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 ~ Introduction
 ~  Materials and Me...
 ~ Results
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  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 4  |  Page : 557-563
 

Evaluation of biomarkers: Galactomannan and 1,3-beta-D-glucan assay for the diagnosis of invasive fungal infections in immunocompromised patients from a tertiary care centre


1 Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication18-Mar-2019

Correspondence Address:
Dr. Shivaprakash M Rudramurthy
Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_18_366

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 ~ Abstract 

Purpose: Due to limitations of traditional microbiological techniques, standardised fungal biomarker tests such as Galactomannan Index (GMI) and 1,3-beta-D-glucan (BDG) are being preferred for diagnosis of invasive fungal infections (IFIs). These tests have been extensively used in developed countries but seldom in developing countries. The present study was performed to evaluate these tests for the diagnosis of IFIs in immunocompromised patients at an Indian tertiary care centre. Materials and Methods: A retrospective hospital-based study was done in immunocompromised patients with clinical suspicion of IFI. The demographic, clinical, radiological and mycological details of the patients were recorded. The patients were categorised into proven, probable and no IFI (as per European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria). The sensitivity and specificity of BDG Fungitell and Platelia Aspergillus antigen assays was estimated. Results: A total of 70 consecutive patients were included, of which 41 had IFI (10 proven and 31 probable) while 29 had no IFI. A significant association was found between IFI and the presence of a central venous line (P = 0.035) and history of intake of T-cell immunosuppressants (P = 0.001). Median BDG values (pg/ml) in patients with proven IFI, probable IFI and no IFI were 300 (range: 70–500), 165 (range: 53–500) and 45 (range: 31–500), respectively. The receiver operating characteristic (ROC) curve analysis for BDG revealed an area under the curve of 0.995, sensitivity: 97.4% and specificity: 96.6% for IFI diagnosis. The ROC curve analysis of GMI revealed an AUC of 0.75 and 90% patients with invasive aspergillosis (IA) had positive GMI. Conclusion: BDG has good sensitivity and specificity for distinguishing IFI from no IFIs and GMI may be used for diagnosing IA.


Keywords: Beta-D-glucan, galactomannan, invasive fungal infection, immunocompromised, India


How to cite this article:
Singh S, Kaur H, Choudhary H, Sethi S, Malhotra P, Gupta KL, Rudramurthy SM, Chakrabarti A. Evaluation of biomarkers: Galactomannan and 1,3-beta-D-glucan assay for the diagnosis of invasive fungal infections in immunocompromised patients from a tertiary care centre. Indian J Med Microbiol 2018;36:557-63

How to cite this URL:
Singh S, Kaur H, Choudhary H, Sethi S, Malhotra P, Gupta KL, Rudramurthy SM, Chakrabarti A. Evaluation of biomarkers: Galactomannan and 1,3-beta-D-glucan assay for the diagnosis of invasive fungal infections in immunocompromised patients from a tertiary care centre. Indian J Med Microbiol [serial online] 2018 [cited 2019 May 21];36:557-63. Available from: http://www.ijmm.org/text.asp?2018/36/4/557/254394



 ~ Introduction Top


Despite the advent of new antifungal agents, invasive fungal infections (IFIs) continue to remain a major cause of concern in immunocompromised patients due to high morbidity and mortality. Rapid and accurate diagnosis of IFI is essential, but challenging due to non-specific clinical-radiological findings, need for invasive sampling and a low sensitivity of conventional culture and histopathology techniques. Prompt recognition and treatment of life-threatening IFIs in patients with immunosuppression such as those with haemato-oncological malignancies, congenital or acquired immunodeficiencies, transplant recipients and immunosuppressive medication are crucial for improved outcomes. Non-culture-based detection of fungal biomarkers in serum and high-resolution radiology techniques have improved our diagnostic approach. The detection of galactomannan (GM) and 1,3-beta-D-glucan (BDG) has been evaluated for IFI diagnosis and is included in the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) revised diagnostic criteria for IFI.[1]

The performance of these assays has been evaluated extensively in immunosuppressed patients in developed countries, and there is substantial evidence supporting their use for IFI diagnosis.[2],[3],[4] However, studies evaluating their role in the Indian scenario are limited.[5],[6] The present study was performed to assess the utility of the FDA approved Fungitell BDG assay and Platelia Aspergillus antigen assay as an aid in the diagnosis of IFIs in immunocompromised patients admitted at our centre, a tertiary care hospital. This to the best of our knowledge is the first study from India studying the role of both these tests in this group of patients.


