungal disease and were enrolled into the study (35 proven, 16 probable, 61 possible). We then analyzed the 35 patients with histological proven pulmonary fungal disease. For the 35 proven patients, the fungal species had Aspergillus (18, or 51.4 %), Cryptococcus (8, or 22.9 %), Mucor (2, or 5.7 %), and Coccidioidomycosis (1, or 2.9 %), and 1 patient (2.9 %) had coinfection (Aspergillus and Mucor). The remaining 5 cases had fungal hyphae by histological specimen examination, but the strains were not identified through either histology or culture. The baseline data are given in Table 1. The mean age of the patients was 48.8 ± 15.0 years (range 17–73 years), with men representing the majority (60.0 %), who were more vulnerable to pulmonary cryptococcosis (P = 0.004, 1 - b = 0.739). Among the 35 patients, 22 patients (62.9 %) had significant predisposing factors, including broad-spectrum antibiotic therapy C7 days before admission (22.9 %), hypoalbuminemia (22.9 %), tuberculosis (22.9 %), cancer (14.3 %), and other pulmonary diseases, such as bronchiectasis, chronic bronchitis, chest trauma and aspiration of traumatic
Chest computed tomography (CT) was performed in 31 (88.6 %) patients before and after diagnosis of pulmonary fungal infections, which gave us the required evidence to evaluate the radiological characteristics of pulmonary fungal infection and the efficacy of antifungal treatment. Some representative CT images and corresponding pathological images are performed (Fig. 1). The radiological presentations were non-specific in the groups of different species. Among the 31 patients with CT images, the most frequently observed CT abnormality was infiltrates (n = 19, or 61.3 %), followed by nodules (n = 9, or 29.0 %) and crumb lesions (n = 5, or 16.1 %). Lesions were predominantly involved only in the single lobe (51.6 %). The air crescent sign and cavity were rare in immunocompetent patients (9.7 and 12.9 %). Laboratory Findings All cases were histologically proven by the presence of fungal organisms in lung biopsy specimens. The lung biopsy specimens were obtained by thoracoscopic surgery and thoracotomy (20/35, or 57.1 %), CT-guided percutaneous pneumocentesis (8/35, or
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Mycopathologia Table 1 Clinical characteristics of pulmonary fungal disease in immunocompetent patients Characteristics
Aspergillosis
Cryptococcosis
Mucormycosis
Other
Total
P
No. of patients (% of total)
18 (51.4)
8 (22.9)
2 (5.7)
7 (20.0)
35 (100.0)
–
11 (61.1) 7 (38.9)
8 (100.0) 0 (0.0)
0 (0.0) 2 (100.0)
2 (28.6) 5 (71.4)
21 (60.0) 14 (40.0)
0.004*
47.8 ± 16.5
47.3 ± 10.8
58.0 ± 8.0
50.6 ± 14.3
48.8 ± 15.3
0.819
Yes
4 (22.2)
5 (62.5)
0 (0.0)
2 (28.6)
11 (31.4)
0.218
No
14 (77.8)
3 (37.5)
2 (100.0)
5 (71.4)
24 (68.6)
Broad-spectrum antibiotics C7 days
3 (16.7)
3 (37.5)
1 (50.0)
1 (14.3)
8 (22.9)
Hypoalbuminemia
6 (33.3)
0 (0.0)
1 (50.0)
1 (14.3)
8 (22.9)
0.170
Tuberculosis
5 (27.8)
1 (12.5)
0 (0.0)
2 (28.6)
8 (22.9)
0.852
Cancer
4 (22.2)
0 (0.0)
0 (0.0)
1 (14.3)
5 (14.3)
0.542
Other pulmonary diseases
3 (16.7)
1 (12.5)
1 (50.0)
0 (0.0)
5 (14.3)
0.370
Diabetes mellitus
1 (5.6)
0 (0.0)
0 (0.0)
1 (14.3)
2 (5.7)
0.501
Without predisposing factor
7 (38.9)
3 (37.5)
1 (50.0)
2 (28.6)
13 (37.1)
1.000
Fever
1 (5.6)
2 (25.0)
1 (50.0)
1 (14.3)
5 (14.3)
0.183
Cough Hemoptysis
15 (83.3) 12 (66.7)
5 (62.5) 1 (12.5)
2 (100.0) 2 (100.0)
5 (71.4) 2 (28.6)
27 (77.1) 17 (48.6)
0.601 0.017**
Dyspnea
2 (11.1)
0 (0.0)
0 (0.0)
0 (0.0)
2 (5.7)
1.000
Chest pain
0 (0.0)
0 (0.0)
0 (0.0)
1 (14.3)
1 (2.9)
0.257
Moist crackles
4 (22.2)
2 (25.0)
0 (0.0)
1 (14.3)
7 (20.0)
