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ORIGINAL CONTRIBUTION - CLINICS IN HEMATOLOGY
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 66-73

Role of galactomannan assay in bronchoalveolar lavage fluid in the diagnosis of invasive aspergillosis in high risk patients with hematological disorders


1 Department of Hematology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
2 Department of Pulmonary and Critical Care Medicine and Sleep Medicine, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
3 Department of Microbiology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
4 Department of Radiodiagnosis, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication30-Dec-2016

Correspondence Address:
Dipendra Kumar Gupta
Department of Hematology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-0977.197208

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  Abstract 

Introduction: Invasive aspergillosis (IA) is the most frequent invasive fungal infection occurring in high risk patients with haematological disorders and also an important cause of morbidity and mortality in them. Lungs comprise the primary site of IA in the vast majority of cases, and the most frequently occurring form of IA. Early diagnosis followed by early initiation of therapy improves outcome. The current culture based diagnostic methods are insensitive and slow. Detection of Aspergillus galactomannan (GM) in serum using the platelia Aspergillus enzyme immunoassay (GM EIA) represents sensitive, non-culture-based tool for the early diagnosis of IA. Recent studies have shown that during IPA, GM is released earlier and in higher concentration in the BAL fluid than in serum. Thus, an early and accurate diagnosis of IPA can be reached by detecting antigen in BAL samples. Materials and Methods: Thirty consecutive high risk patients with haematological disorders satisfying the inclusion and exclusion criteria according to EORTC-MSG diagnostic criteria and undergoing indoor treatment were recruited between November 2013 and December 2014 into the study. In all the patients, bronchoalveolar lavage (BAL) fluid GM and serum GM assays were assayed. Results: The diagnostic accuracy of the two tests was measured by calculating the sensitivity, specificity, predictive values and receiver operating characteristic curve (ROC). The optimal BAL GM index for diagnosing probable and possible IPA was >1.00 OD, resulting in a sensitivity and specificity of 93.75% and 78.57% respectively. As per ROC curve, when the optimal BAL GM index for the diagnosis of probable and possible invasive pulmonary aspergillosis (IPA) was OD >0.5, it resulted in sensitivity and specificity of 50% and 71.43% respectively. BAL GM was thus found to have a significantly higher sensitivity as compared to serum GM. Conclusion: In all high-risk patients with haematological disorders where the clinical and radiological findings favour the possibility of invasive pulmonary aspergillosis, conducting a GM assay in BAL fluid sample is far more rewarding than carrying out the traditional serum GM assay. BAL GM has a high diagnostic accuracy when correlated with the EORTC/MSG diagnostic criteria, and this high diagnostic yield is useful in obviating the unnecessary widespread use and abuse of empirical antifungal therapy in patients with IPA.

Keywords: Bronchoalveolar lavage, galactomannan assay, invasive aspergillosis, invasive pulmonary aspergillosis


How to cite this article:
Gupta DK, Kumar A, Suri J C, Gaind R, Agarwal Y. Role of galactomannan assay in bronchoalveolar lavage fluid in the diagnosis of invasive aspergillosis in high risk patients with hematological disorders. Astrocyte 2016;3:66-73

How to cite this URL:
Gupta DK, Kumar A, Suri J C, Gaind R, Agarwal Y. Role of galactomannan assay in bronchoalveolar lavage fluid in the diagnosis of invasive aspergillosis in high risk patients with hematological disorders. Astrocyte [serial online] 2016 [cited 2017 Jun 22];3:66-73. Available from: http://www.astrocyte.in/text.asp?2016/3/2/66/197208


  Introduction Top


Invasive aspergillosis (IA) is the most frequent invasive fungal infection occurring in high risk patients with haematological disorders. This vulnerability to the IA is due to intensive immunosuppressive chemotherapy, prolonged bone marrow suppression, and widespread use of steroids. The increasing awareness of fungal infections among treating physicians has contributed greatly to its diagnosis. [1] IA has emerged as an important cause of morbidity and mortality in these patients. [2] The lungs comprise the primary site of IA in the vast majority of cases, and the most frequently occurring form of IA. [3] Early diagnosis followed by early initiation of therapy improves outcome. [4],[5],[6] The incidence of invasive pulmonary aspergillosis (IPA) is approximately 15% to 20% among haematopoietic stem cell transplant (HSCT) recipients and high risk patients with haematological disorders [7],[8] and case fatality rates are as high as 50% to 90% despite antifungal therapy. [7] The clinical and radiological manifestations of IPA are non-specific and usually develop late.