 ~ Materials and Methods Top


We conducted a retrospective study from January 2016 to December 2016, including immunocompromised patients with clinical suspicion of IFI. These comprised of patients with haematological malignancies, immunosuppression following solid organ or stem cell transplantation and patients with inherited or acquired immunodeficiency. Since the study was retrospective in design and the patients were not subjected to any intervention apart from the standard of care, ethical clearance was not required.

The demographic details, radiological findings and clinical course were then recorded for all enrolled patients. The enrolled patients were divided into the following groups according to the criteria of the EORTC/MSG:[1] (a) proven IFI, (b) probable IFI and (c) non-IFI. Details of any risk factors for acquiring IFI such as neutropenia, prolonged antibiotic intake or intravenous drug abuse were recorded. The results of mycological investigations, including culture, histopathology and fungal biomarkers assays, were recorded. The GM index (GMI) was tested using the Platelia Aspergillus Ag kit (Bio-Rad laboratories, WA, USA) as per the manufacturer's protocol and a value of >0.5 in serum and >1 in bronchoalveolar lavage (BAL) was recorded as positive. The BDG Fungitell assay (Associates of Cape Cod, Inc., MA, USA) was performed as per the protocol supplied by the manufacturer. Interpretation of BDG values was as follows: <60 pg/ml, negative; 60–79 pg/ml, indeterminate and >80 pg/ml, positive as per the manufacturer's guidelines.

All statistical analyses were done using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA, version 22.0 for Windows). The data are represented as mean and median (range) for quantitative variables and numbers for quantitative variables. Normality was checked using the Kolmogorov–Smirnov and Shapiro–Wilk's tests. All proportions were compared using the Chi-square test and results with P < 0.05 were taken as statistically significant.


 ~ Results Top


Details of study population

A total of 70 patients with suspected IFI were enrolled in the study, of which clinical details were available for 64 patients. Haematological malignancies were present in 55.7% of patients (n = 39) with the majority presenting with acute lymphoid leukaemia (14), followed by acute myeloid leukaemia (6), diffuse large B-cell leukaemia (4), chronic myeloid leukaemia (2), angioimmunoblastic T-cell lymphoma (2), aplastic anaemia (2), multiple myeloma (2), acute promyelocytic leukaemia (1), myelodysplastic syndrome (1), non-Hodgkin's lymphoma (1) and hairy cell leukaemia (1). Solid-organ transplantation (SOT) was noted in 24.3% (n = 17; 10 liver transplants and 7 renal transplants). Acquired or congenital immunodeficiency was present in 14.3% (n = 10), which included patients with HIV/AIDS (5), chronic granulomatous disease (1) and leukocyte adhesion defect (1). Chronic inflammatory conditions (including autoimmune diseases) were seen in 5.7% (n = 4), which included systemic lupus erythematosus (2), Crohn's disease (1) and myasthenia gravis (1).

Clinical description invasive fungal infection cases

Amongst the 70 enrolled patients, 41 had IFI, of which 66.7% were male and the median age was 33 (range 5–72) years while 29 were non-IFI, of which 67.9% were male and the median age was 32 (range 1–77) years. Patient's details and diagnosis of IFI are summarised in [Table 1]. Among all patients with suspected IFI, the diagnosis was confirmed in 20 (48.8%) patients with haematological malignancies, 14 (82%) patients with solid-organ transplant, 4 (70%) patients with immunodeficiency and 1 (25%) patient with chronic inflammatory diseases. Majority of the IFI cases among patients with haematological malignancies presented during the acute phase of leukaemia (19 IFI cases in 27 patients; 70.4%) compared to three patients with chronic phase of leukaemia (3 IFI cases in 9 patients; 33.3%).
Table 1: Clinical details of the study population and diagnosis of invasive fungal infection