1.000
0 (0.0)
3 (37.5)
0 (0.0)
2 (28.6)
5 (14.3)
0.033***
Nodules
3 (17.6)
3 (42.9)
0 (0.0)
2 (40.0)
9 (29.0)
0.210
Mass
4 (23.5)
0 (0.0)
1 (50.0)
0 (0.0)
5 (16.1)
0.206
Consolidation
2 (11.8)
0 (0.0)
0 (0.0)
0 (0.0)
2 (6.5)
0.881
Infiltrates
10 (58.8)
4 (57.1)
1 (50.0)
4 (80.0)
19 (61.3)
0.881 0.744
Sex Male Female Age Smoking
Predisposing factors 0.409
Clinical symptoms
Without symptoms a
Radiological findings Lesion appearance
The number of involving lobe Single lobe
10 (58.8)
3 (42.9)
1 (50.0)
2 (40.0)
16 (51.6)
Multilobe in one lung
3 (17.6)
0 (0.0)
0 (0.0)
1 (20.0)
4 (12.9)
4 (23.5)
4 (57.1)
1 (50.0)
2 (40.0)
11 (35.5)
Cavity
3 (17.6)
0 (0.0)
0 (0.0)
1 (20.0)
4 (12.9)
Air crescent sign
2 (11.8)
0 (0.0)
1 (50.0)
0 (0.0)
3 (9.7)
0.274
Air bronchogram
4 (23.5)
4 (57.1)
0 (0.0)
1 (20.0)
9 (29.0)
0.319
Both lungs Lesion characteristics
0.697
Data are represented as number (%) of patients with characteristics * There was a statistically significant difference with gender between subgroups (P = 0.004). ** There was a statistically significant difference with incidence of hemoptysis between subgroups (P = 0.017). *** There was a statistically significant difference with asymptomatic infection between subgroups (P = 0.017) a
Due to a lack of CT graphs, 4 cases (1 pulmonary aspergillosis patient, 1 pulmonary cryptococcosis patient, and 2 other pulmonary fungal infection patients) were not involved
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Fig. 1 Pathological images and corresponding CT images of four immunocompetent patients. The four groups of pictures represent the pathological images and corresponding CT images of immunocompetent patients with aspergillosis (a), cryptococcosis (b), mucor (c), and coccidiodesimmitis (d), and the hyphae in pathological images were indicated by arrows. A 61-year-old man was hospitalized due to a history of hemoptysis for 1 year. A chest CT scan revealed the presence of class round lump in the under area of the left lung. The pathological staining exhibited a mass of Aspergillus hyphae with identical growth direction and acute angled branches, as indicated by the blue arrow (H and E staining, 920 magnification). b A 68-year-old man was hospitalized due to abnormal radiographic shadows during chest X-rays seen during a routine checkup appointment. A chest CT scan revealed the presence of subpleural nodular opacity in the under area of left lung. The pathological staining
exhibited cryptococcal spores in the cytosol and interstitial spaces, as indicated by the black arrow (PAS staining, 920 magnification). c A 66-year-old woman was hospitalized due to a history of cough and fever over a period of 13 days. A chest CT scan revealed the presence of mixed nodular and pneumonic foci in the bilateral lungs. The pathological staining exhibited mycal hyphae with a thick thallus and right angled branches, as indicated by the red arrows (PAS staining, 920 magnification). d A 73-year-old man was hospitalized due to abnormal radiographic shadows during chest X-rays at a routine checkup. A chest CT scan revealed the presence of subpleural nodular opacity in the middle area of left lung. The pathological staining exhibited coccidiodesimmitis spores in necrotic and normal pulmonary alveoli, as indicated by the yellow arrow (H and E staining, 920 magnification). (Color figure online)