The current culture based diagnostic methods are insensitive and slow. Cultures from bronchoalveolar lavage (BAL) and blood are often negative (95%), even in patients who later turn out to be proven cases of IA. [5] Although the histological analyses of CT guided biopsies of the affected sites are sensitive and specific however these are often precluded due to profound cytopenia and bleeding manifestations. [5],[6] Cultures and invasive technique such as transbronchial lung biopsy for cytology and histopathology are limited by poor sensitivity and specificity, and potential complications of an invasive procedure. [9] This diagnostic uncertainty has led to the widespread use and abuse of empirical antifungal therapy in patients with IPA.

An early and accurate identification of fungal pathogens is necessary to reduce the mortality due to IPA. This can be achieved by making use of newer non-invasive diagnostic tests which detect either fungal antigen or fungal DNA in blood, as markers of fungal infection. A new non-culture based technique, galactomannan (GM) assay, has been developed. [6] The detection of Aspergillus galactomannan (GM) in serum using the platelia Aspergillus enzyme immunoassay (GM EIA) represents a sensitive, non-culture-based tool for the early diagnosis of IA in patients with haematological malignancies. [10] GM is released during hyphal tip growth, and being a water soluble carbohydrate, it can also be detected in body fluids other than serum. [11] Recent studies have shown that during IPA, GM is released earlier and in higher concentration in the BAL fluid than in serum. [12] Thus an early and accurate diagnosis of IPA is potentially possible by detecting antigen in BAL samples. Lungs are the primary site of entry of Aspergillus conidia in IPA. GM is predominantly released by Aspergillus hyphae during growth and to a much lesser extent by conidia, hence, the detection of galactomannan in BAL fluid provides a better evidence for Aspergillus infection than a culture or polymerase chain reaction (PCR) which are unable to discriminate between contaminating conidia and hyphal growth. In contrast to culture of BAL fluid, GM antigen detection in BAL specimens when combined with high-resolution CT can lead to an early diagnosis and quick initiation of treatment, resulting in better survival rates. [13]

In an attempt to improve the sensitivity of the GM assay in patients with IPA and to reach an early diagnosis, several studies have investigated the role of GM detection in BAL fluid in non-haematological or mixed populations besides those affected with haematological disorders. [14] However, such relevant data in Indian population is until now scarce. This study was undertaken to assess the efficacy of GM assay in BAL fluid in high risk IPA patients with haematological disorders. Further, the results of GM assay in BAL fluid were compared with serum GM assay for identifying their relative role in diagnosing IPA.


  Materials and Methods Top


Conducted at a tertiary care public teaching hospital between November 2013 and December 2014, this single centre, cross-sectional, observational study comprises of 30 consecutive high risk in-patients with haematological disorders, who satisfied the inclusion and exclusion criteria as laid down in the European Organisation for Research and Treatment of Cancer and Mycosis Study Group (EORTC-MSG) diagnostic criteria. Due approval was obtained from the institutional ethical committee and a written informed consent from all patients.

The patients were of both sexes, ages 18 years and older, and met at least one of the following host criteria: ( a) a recent history of neutropenia (<0.5 × 10 9 /L) lasting for >10 days or ongoing neutropenia, temporally related to the onset of fungal disease; b) a history of prolonged use of corticosteroids (excluding patients with allergic bronchopulmonary aspergillosis) at an average minimum dose of 0.3mg/kg/day prednisone equivalent for >3 weeks; and c) a history of having received treatment with other recognized T-cell immunosuppressant such as cyclosporine, TNF-α blockers, or specific monoclonal antibodies; and d) a history of use of nucleoside analogues during the past 90 days.