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Diagnosis of invasive fungal infection

Radiological findings consistent with fungal infection were described in 52.8% (n = 19) of IFI patients versus 24.1% (n = 7) in non-IFI patients. The most common radiological finding in IFI patients was the presence of reticulo-nodular shadows and ground-glass opacities on chest radiograph (36.8%, n = 7) and bilateral parenchymal infiltrates (26.3%, n = 5), followed by halo sign (air-crescent sign) on CECT chest (15.8%, n = 3), perihilar consolidation (10.5%, n = 2), pan-sinusitis (5.3%, n = 1) and presence of multiple infarcts in brain on MRI (5.3%, n = 1).

The presence of IFI was associated with culture positivity at any site (including non-sterile sites such as urine and sputum) in 42.9% versus 3% in non-IFI patients. The median BDG values (pg/ml) recorded in serum samples of patients with proven IFI, probable IFI and non-IFI were 300 (range 70–500), 165 (range 53–500) and 45 (range 31–80) respectively. The results of BDG assay are shown in [Figure 1] and [Table 2].
Figure 1: Range of 1,3-beta-D-glucan values (pg/ml) for patient groups measured by the Fungitell 1,3-beta-D-glucan assay

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Table 2: Diagnosis of invasive fungal infections (as per the European Organization for Research and Treatment of Cancer/Mycoses Study Group definition) and results of 1-3, beta-D-glucan detection (Fungitell assay)

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Proven IFI – The serum BDG in patients with proven IFI (n = 10) was positive (i.e., >80 pg/ml) in 9 (90%) while one (10%) was in intermediate BDG range and none were BDG negative. The patient with BDG in intermediate range (BDG value = 70 pg/ml) was a 6 years old, immunodeficient child who presented with sepsis. Blood culture was positive for Candida lusitaniae; however, only a single sample of BDG was available in this case, therefore, no rise in BDG could be demonstrated by serial sampling.

Probable IFI – In the patients with probable IFI (n = 31) all but one patient had a positive BDG value. In the patient with negative BDG result, a value of 53 pg/ml was recorded. This patient was a 34-year-old post-renal transplant recipient, who had invasive mucormycosis (IM). He presented with respiratory difficulty, and chest radiography revealed ground-glass opacities. Mycological investigation of sputum revealed aseptate hyphae on calcofluor mount microscopy and Rhizopus oryzae on culture. He responded to treatment with amphotericin-B.

Non-IFI – In patients without IFI (n = 29), 23 (79.3%) were BDG negative, 5 (17.2%) were in the intermediate range and one patient had a positive BDG value. This patient with false-positive BDG result (BDG value = 80 pg/ml) was 22 years, male with ALL. His fungal workup was requested due to diffuse abdominal wall thickening on CECT abdomen; however, due to negative GMI, negative fungal cultures and lack of other clinical features, he was discharged after 1 week of hospital stay. Serial sample was not available for BDG testing.

The receiver operating characteristics curve of 1-specificity (false-positive results) versus sensitivity (true-positive results) using different values of BDG cut-off to define positivity is shown in [Figure 2]. The value of area under curve (AUC) should be >0.75 for a receiver operating characteristic (ROC) curve with good discriminatory capacity; here, this value is 0.986. Thus, the value of BDG is a useful for screening IFI in these patients. Since an increase in sensitivity parallels the same decrease in specificity as shown in [Table 3], it is not possible to estimate a good cut-off value (with high sensitivity and specificity) for the BDG assay. A sensitivity of 95.1% and specificity of 96% for diagnosis of IFI (proven/probable) was noted at the kit cut-off of 80 pg/ml which we have used for interpretation of test results. Two cases were identified as IM since Mucorales are known to produce low levels of BDG, we also performed the ROC analysis after exclusion of these two cases, and a higher AUC of 0.995 was seen with a sensitivity of 97.4% and specificity of 96.6% at kit cut-off.
Figure 2: Receiver operating characteristics curve showing the sensitivity and false-positive rates (1-specificity) in detecting invasive fungal infection (proven/probable) using Fungitell 1,3-beta-D-glucan assay. (a) Receiver operating characteristics on including all cases of invasive fungal infection and (b) receiver operating characteristics on excluding two cases of invasive mucormycosis