22.9 %), and TBLB (transbronchial lung biopsy) (8/ 35, or 22.9 %). Of the 35 patients, 7 (20 %) had a positive fungal culture, all of which were Aspergillus. Clinical specimens, including sputum, BALF, transbronchial biopsies, and serum samples were collected for culture and serum antigen detection. Table 2 shows the sensitivity of various microbiological methods. The G test (1,3-b-D-glucan antigen) had the highest sensitivity of 83.3 % in noninvasive methods, while transbronchial biopsy culture showed a sensitivity of 66.7 % in invasive inspection.
patients (54.3 %) were treated with medication alone, and 5 patients (14.3 %) were treated with surgery only. At the end of the follow-up, 19 patients were cured, 9 patients showed improvement, 5 patients died, and 2 patients withdrew from the study. The overall crude mortality rate was 14.3 %, and the mortality attributable to pulmonary fungal infection was 2.9 %. For all participants involved in the study, factors that were significantly associated with mortality by Kaplan–Meier analysis were hypoalbuminemia (P = 0.005, 1 - b = 0.9929), cancer (P = 0.008, 1 - b = 0.9996), and positive culture (P = 0.044, 1 - b = 0.9093). In multivariate Cox models with forward likelihood ratio selection (entry level, P = 0.05), the independent risk factor for prognosis was hypoalbuminemia (RR = 7.56, 95 % CI 1.38–41.46). Figure 2 illustrates the survival curves for patients with or without hypoalbuminemia. For pulmonary aspergillosis, factors that were significantly associated with mortality by Kaplan–
Treatment and Prognostic Factors All patients were followed up for 2 years since diagnosed, except for five deceased patients and two patients who were lost to follow-up. The outcome was evaluated based on the criteria Walsh put forward according to the species of pulmonary fungal infection (Table 3). Among the 35 patients, 9 patients (25.7 %) were treated with surgery and postsurgical medication, 19
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Mycopathologia Table 2 Sensitivity of invasive and noninvasive diagnostic methods of pulmonary fungal disease in immunocompetent patients Diagnostic methods
Aspergillosis (n = 18)
Cryptococcosis (n = 8)
Mucormycosis (n = 2)
Total (n = 35)
Sputum culture
33.3 % (5/15)
0 (0/4)
0 (0/1)
22.7 % (5/22)
G test*
80.0 % (8/10)
–
–
83.3 % (10/12)
GM test**
44.4 % (4/9)
–
–
40.0 % (4/10)
BALF culture
33.3 % (2/6)
0 (0/1)
0 (0/1)
25.0 % (2/8)
Transbronchial biopsy culture
66.7 % (2/3)
0 (0/0)
0 (0/0)
66.7 % (2/3)
Noninvasive methods
Invasive methods
Data show the sensitivity (positive/all cases underwent the procedure) * The G test was unavailable for Cryptococcus and Mucor. ** The GM test is not available for species other than Aspergillus
Table 3 Outcome of pulmonary fungal disease, as it relates to therapy, and fungal species identified Outcome
Total
Azoles*
AmB**
Azoles ? AmB
Surgery
Surgery ? medicine
Aspergillosis (n = 18) CR
9 (50.0)***
2 (22.2)****
0
0
1 (11.1)
6 (66.7)
PR
3 (16.7)
2 (66.7)
0
0
0
1 (33.3)
NC/PD
5 (27.8)
4 (80.0)
0
1 (20.0)
0
0
Not available
1 (5.6)
–
–
–
–
–
Cryptococcosis (n = 8) CR
6 (75.0)
3 (50.0)
0
1 (16.7)
1 (16.7)
1 (16.7)
PR
1 (5.6)
1 (100.0)
0
0
0
0
NC/PD
0
0
0
0
0
0
1 (5.6)
–
–
–
–
–
CR
1 (50.0)
0
1 (100.0)
0
0
0
PR
1 (50.0)
0
0
0
1 (100.0)
0
NC/PD
0
0
0
0
0
0
Not available
0
0
0
0
0
0
CR
3 (42.9)
1 (33.3)
0
0
1 (33.3)
1 (33.3)
PR
4 (51.1)
0
0
3 (75.0)
1 (25.0)
0
NC/PD
0
0
0
0
0
0
Not available
0
0
0
0
0
0
Not avaliable Mucormycosis (n = 2)
Other (n = 7)
CR complete response, PR partial response, NC/PD no change or progressive disease * The azole-based therapy in this study included fluconazole, voriconazole, and itraconazole. ** AmB treatment included amphotericin B and liposomal amphotericin B. *** Data show the number (%) of each fungal species. **** Data show the number (%) of each efficiency degree