In addition to above, each patient had one of the following "specific" radiological imaging signs on a HRCT scan of the lungs: (a) well defined nodule (s) with or without a halo sign [Figure 1], (b) wedge shaped infiltrate, (c) air crescent sign [Figure 2], (d) cavity and the presence of a new non-specific focal infiltrate plus at least one of the following symptom/sign: pleural rub, pleural pain, or haemoptysis.
Figure 1: Pulmonary HRCT section exhibiting the "halo sign"

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Figure 2: Pulmonary HRCT section demonstrating the "air crescent sign"

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Those patients who had a history of receiving β-lactam antibiotics like Ampicillin-Sulbactam, Piperacillin-Tazobactam and Amoxycillin-Clavulanic Acid; or systemic antifungal therapy with Amphotericin B, Itraconazole, Voriconazole or Caspofungin; or with a pulmonary infiltrate before the onset of febrile neutropenia; and known cases of pulmonary aspergillosis without radiological evidence of pulmonary infiltrate were not included in the study.

Each patient went through a complete blood count, urine for routine and microscopic examination, kidney function tests, liver function tests, serum electrolytes, random blood sugar, chest X-ray, high resolution computed tomography (HRCT) of chest, blood for fungal culture and sensitivity, sputum for fungal culture and sensitivity, blood for GM Elisa, BAL for fungal culture and sensitivity [Figure 3] [Figure 4] [Figure 5] [Figure 6] [Figure 7] [Figure 8] and BAL for GM assay. On the basis of history, physical examination and preliminary investigations, each patient was categorized into proven, probable and possible categories for IPA.{Figure 1}{Figure 2}
Figure 3: Sabouraud dextrose agar medium demonstrating growth of Aspergillus flavus from bronchoalveolar lavage fluid specimen

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Figure 4: Sabouraud dextrose agar medium demonstrating growth of Aspergillus fumigatus from bronchoalveolar lavage fluid specimen

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Figure 5: Calcoflour stained bronchoalveolar lavage fluid specimen which demonstrates the branching hyphae of Aspergillus fumigatus

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Figure 6: Digital microscopic image exhibiting the multiple vesicles of Aspergillus flavus bearing conidiophores (×1000)

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Figure 7: Digital microscopic image demonstrating the multiple conidial heads of Aspergillus fumigatus with spore heads radiating from central structure resembling Aspergillum (perforated globe used for sprinkling of holy water!) (×1000)

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Figure 8: Periodic Acid Schiff staining of a bronchoalveolar lavage fluid specimen highlighting the dichotomously branching septated hyphae of Aspergillus (×1000)

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Both whole blood and BAL samples were collected in plain vacutainers for GM EIA. GM EIA testing was performed using the Platelia Aspergillus EIA (Bio-Rad, Vienna, Austria) test kits. Results was recorded as an index relative to the optical density of the control sample obtained in the same run; and an optical density (OD) index >1 was taken as positive.

Each patient went through a diagnostic bronchoscopy with BAL for evaluation of pulmonary lesions. BAL fluid samples were obtained by wedging the tip of the bronchoscope against the bronchus leading to the radiographic maximal affected bronchopulmonary segment, followed by instillation and aspiration of 40-80 mL of 0.9% sterile saline. Up to 20 mL of the first aliquot was sent for GM testing. The investigators were blinded to the diagnosis and clinical characteristics. In brief, 300 μL of each BAL fluid sample was added to 100 μL of treatment solution, boiled for 3 minutes, and centrifuged at 10,000 g for 10 minutes. 50 μL each of supernatant and conjugate were mixed and incubated in microtiter plates pre-coated with monoclonal antibody EB-A2 for 90 minutes at 37°C. Wells were washed and incubated in the dark with 200 μL of chromogen solution for 30 minutes. Reactions were stopped and absorbance at 450 nm read using a plate reader. Positive and negative controls were included in each assay. Results were recorded as an index relative to the OD of the cut-off control, and retesting of the BAL samples were performed if the OD index was >1. For serum GM assay, 10mL of whole blood was collected in plain vaccutainer and sent to Department of Microbiology, where serum was separated immediately. The process of GM assessment was similar to that of BAL fluid.