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Table 3: Values of beta-D-glucan cut-off with range of sensitivity and specificity for invasive fungal infection diagnosis in the study population

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Description of invasive fungal infection cases

Among the cases of IFI, invasive aspergillosis (IA) was seen in 48.8% (n = 20) of which, one was proven IFI and 19 were probable IFI. The case of proven IA was due to A. flavus demonstrated on histopathology and culture of nephrectomy tissue biopsy in a post-renal transplant recipient.

Invasive candidiasis (IC) was seen in 22% (n = 9) cases of which, nine were proven IFI and one was probable IFI. Majority of the cases of proven IC were caused by Candida albicans (44.4%, n = 4), followed by Candida tropicalis (33.3%, n = 3), Candida glabrata (11.1%, n = 1) and C. lusitaniae (11.1%, n = 1), and in all cases, Candida species were isolated from bloodstream.

We diagnosed IM in 4.8% (n = 2) of IFI cases. Both patients were post-renal transplant recipients; one was culture proven IM, positive for Rhizopus oryzae (proven IM) and the second was a case of probable IM (sputum microscopy positive, with radiological evidence of fungal infection). In two acute lymphocytic leukaemia patients, a case each of probable IFI due to Paceliomyces spp. and Scedosporium spp. was seen. Fungal culture and serological tests could not reveal any fungal agent in 17.1% (n = 7) of cases. The median values of BDG (pg/ml) were 230, 280, 74, 364 and 250 in cases of IA, IC, IM, Paceliomyces spp. IFI and Scedosporium spp. IFI, respectively.

Amongst the patients with IA, serum GMI was performed in all (n = 20) and a sensitivity and specificity of 90% both, respectively, was noted. The ROC analysis revealed an AUC of 0.7 of serum GMI for IFI diagnosis with a sensitivity and specificity of 56.4% and 90%, respectively. The detection of GMI in BAL was done in seven patients (including five cases of IA). [Table 4] shows the comparison of serum GMI, BAL GMI and BDG in relation to IFI diagnosis. The ROC analysis revealed an AUC of 0.667 of BAL GM at a cut-off of 1.0 for the detection of IFI and 90% (n = 4) cases of IA had positive BAL GMI while both of the cases without IA had a negative BAL GMI.
Table 4: Comparison of serum and bronchoalveolar lavage galactomannan levels with serum beta-D-glucan in relation to invasive fungal infection diagnosis

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Risk factors and outcome analysis for invasive fungal infection

Risk factors and clinical outcome could be recorded in 64 patients of which 35 had IFI and 29 had no IFI. The details of risk factors associated with IFI are summarised in [Table 5]. Statistically significant association was found between the presence of IFI with the presence of a central line (P = 0.035) and use of T-cell immunosuppressants (P = 0.001). The presence of IFI was associated with a higher mortality with 9 (25.7%) in patients with IFI versus 3 (10.3%) in non-IFI patients, P = 0.197. The median duration of stay was also longer in patients with IFI at 20 days stay (range 3–90) while it was 13.5 days (range 5–60) in patients without IFI.
Table 5: Distribution of risk factors amongst immunocompromised patients with invasive fungal infections

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 ~ Discussion Top


We evaluated fungal serum biomarkers GM and BDG for the diagnosis of proven and probable IFI in immunocompromised patients. Our study revealed that the BDG assay has a higher sensitivity and specificity than GM for the detection of IFI.