Meier analysis were hypoalbuminemia (P \ 0.001, 1 - b = 0.9906), cancer (P \ 0.001), and therapy combining with surgery or not (P = 0.016). Despite
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the variety of treatment options, the majority of pulmonary cryptococcosis patients had a good prognosis.
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Fig. 2 Kaplan–Meier plots of survival according to hypoalbuminemia. The survival time of patients without hypoalbuminemia was significantly improved as compared those with hypoalbuminemia (P = 0.005)
Discussion The present retrospective study was conducted over a period of 9 years and allowed the analysis of 35 proven pulmonary fungal diseases in immunocompetent patients, which mainly described the epidemiology, clinical characteristics, treatment, and prognostics factors for infection with different fungal species. The main fungal species identified were Aspergillus, Cryptococcus, and Mucor, whereas another study of pulmonary mycosis in China showed the top 3 fungal species were Aspergillus, Candida, and Cryptococcus [20]. It has been seen that pulmonary candidiasis was more common in Liu’s study, which may be ascribed to the difference in constitution of patients. Patients clinically proven and pathologically proven were included in Liu’s study, whereas only pathologically proven patients were analyzed in our study. It was believed the ‘‘real’’ pulmonary candidiasis (pathologically proven) was very rare based on autopsy studies, which was also expressed in clinical practice guidelines for the management of candidiasis by the Infectious Diseases Society of America in 2009 [21]. The study demonstrated that pulmonary fungal disease was not rare in immunocompetent hosts, especially those with predisposing factors, such as antibiotics, hypoalbuminemia, tuberculosis, and cancer. Predisposing factors such as chronic obstructive pulmonary disease (COPD), prolonged use of steroids, advanced liver disease, chronic renal replacement therapy, near-drowning, and diabetes mellitus have been described in pulmonary aspergillosis in non-
neutropenic patients [22]. Predisposing factors known for pulmonary cryptococcosis in immunocompetent patients are sex, brain involvement at presentation, smoking, oral corticosteroids, pulmonary condition, monoclonal antibodies, and cancer [23–26]. With regard to clinical symptoms, cough, hemoptysis, and fever were the most common clinical manifestations. Most symptoms were non-specific, except for hemoptysis that was associated with pulmonary aspergillosis and asymptomatic infection that was associated with pulmonary cryptococcosis. The radiological presentations varied. However, they were non-specific in the groups of different fungal species. For pulmonary aspergillosis patients, it was reported that consolidation-or-mass, halo signs, and angioinvasive form were observed less often in non-neutropenic transplant recipients than in neutropenic patients (56, 26, and 32 %) versus (78, 55, and 60 %, P = 0.01, P = 0.002, and P = 0.003, respectively) [27]. Computed tomography of immunocompetent patients with pulmonary cryptococcosis most commonly demonstrated multiple, small, welldefined, and smoothly marginated pulmonary nodules in the middle and upper lung [28]. Although tissue biopsy is the most accurate means of confirming the diagnosis of a definitive pulmonary fungal disease, there are other diagnostic tests, such as fungal culture, G test, GM test, and sCRAG test. In the present study, the sensitivity of sputum culture, BALF culture, and transbronchial biopsy culture were 33.3, 33.3, and 66.7 %, respectively. Moreover, the