The results were statistically analysed. GM EIA in serum and BAL were evaluated in terms of their respective sensitivity, specificity, positive predictive value, and negative predictive value. Receiver Operating characteristic (ROC) curves, and area under the curve (AUC) were determined to establish the discriminatory capability and diagnostic accuracy of the GM assay in samples of BAL fluid and serum. Serum and BAL GM were compared using the McNemar Test and Kappa value was determined to assess the degree of agreement between BAL GM and serum GM tests.


  Results Top


Of the 30 patients, the youngest was 18 years, the oldest 80 years; the mean age of the patients was 42.33 years with a standard deviation of ± 13.88. The median age of patients was 40.5 years with inter quartile range of 32.00-50.00. The maximum number of patients (N = 10) were in the age group of 41-50 years. Nineteen (63.33%) were males and 11 (36.67%) females [Table 1].
Table 1: Demographics and European Organisation for Research and Treatment of Cancer and Mycosis Study Group Diagnostic Characteristics of the Study Group (n=30)


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The patients were divided into four groups according to the EORTC/MSG diagnostic criteria for the IPA [Table 1]. While 8 (26.67%) patients were categorized as high risk with no evidence of IPA, 22 (73.33%) had evidence of IPA. Of these 22 patients, 16 were (53.33%) identified as probable IPA, while 6 (20%) as possible IPA. None fell in the category of proven IPA.

GM in BAL fluid was found positive in 60% patients [Table 2].
Table 2: Results of Galactomannan in Bronchoalveolar Lavage Fluid (n=30)


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Of the 16 (53.33%) probable IPA cases, BAL GM tested positive in 15 (83.33%). In contrast, out of 6 possible IPA, 1 (5.56%) tested positive. Only 2 (11.11%) patients identified positive without IPA. BAL GM indices among patients with probable IPA were significantly higher than in those with possible IPA and those at risk (P < 0.0005) [Table 3].
Table 3: Results of Galactomannan in Bronchoalveolar Lavage Fluid in Different Groups of Patients (n=30)


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Of the 16 (53.33%) probable IPA patients, serum GM tested positive in 8. Of 6 possible IPA patients, 2 were found positive. Serum GM indices among patients with probable IPA were significantly higher than in those with possible IPA and those at risk (P = 0.466). In total, the serum GM was positive in 12 (40.00%) of the 30 patients and negative in 18 (60.00%) patients [Table 4]. The BAL culture was positive in 16 (53.33%) patients and negative in 14 (46.67%) patients [Table 5].
Table 4: Serum Galactomannan Results in Diverse Patient Groups (n=30)


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Table 5: Results of Bronchoalveolar Lavage Culture and Sensitivity in Patients (n=30)


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The results of GM in the BAL and serum were compared. 9 patients had a positive GM in both BAL and serum, while GM was negative in 9 patients in both BAL and serum. However, while GM was positive in another 9 patients, the serum was negative for GM. This discordance, albeit of a different kind, was also obvious in another 3 patients, where GM was positive in the serum but negative in BAL [Table 6].
Table 6: Comparative Results of Galactomannan in the Serum vis -á - vis Bronchoalveolar Lavage (n=30)


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Since the kappa value is between 0.21-0.40, the results of BAL GM and serum GM demonstrate a fair agreement between themselves [Table 7].
Table 7: Agreement between Bronchoalveolar Lavage Fluid Galactomannan and Serum Galactomannan (n=30)


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As per the ROC, the optimal BAL GM index for diagnosing probable and possible IPA was >1.00 OD, with a sensitivity and specificity of 93.75% and 78.57% respectively [Table 8] and [Figure 9].
Figure 9: Receiver Operating Characteristic Curve of Bronchoalveolar Lavage Galactomannan

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Table 8: Analysis of Receiver Operating Characteristic Curve of Galactomannan in Bronchoalveolar Lavage Fluid and Serum (n=30)