Limitations of traditional mycological culture, the need for invasive sampling and non-specific radiological findings make the diagnosis of IFI challenging. Evaluation of non-invasive, rapid tests for IFI diagnosis is essential, particularly in immunocompromised patients. Although various studies worldwide have evaluated the use of BDG and GM as a biomarker of IFI in such patients, there is scant data regarding their diagnostic potential in Indian patients.

In a recent study, BDG assay, GM detection and pan-fungal polymerase chain reaction (PCR) were compared for the diagnosis of IFI in pediatric cancer patients.[5] They described GM detection with PCR as the best diagnostic combination while a sensitivity of 88% and a specificity of 59.5% were recorded for the BDG detection assay (Fungitell). The reason for poor performance of BDG could be due to the inclusion of only paediatric patients in this study. Dietary glucans from milk and milk products may cause false-positive results in this patient group and further evaluation for use in paediatric population is warranted.

In another study from South India evaluating the role of BDG in critically ill patients with IC, the sensitivity and specificity of the Fungitell BDG assay were 97.8% and 16.6%, respectively, at the kit cut-off of 80 pg/mg and 97.8% and 63.3% at a cut-off of 143.5 pg/ml.[6] Although the sensitivity of BDG in this study is comparable to our findings, the specificity at the kit cut-off was meagre. This was possibly due to the use of beta-lactam antibiotics, intravenous albumin and concomitant bacteraemia in the patients in their study. Since it is practically impossible to avoid these in the ICU settings, the authors have attributed the low specificity of the assay to these factors.

A recent meta-analysis including 28 studies reporting the performance of BDG assay for the diagnosis of IFI suggests that a cut-off of 60 pg/ml best distinguishes patients with and without IFI.[2] We describe an AUC of 0.995, sensitivity and specificity of 97.4% and 96.6%, respectively, at the kit cut-off of 80 μg/ml indicating good diagnostic test accuracy at this cut-off. A lower cut-off would provide better specificity, at the cost of sensitivity.

We noted BDG levels greater than 80 pg/ml in all cases of proven IFI, except one case of IC due to C. lusitaniae (BDG = 72 pg/ml; intermediate). In a recent study by Mikulska et al., it was seen that BDG sensitivity is dependent on the Candida species causing IFI and BDG levels are the highest in C. albicans while levels as low as 72 pg/ml are seen in candidemia due to Candida parapsilosis.[7] In vitro studies have also reported lower levels of BDG in non-albicans species such as C. lusitaniae when compared with other species.[8]

Since the environmental fungal spore burden, patient colonisation rates and dietary habits of Indian patients may influence their baseline BDG levels, the local evaluation of this test is essential to determine if the kit cut-offs based on Western literature are accurate in our setting. Although we did not test BDG in healthy population for a baseline value, 97% (n = 28) of the patients without IFI had BDG levels <80 pg/ml. Our study suggests that the performance of this test at the cut-off provided by the manufacturer is adequate; however, further studies taking into account the baseline BDG levels of Indian patients are required.

In this study, one patient without IFI had a false-positive BDG value; however, the reason could not be determined since the patient was discharged shortly after sample requisition. Such results are possible due to concomitant therapy with antimicrobials (e.g., carbapenems and ampicillin-sulbactam), dialysis, cross-interaction with bacteria or prior use of antifungal therapy.[9],[10] These factors were not present in this patient; however, the reason of false positivity could not be investigated further since the patient was discharged within 1 week of admission.

The most common opportunistic IFI in immunocompromised patients in our study was IA (1 proven and 19 probable cases), and serum GM was tested in all these cases. A meta-analysis of studies evaluating the diagnostic performance of GM has reported an overall sensitivity and specificity of 78% and 81%, respectively, for IA diagnosis.[4] We observed a high sensitivity and specificity (both 90%) of GM for the diagnosis of IA, while a lower sensitivity of 56.4% was observed for diagnosis of IFI in general. This is expected since GM is known to be produced by Aspergillus species and not by Mucorales and Candida species. Other studies have reported 71%–89.7% sensitivity and 89%–98.1% specificity for IA diagnosis among immunocompromised patients.[11],[12]

A recent advance in diagnosing IA is the detection of GM in BAL samples and a study assessing the role of GM quantification in BAL of lung transplant recipients has described a sensitivity of 60% and a specificity of 95% at a cut-off of 0.5 and a same sensitivity with higher specificity of 98% at a cut-off of 1.0.[13] Although we recorded a 90% positivity of BAL GMI for IA diagnosis while both the non-IA cases were BAL GMI negative, it is difficult to comment on the diagnostic accuracy due to the low number of samples tested.

