|Year : 2017 | Volume
| Issue : 2 | Page : 237-242
Evaluation of serum galactomannan enzyme immunoassay at two different cut-offs for the diagnosis of invasive aspergillosis in patients with febrile neutropenia
Ritin Mohindra1, Malini R Capoor2, Shikha Puri2, Hitesh Raheja1, Dinesh K Gupta1, B Gupta3, Ranadip Chowdhury3
1 Department of Hematology, VMMC and Safdarjung Hospital, New Delhi, India
2 Department of Microbiology, VMMC and Safdarjung Hospital, New Delhi, India
3 Department of Medicine, VMMC and Safdarjung Hospital, New Delhi, India
|Date of Web Publication||5-Jul-2017|
Malini R Capoor
C-99, Neelambar Apartment, Opp. Sainik Vihar, Peetampura, New Delhi - 110 034
Source of Support: None, Conflict of Interest: None
Background: Invasive aspergillosis (IA) is an increasingly common and fatal opportunistic fungal infection in patients with haematological diseases. Early diagnosis is difficult as mycological culture techniques have low sensitivity and the radiological tools have low specificity. Galactomannan enzyme immunoassay (GEI) detects galactomannan in the human serum with a reported sensitivity and specificity between 30% and 100%. Aims: The aim of this study was to analyse the role of GEI in diagnosis of IA in patients with febrile neutropenia and to evaluate the role of GEI in the diagnosis of IA as per the revised (2008) European Organization for Research and Treatment of Cancer–Mycoses Study Group (EORTC–MSG) criteria at two different optical density (OD) cut-offs of 0.5 and 1.0. Setting: This prospective study was conducted in Safdarjung Hospital, New Delhi, India. Methods: GEI testing was performed in adult patients of febrile neutropenia with evidence of IA. Results at two different OD indices (ODIs) of 0.5 and 1.0 were analysed. The evaluation of the diagnostic parameter, that is, GEI was measured in terms of sensitivity, specificity and positive and negative predictive value and was validated with the revised (2008) EORTC–MSG diagnostic criteria of IA. Results: One hundred and eleven patients had evidence of IA, of which 79 patients were GEI positive when cut-off ODI was 0.5, whereas with cut-off ODI 1.0, 55 patients were GEI positive. Conclusion: ODI of 1.0 should be considered as positive while in patients with OD between 0.5 and 1.0, repeat sampling from the patient is recommended.
Keywords: Febrile neutropenia, galactomannan enzyme immunoassay, invasive aspergillosis, revised (2008) EORTC-MSG diagnostic criteria
|How to cite this article:|
Mohindra R, Capoor MR, Puri S, Raheja H, Gupta DK, Gupta B, Chowdhury R. Evaluation of serum galactomannan enzyme immunoassay at two different cut-offs for the diagnosis of invasive aspergillosis in patients with febrile neutropenia. Indian J Med Microbiol 2017;35:237-42
|How to cite this URL:|
Mohindra R, Capoor MR, Puri S, Raheja H, Gupta DK, Gupta B, Chowdhury R. Evaluation of serum galactomannan enzyme immunoassay at two different cut-offs for the diagnosis of invasive aspergillosis in patients with febrile neutropenia. Indian J Med Microbiol [serial online] 2017 [cited 2018 Feb 20];35:237-42. Available from: http://www.ijmm.org/text.asp?2017/35/2/237/209595
| ~ Introduction|| |
Invasive aspergillosis (IA) is an increasingly common and often fatal opportunistic fungal infection in patients with haematological diseases due to the growing use of high-dose chemotherapy and powerful immunosuppressive agents. The incidence is quoted to be ranging between 33% and 43% in patients with haematological malignancies and between 8% and 15% in patients undergoing allogenic haematopoietic stem cell and solid organ transplantation.,,,,, However, the clinical symptoms and radiological signs of IA are frequently non-specific and occur late in the course of the disease, making early diagnosis virtually impossible. Furthermore, obtaining a tissue biopsy may not be feasible in these critically ill patients due to associated thrombocytopenia and other coagulation defects.
Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus hyphae during growth , and is an essential molecule of these opportunistic fungal pathogens. GM being a water-soluble carbohydrate can be detected in several body fluids. The only commercially available laboratory test with proven utility for detection of IA is the GM enzyme immunoassay (GEI). It is a single-step immune-enzymatic sandwich microplate assay which detects GM in the human serum. 1,3-beta-d-glucan (BDG) is another marker which is becoming increasingly important in the diagnosis of IA; however, the BDG assay is a generic marker for invasive fungal disease rather than being a specific marker for IA, thus being widely distributed in the fungal kingdom unlike GEI., The reported sensitivity and specificity of serum GEI for diagnosis of IA have been documented to be 30%–100%; the high variability attributed to differing patient populations, diagnostic procedures and definitions of IA used., However, when combined with other diagnostic modalities and clinical judgement, GEI can be very effective in early diagnosis of IA, especially in countries with limited resources like India, where molecular testing is available in reference laboratories only. GEI measurements have been studied extensively, gaining general acceptance as a non-invasive diagnostic tool for IA for at-risk patients and have been included as a mycological criterion for the case definition of probable IA by the European Organization for Research and Treatment of Cancer–Mycoses Study Group (EORTC–MSG) consensus group.,,, The EORTC–MSG panel included a positive GEI as a microbiological criterion of IA, without specifying a cut-off value to define a positive result. Furthermore, early aggressive antifungal therapy following GEI positivity can help improve outcomes.
The objective of this study was to analyse the role of serum GEI in diagnosis of IA in patients with febrile neutropenia. We also tried to evaluate the role of GEI in the diagnosis of IA as per the revised (2008) EORTC–MSG criteria at two different optical density (OD) cut-offs of 0.5 and 1.0.
| ~ Methods|| |
This study was conducted in Safdarjung Hospital, a 1700 bedded tertiary care health centre in New Delhi, India during 2010–2013. Adult patients aged ≥18 years with febrile neutropenia, that is, oral temperature >38.5°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count <0.5 × 109/l or expected to fall below 0.5 × 109/l undergoing indoor treatment in the Departments of Medicine and Haematology and naive to antibiotics such as ampicillin–sulbactam, piperacillin–tazobactam and amoxycillin–clavulanic, and mould-specific systemic antifungals such as amphotericin B, itraconazole, voriconazole and caspofungin were enrolled and profiled as a part of this prospective study.
The patients were evaluated by diagnostic workup including detailed clinical assessment, followed by complete haemogram testing. On confirmation of diagnosis of febrile neutropenia, serum GEI testing was performed in all patients. Results of serum GEI at two different OD indices (ODIs) of 0.5 and 1.0 were analysed. Serum galactomannan concentrations were determined by the Platelia AspergillusEIA (Bio-Rad, Vienna, Austria) test kits in accordance with the manufacturer's instructions. The test variable was titre of the Aspergillus GM antigen. Results were recorded as an index relative to the OD of the control sample obtained in the same run, with an index ≥0.5 and ≥1.0 were analysed. The positive sera were repeat tested as per manufacturer's instructions. Twenty-five control samples from healthy blood donors were also tested in whom the ODI of the serum GM ranged from 0.1 to 0.4. Mycological workup involving microscopy and culture for fungi from sterile (blood and biopsy) and non-sterile sites (sputum and bronchoalveolar lavage) to look for any sign of fungal infection and high-resolution computerised tomography (HRCT) scan of chest was performed in patients with febrile neutropenia. The patients were then categorised into proven IA, probable IA or possible IA based on the revised (2008) EORTC–MSG criteria.
The evaluation of the diagnostic parameter, that is, GEI was measured in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and was validated with the revised (2008) EORTC–MSG diagnostic criteria of IA. Sensitivity, specificity, PPV and NPV were calculated using the 2 × 2 contingency tables. Receiver operator characteristic (ROC) curves were calculated using the SPSS (IBM SPSS Statistics V21.0 for windows, United States) software.