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As per the ROC, the optimal serum GM index for the diagnosis of probable and possible IPA was OD >0.5, with a sensitivity and specificity of 50% and 71.43% respectively [Table 8] and [Figure 10].
Figure 10: Receiver Operating Characteristic Curve of Serum Galactomannan

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A comparison was made between the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, and negative predictive value of bronchoalveolar lavage galactomannan and serum galactomannan, which clearly demonstrates the superiority of the former over the latter [Table 9].
Table 9: Comparative Sensitivity, Specificity, Positive likelihood ratio, Negative likelihood ratio, Positive Predictive Value, and Negative Predictive Value of Bronchoalveolar Lavage Galactomannan and Serum Galactomannan


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  Discussion Top


A major cause of morbidity and mortality in high risk patients with various haematological conditions, IPA imposes a huge financial burden on any healthcare system. The "gold standard" for its diagnosis vests in microscopy and culture of lung tissue. However, this so-called gold standard suffers with several limitations: it is invasive, carries a significant morbidity and mortality, has a poor yield and is time consuming. This void has recently been filled with BAL GM assay, which enjoys a higher sensitivity than polymerase chain reaction (PCR) and serum GM; and can be useful as an adjunct in the diagnosis of proven and probable IA. [15] This assay helps clinicians in prompt detection of IPA and thus paves the way for a quick, timely, aggressive antifungal therapy, while obviating avoidable empirical treatment in those with no substantive evidence of IPA.

Studies regarding BAL GM assay, however, have been scarce until now in the Indian subcontinent. The results of this study bear out its usefulness in all high-risk patients with haematological disorders, be it aplastic anaemia, ALL, AML, or lymphoma. Of the 16 probable IPA patients in the study, BAL GM tested positive in 15 (83.33%); while among the 6 possible IPA patients, 1 (5.56%) was found positive. Only 2 (11.11%) patients were identified as positive without IPA. BAL GM indices among patients with probable IPA were significantly higher than possible IPA patients and at risk group (P < 0.0005).

Detection of GM in BAL was found to possess an excellent sensitivity (93.75%), moderate specificity (78.57%), and a PPV of 83.33%, when a cut off OD index of >1.0 was used in patients with IPA. A number of published works have reported a similar sensitivity and specificity for GM in BAL [Table 10]. [16],[17],[18],[19]

Some works have, however, exhibited a significantly lower sensitivity between 55% and 60% for BAL GM. [20] There may be several potential reasons for this lower sensitivity. This variability may stem from the selection of patients. Recent studies including this study employ the EORTC/MSG 2008 criteria, while the two studies demonstrating lower sensitivity of BAL GM did not.

This variance in sensitivity may also possibly relate to the severity of neutropenia in a study cohort. The degree of neutropenia could have a direct relationship to the expression of GM; it is likely that as neutropenia becomes more pronounced, the growth of the hyphae of molds becomes more florid. In the studies where BAL GM was found to have a lower sensitivity, the subjects may not have suffered with severe neutropenia. However, not all studies favor this thought.

Prophylactic or empirical administration of mold-active antifungal therapies may be another possible cause of lowered sensitivity of BAL GM. However, this clinical theorem is also controversial. While some studies report no impact of antifungal therapies on the sensitivity of BAL GM, [20],[21] others describe a decreased sensitivity in those who had received more than 3 days of antifungal treatment. [18],[22] The present study, however, did not include patients on antifungal drugs.

The most crucial factor that affects the sensitivity of BAL GM is the standardisation of procedure in drawing BAL fluid for the assay. The amount of BAL fluid collected can influence the GM concentration and, consequently, the results of the assay. [23] If a larger aliquot is taken, the GM concentration shall be higher and greater shall be the sensitivity of BAL GM. [18] The choice of site from where the BAL fluid is picked is also liable to effect the result. If a homogenized alveolar sample is taken, rather than a bronchial sample, the sensitivity of BAL GM is likely to be far greater.