A study comparing GMI and BDG for the diagnosis of IA showed identical sensitivity and specificity of 87.5% and 89.6%, respectively, and a combination of both tests was found to improve the specificity (to 100%) without affecting the sensitivity.[14] Thus, these tests can be used complementary to each other and seem to have considerable concordance in our study. BDG is known to become positive earlier than GMI [14] and testing for BDG could help in making a diagnosis in two patients with IA that were not detected by GMI testing.

In this study, the clinical data of the patients with haematological malignancies revealed that those patients in acute phases of leukaemia such as ALL, AML, APML and blast crisis in CML had a higher rates of IFI compared to those in the chronic phase (70% vs. 33%). The rates of IFI were highest in suspected IFI patients with SOT (82%). This is expected since post-transplant recipients are often on strong immunosuppression in the form of steroids and T-cell immunosuppressants. Steroids inhibit chemotaxis of polymorphonuclear cells in addition to hampering oxidative bursts and their activity against hyphae.[15] The use of T-cell immunosuppressants was significantly associated with IFI in our study. Drugs targeting T-lymphocytes have been known to cause transitory neutropenia, and similarly, TNF-a blockage therapy has been associated with IA.[16],[17]

Following the diagnosis of acute leukaemia, the cumulative probability of developing IFI is 11.1% at 100 days and patients undergoing treatment for haematologic malignancies have a mortality of 35% due to such infections.[18] The rising incidence of IFI also results in a substantial increase in the hospital stay and associated health-care expenditures.[19] Previous studies have shown that cancer patients with aspergillosis have an average of 26-day longer hospital stay, incur higher costs and have a greater mortality rate during hospitalisation (31% vs. 7%) compared to non-IFI cases.[20] We also observed a high mortality of 25.7% in patients with IFI, which was two times higher than the mortality seen in non-IFI patients. However, there was no statistically significant difference between the two, probably because the patient population in the study is inherently morbid and aetiology-specific mortality due to IFI could not be established since autopsy findings for all patients were not available. As expected a longer median length of stay of 20 versus 13.5 days in patients of IFI was noted compared to those without IFI, although the cost analysis of this extended stay needs further evaluation.


 ~ Conclusion Top


Diagnosing IFI in immunocompromised patients and those with haematological malignancies is immensely challenging. Detection of biomarkers such as GM and BDG is a ray of hope in providing accurate and rapid screening of IFI in this patient population. This to the best of our knowledge is the first study from India evaluating the role of both serum GM and BDG assay in these patients. Compared to the Western countries, the environmental factors including the fungal spore burden, fungal disease prevalence and patient characteristics vary in the Indian population, it is important to understand the performance of these tests in Indian settings. A good sensitivity and specificity make them valuable screening tools in our settings. Prospective studies in other patient groups can provide greater insight into the role of this test in the future and must be undertaken.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

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Morgan J, Meltzer MI, Plikaytis BD, Sofair AN, Huie-White S, Wilcox S, et al. Excess mortality, hospital stay, and cost due to candidemia: A case-control study using data from population-based candidemia surveillance. Infect Control Hosp Epidemiol 2005;26:540-7.  Back to cited text no. 19
    
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Dasbach EJ, Davies GM, Teutsch SM. Burden of aspergillosis-related hospitalizations in the United States. Clin Infect Dis 2000;31:1524-8.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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2004 - Indian Journal of Medical Microbiology
Published by Wolters Kluwer - Medknow

Online since April 2001, new site since 1st August '04