The study was approved by the Ethical Committee (Institute Review Board).
| ~ Results|| |
A total of 267 patients with febrile neutropenia were profiled during the study, of which 111 patients with evidence of IA as per the revised (2008) EORTC–MSG criteria were recruited in the study [Table 1]. Subcategorisation into proven IA, probable IA and possible IA was done as per the revised (2008) EORTC–MSG criteria. When an ODI of 0.5 was taken as positive, two patients (1.80%) had proven IA, 77 patients (69.37%) probable IA and 32 patients (28.83%) had possible IA. With ODI 1.0, two patients had proven IA, whereas the number of patients with probable IA and possible IA was 53 (47.75%) and 56 (50.45%), respectively [Table 2].
|Table 1: Division of patients profiled at optical density cut-off 0.5 and 1.0|
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|Table 2: Categorisation of patients into proven invasive aspergillosis, probable invasive aspergillosis and possible invasive aspergillosis based on the revised (2008) European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria|
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Based on microbiology, a total of 56 patients were smear positive for Aspergillus while culture positivity for Aspergillus species was present in 46 patients (44 probable IA and 2 proven IA). Of the 46 culture positive patients, 37 were Aspergillus flavus and nine were Aspergillus fumigatus.
Both patients with proven IA had ground glass opacities on HRCT. In patients with IA, the CT finding distribution was (n): diffuse reticular alveolar opacities, non-specific infiltrate and consolidation, multifocal and peripheral ground glass opacities, infiltrate with multiple nodules, halo sign, reverse reverse halo sign, tree in bud appearance  and bilateral pleural effusion.
Outcome was determined on the basis of 60-day all-cause mortality. Of the 111 patients included in this study, after 60 days, mortality was seen in 24 patients (21.62%). Higher OD values of GEI also correlated with culture positivity, HRCT findings and mortality.
Galactomannan enzyme immunoassay test performance
Sensitivity, specificity, positive predictive value and negative predictive value of the galactomannan enzyme immunoassay
In the two patients with proven IA, the sensitivity, specificity, PPV and NPV were all 100% at OD 0.5 and 1.0. In patients with probable IA, at cut-off ODI of 0.5, the sensitivity, specificity, PPV and NPV of the GEI were 100%, 95.2%, 92.3% and 100%, respectively. When the cut-off ODI was taken as 1.0, the sensitivity, specificity, PPV and NPV of the GEI were 95.8%, 97.6%, 95.8% and 97.6%, respectively [Table 3] and [Table 4].
|Table 3: Sensitivity, specificity and positive and negative predictive value of patients with proven invasive aspergillosis as per revised (2008) European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria|
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|Table 4: Sensitivity, specificity and positive and negative predictive value of patients with probable invasive aspergillosis as per revised (2008) European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria|
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Effect of decreasing the cut-off value
ROC curves using SPSS (IBM SPSS Statistics V21.0 for windows, United States) software were calculated to illustrate the trade-off in rates of true positive results (sensitivity) versus false positive results (1-specificity) as the cut-off for the test was shifted from high (1.0) to low (0.1) OD indices [Figure 1]. The diagnostic accuracy was given by the area under ROC curves. To determine the optimal OD cut-off, sensitivity and specificity of the test at various cut-offs were calculated. At OD cut-off 0.5, there was an increase of sensitivity up to 100% with a loss of specificity up to 95.2% from 97.6%. When the cut-off ODI was taken as 1.0, the sensitivity, specificity, PPV and NPV of the GEI were 95.8%, 97.6%, 95.8% and 97.6%, respectively. ROC curve of the ODI of patients' serum GEI depicts that at ODI 1.0 the diagnostic accuracy of GEI is optimum [Figure 1].
|Figure 1: Receiver operator curve of the optical density index of patients' serum sample depicting at optical density index 1 the diagnostic accuracy is optimum|
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| ~ Discussion|| |
IA remains the most common mould infection amongst patients with febrile neutropenia, causing significant mortality and morbidity in these patients. Securing a firm diagnosis of the disease is difficult as the patient may not exhibit reliable symptoms and signs in the presence of neutropenia and immune-modulating drugs, such as corticosteroids. Over the years, the diagnostic capability for the detection of IA has improved through the use of Aspergillus GM antigen. GM from the Aspergillus cell wall is released during invasive disease, and the level of circulating GM may be indicative of the intrinsic fungal burden in the host.