The ODI of BAL GM in the present study was >1.0, while ODI of serum GM was >0.5.

In the present study, the detection of GM in the serum had a sensitivity of 50%, a specificity of 71.4%, PPV of 66.67% and NPV of 55.56%. The strength of agreement between serum GM and EORTC/MSG clinical criteria measured was poor (ⱪ value 0.121). In comparison, the sensitivity, specificity, PPV and NPV of BAL GM was far superior: 93.7%, 78.6%, 83.33% and 91.67% respectively. The strength of agreement between BAL GM and EORTC/MSG clinical criteria was moderate (ⱪ value 0.421).

Until now, few studies have compared the sensitivity of BAL GM and serum GM. Such a comparison, however, is liable to suffer with one important limitation. The focus for diagnosis of probable IA mostly lies on serum GM detection, and BAL samples are picked only if GM is detected in the serum. This is liable to result in inordinate delays in picking a BAL sample. Whereas, in actuality, GM in the infected alveoli is likely to precede the appearance of GM in the serum. This delay can be obviated if BAL samples were to be collected on the same day as the serum samples. The work of Becker et al. which found sensitivity of GM detection in BAL fluid to be 100% in comparison to 47% in serum underscores the significance of this strategy. [13]

This study however has several limitations. Due to the high patient load and infrastructure constraints, sometimes the bronchoscopy and collection of BAL fluid specimen was delayed. Also, the amount of BAL fluid sent for GM detection varied between patients. Both these factors could impact results, and, ideally, should be standardized. This study also did not consider the influence of severity of neutropenia on BAL GM results. Repeated weekly serum GM assay may be critical to enhance its sensitivity, however, this study did this assessment just once.


  Conclusion Top


A BAL GM assay, in all high-risk haematological patients fulfilling the EORTC/MSG diagnostic criteria, has a far superior yield than serum GM. With its favorable sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, and negative predictive value over serum GM, it promises to be a useful tool in making an early diagnosis and consequently, allowing for an improved outcome due to a timely commencement of antifungal treatment. The test can obviate the empirical and avoidable use of antifungal therapy in BAL GM negative patients.

Further, the usefulness of BAL GM assay can possibly be improved if the timing of bronchoscopic lavage, the selection of alveolar site for taking the BAL fluid specimen, and the amount of BAL fluid sample sent for the assay were to be optimized. Studies have highlighted the significance of these analytical variables in the results of BAL GM assay, and multi-center research can possibly unveil their impact.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et al. The epidemiology of fungal infections in patients with hematologic malignancies: The SEIFEM-2004 study. Haematologica 2006;91:1068-75.  Back to cited text no. 1
    
2.
Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006;173:707-17.  Back to cited text no. 2
    
3.
Baddley JW, Andes DR, Marr KA, Kontoyiannis DP, Alexander BD, Kauffman CA, et al. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis 2010;50:1559-67.  Back to cited text no. 3
    
4.
von Eiff M, Roos N, Schulten R, Hesse M, Zühlsdorf M, van de Loo J. Pulmonary aspergillosis: Early diagnosis improves survival. Respiration 1995;62:341-7.  Back to cited text no. 4
    
5.
Verweij PE, Donnelly JP, De Pauw BE, Meis Jacques FGM. Prospects for the early diagnosis of invasive aspergillosis in the immunocompromised patient. Reviews in Medical Microbiology 1996;7:105-13.  Back to cited text no. 5
    
6.
Cuenca-Estrella M, Bassetti M, Lass-Flörl C, Rácil Z, Richardson M, Rogers TR. Detection and investigation of invasive mould disease. J Antimicrob Chemother 2011;66 Suppl 1:i15-24.  Back to cited text no. 6
    
7.
Patterson TF, Kirkpatrick WR, White M, Hiemenz JW, Wingard JR, Dupont B, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore) 2000;79:250-60.  Back to cited text no. 7
    
8.
Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002;34:909-17.  Back to cited text no. 8
    
9.
Knox KS, Meinke L. Role of bronchoalveolar lavage diagnostics in fungal infections. Clin Chest Med 2009;30:355-65, viii.  Back to cited text no. 9
    