G test and GM test showed improved sensitivity for the diagnosis of pulmonary aspergillosis (80 and 44.4 %). Although culturing of the organism is considered the gold standard of etiological diagnosis, it has poor sensitivity and requires a large quantity of specimen and laboratory infrastructure. For serum antigen detection of pulmonary fungal infection, the G test and GM test are important noninvasive diagnostic methods, with a good sensitivity and specificity for candidiasis and aspergillosis [29]. Up to the end of the follow-up period, the overall mortality rate was 14.3 %. For all populations of the study, hypoalbuminemia, cancer, and positive culture were risk factors for mortality, whereas hypoalbuminemia was the only independent risk factor for mortality. Factors significantly associated with mortality in pulmonary aspergillosis were hypoalbuminemia, cancer, and therapy combining with surgery or
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not, compared with reported risk factors as corticosteroid therapy, organ failure, lung cancer, liver cirrhosis, disseminated infection, mechanical ventilation and coinfection with bacterial pneumonia and cytomegalovirus [16, 30–34]. Despite a variety of treatment therapy, all cases with pulmonary cryptococcosis showed favorable outcomes (cure or improvement). Reported prognostic factors correlated with mortality in pulmonary cryptococcosis were age C60 years, organ failure, and oral corticosteroids [35, 36]. Hypoalbuminemia is a predictor of mortality in patients with various illnesses [37–41]. Our study was the first to suggest the association between hypoalbuminemia and the mortality of IPFD. Albumin has essential physiologic effects necessary for health such as vasodilatation, inhibition of endothelial cell apoptosis, antioxidant effects, reduced platelet aggregation, and marker of inflammation in acute phase response [42– 44]. Hypoalbuminemia may acts via effects on antibiotics [45], malnutrition after surgery, or the underlying cause of hypoalbuminemia reduces survival. In summary, despite antifungal treatment and other combination regimens, the morbidity of pulmonary fungal disease in immunocompetent patients has greatly increased, with Aspergillus and Cryptococcus as the most common pathogens. The characteristic clinical features of pulmonary fungal disease were frequently lacking in immunocompetent patients, especially in pulmonary cryptococcosis. Transbronchial biopsy culture was important to determine the etiological diagnosis, which had a higher sensitivity than fungal culture. Whether patients were given surgery or drug therapy, the clinical outcome of pulmonary fungal disease in immunocompetent patients did not show significant differences. Hypoalbuminemia was an independent risk factor for poor prognosis.
Limitations The work was a single-center retrospective study with small sample size, which may reduce the comparability and credibility of the conclusions. Therefore, we will expand the sample size in further study. We are also looking forward to see more credible data about invasive pulmonary fungal disease in immunocompetent patients form multicenter prospective clinical studies.
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Acknowledgments The work was supported by Grants from the National Science Foundation of China (Grant Number 81273571) and Jiangsu Clinical Research Center for Respiratory diseases (BL2012012). Compliance with Ethical Standards Conflict of interest The authors declare that they have no conflict of interest.
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