In literature review of numerous studies, significant heterogeneity was observed, particularly in the sensitivity and specificity of the test applied. Studies of the efficacy of GEI to diagnose IA published recently based on the revised (2008) EORTC–MSG criteria suggest that the proportion of patients with IA that are positive for GEI continues to vary ranging from 13% to 87.5%. The specificity of the assay on serum tends to range from 21% to 100% and in most cases was >80%. In the present study, we tried to establish the optimum OD cut-off for GEI.
The higher incidence of IA (41.57%) amongst patients with febrile neutropenia in our study compared to other investigators may be credited to various factors like the heterogeneity in the host populations, prior use of antifungal agents and the timing of the test in the other studies.,,,,,,,,,, However, in our study, the patient population selected was homogenous, samples were collected before any mould-specific antifungal therapy and the test was performed at the onset of febrile neutropenia only.
The incidence of GM positivity in our study was 69.37% and 47.75% at OD cut-off 0.5 and 1.0, respectively. This high incidence as against the previous work on GEI can be attributed to the use of a serum cut-off OD ranging from 0.5 to 2.5 in GEI as positive by the other investigators.,,,,,, Furthermore, in those studies on serum GEI, patients who had taken prior systemic antifungal treatment were included in the study, whereas only patients naive to antifungals were recruited in our study.
In this study, it was observed that raising the cut-off OD of the serum GEI from 0.5 to 1.0 increases the specificity and the PPV significantly but slightly decreases the sensitivity and the NPV. Whereas, reducing the cut-off OD to 0.5 gives a good sensitivity and NPV at the cost of a reduced specificity and PPV for GEI. Our findings are in concordance with most other investigators [Table 5].,,,,,,,,,,,,,,,,
|Table 5: Comparison of the findings of the present study with a few other studies of serum galactomannan enzyme immunoassay based on the revised (2008) European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria|
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| ~ Conclusion|| |
Thus, we recommend that patients with an OD of ≥1.0 should be labelled as GM positive, whereas those with <0.5 OD should be labelled as GM negative, and in those with OD ranging from 0.5 to 1.0, repeat sampling from the patient is advisable.
After a meticulous analysis of work done by previous researchers on GEI, it was found that false positive results for GM testing are seen with drugs derived from fungi (ampicillin–sulbactam, piperacillin–tazobactam and amoxicillin–clavulanic acid), subclinical infection, intestinal colonisation, cross-reaction with cyclophosphamide and adsorption of dietary GM from a damaged gut. False-positive results for GM testing have also been shown in bacteremic patients and patients on haemodialysis. These results are more likely to occur in patients undergoing liver transplantation for autoimmune liver disease than in patients with other liver conditions. In the current study, the patients were naive to aforementioned drugs and were free from these conditions, thus removing all confounding factors and improving the validity of our results.
Furthermore, the timing of collection of the sample may influence the test results, with reactivity being less likely to occur in samples collected at trough levels or before the administration of the antibiotic dose. It was demonstrated that a false-positive GM test can persist for over 10 days after the administration of a β-lactam antibiotics. However, these were already excluded from our study, thereby reducing false positives.
It can be concluded that GEI in serum has a high diagnostic accuracy when the test results are correlated with revised (2008) EORTC–MSG criteria. It seems more reasonable not to automatically treat all patients with fever refractory to broad spectrum antibiotics with antifungal agents, but rather to decide on an individual basis taking into account the serum GEI positivity. A negative GEI can curtail the usage of unwarranted antifungal therapy, especially in resource poor country like India.
In view of our findings, we recommend that an OD of 1.0 should be taken as positive while in patients with OD between 0.5 and 1.0, repeat sampling from the patient is recommended. Furthermore, since the GM indices begin to rise at the onset of fever and then continue to do so, it is recommended to increase the frequency of serum GEI to daily testing or twice weekly. It is an important screening tool in high-risk patient as it begins to rise before fever and much before radiological signs of IA, thereby reducing the need of inappropriate antifungal therapy. The impact of such an approach on outcome and costs has to be explored further. Finally, the utility of GM in other body fluids such as bronchoalveolar lavage and cerebrospinal fluid which come positive before serum GM should be further evaluated; to diagnose the cases of IA who present early in the course of the disease.
The authors would like to acknowledge the help of late Mrs. Kamlawati, Senior Technician, Microbiology, Safdarjung Hospital, for putting up the conventional tests for the study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]