10.
Leeflang MM, Debets-Ossenkopp YJ, Visser CE, Scholten RJ, Hooft L, Bijlmer HA, et al. Galactomannan detection for invasive aspergillosis in immunocompromized patients. Cochrane Database Syst Rev 2008;(4):CD007394. doi: 10.1002/14651858.CD007394.  Back to cited text no. 10
    
11.
Klont RR, Mennink-Kersten MA, Verweij PE. Utility of Aspergillus antigen detection in specimens other than serum specimens. Clin Infect Dis 2004;39:1467-74.  Back to cited text no. 11
    
12.
Park SY, Lee SO, Choi SH, Sung H, Kim MN, Choi CM, et al. Aspergillus galactomannan antigen assay in bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. J Infect 2010;61:492-8.  Back to cited text no. 12
    
13.
Becker MJ, Lugtenburg EJ, Cornelissen JJ, Van Der Schee C, Hoogsteden HC, De Marie S. Galactomannan detection in computerized tomography-based broncho-alveolar lavage fluid and serum in haematological patients at risk for invasive pulmonary aspergillosis. Br J Haematol 2003;121:448-57.  Back to cited text no. 13
    
14.
Nguyen MH, Leather H, Clancy CJ, Cline C, Jantz MA, Kulkarni V, et al. Galactomannan testing in bronchoalveolar lavage fluid facilitates the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies and stem cell transplant recipients. Biol Blood Marrow Transplant 2011;17:1043-50.  Back to cited text no. 14
    
15.
Zou M, Tang L, Zhao S, Zhao Z, Chen L, Chen P, et al. Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis. PLoS One 2012;7:e43347.  Back to cited text no. 15
    
16.
Maertens J, Buvé K, Theunissen K, Meersseman W, Verbeken E, Verhoef G, et al. Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients. Cancer 2009;115:355-62.  Back to cited text no. 16
    
17.
Torelli R, Sanguinetti M, Moody A, Pagano L, Caira M, De Carolis E, et al. Diagnosis of invasive aspergillosis by a commercial real-time PCR assay for Aspergillus DNA in bronchoalveolar lavage fluid samples from high-risk patients compared to a galactomannan enzyme immunoassay. J Clin Microbiol 2011;49:4273-8.  Back to cited text no. 17
    
18.
Luong ML, Clancy CJ, Vadnerkar A, Kwak EJ, Silveira FP, Wissel MC, et al. Comparison of an Aspergillus real-time polymerase chain reaction assay with galactomannan testing of bronchoalvelolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in lung transplant recipients. Clin Infect Dis 2011;52:1218-26.  Back to cited text no. 18
    
19.
D'Haese J, Theunissen K, Vermeulen E, Schoemans H, De Vlieger G, Lammertijn L, et al. Detection of galactomannan in bronchoalveolar lavage fluid samples of patients at risk for invasive pulmonary aspergillosis: Analytical and clinical validity. J Clin Microbiol 2012;50:1258-63.  Back to cited text no. 19
    
20.
Bergeron A, Belle A, Sulahian A, Lacroix C, Chevret S, Raffoux E, et al. Contribution of galactomannan antigen detection in BAL to the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies. Chest 2010;137:410-5.  Back to cited text no. 20
    
21.
Penack O, Rempf P, Graf B, Blau IW, Thiel E. Aspergillus galactomannan testing in patients with long-term neutropenia: Implications for clinical management. Ann Oncol 2008;19:984-9.  Back to cited text no. 21
    
22.
Musher B, Fredricks D, Leisenring W, Balajee SA, Smith C, Marr KA. Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid. J Clin Microbiol 2004;42:5517-22.  Back to cited text no. 22
    
23.
Hsu LY, Ding Y, Phua J, Koh LP, Chan DS, Khoo KL, et al. Galactomannan testing of bronchoalveolar lavage fluid is useful for diagnosis of invasive pulmonary aspergillosis in hematology patients. BMC Infect Dis 2010;10:44.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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