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Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in non-hematological patients
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www.elsevierhealth.com/journals/jinf
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Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in non-hematological patients* vila a, E. Gomez Garcia de la Pedrosa b, n a,*, P. Martı´n-Da J. Fortu J.T. Silva c, J. Garcia-Rodrı´guez d, D. Benito a, E. Venanzi a, ~ o a, M. Ferna ndez-Ruiz c, F. Lazaro d, R. Garcı´a-Luja n e, F. Castan d f a c I. Quiles , J.J. Cabanillas , S. Moreno , J.M. Aguado Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Instituto de Investigacion Ramon y Cajal (IRYCIS), Universidad de Alcala, Madrid, Spain b Department of Microbiology, Hospital Universitario Ramon y Cajal, Instituto de Investigacion Ramon y Cajal (IRYCIS), Universidad de Alcala, Madrid, Spain c Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigacion Hospital “12 de Octubre”, Universidad Complutense, Madrid, Spain d Department of Microbiology, Hospital Universitario La Paz, Instituto de Investigacion Hospital Universitario La Paz (IdiPAZ), Universidad Autonoma, Madrid, Spain e Department of Pneumology, Hospital Universitario “12 de Octubre”, Instituto de Investigacion Hospital “12 de Octubre”, Universidad Complutense, Madrid, Spain f Department of Pneumology, Hospital Universitario La Paz, Instituto de Investigacion Hospital Universitario La Paz (IdiPAZ), Universidad Autonoma, Madrid, Spain a
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Accepted 26 February 2016 Available online - - -
KEYWORDS Galactomannan; Bronchoalveolar lavage fluid; Invasive aspergillosis
Summary Background: The role of galactomannan (GM) in serum or bronchoalveolar lavage fluid (BALF) for the diagnosis of invasive pulmonary aspergillosis (IPA) has been extensively evaluated in hematological patients, however its performance in non-hematological patients is not well established. Methods: We performed a multicenter retrospective study in 3 university hospitals in Madrid, Spain between 2010 and 2014. The study population comprised patients with chronic obstructive pulmonary disease (COPD) and patients with immunosuppressive conditions in whom IPA
~ ola de Investigacio n en Patologı´a Infecciosa; SEIMC, Sociedad Espan ~ola de Enfermedades Infecciosas y MiAbbreviations: REIPI, Red Espan crobiologı´a Clı´nica. * The study was presented in part at ICAAC 2015, San Diego, California (USA), 17e21 September, 2015. Q3 * Corresponding author. Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Carretera Colmenar km 9,1, 28034 Madrid, Spain. n). E-mail address: [email protected] (J. Fortu http://dx.doi.org/10.1016/j.jinf.2016.02.019 0163-4453/ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association. n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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was suspected and for whom BALF GM was available. Patients with hematological disorders were excluded. Results: A total of 188 patients (35 with COPD and 153 with immunosuppressive conditions) were analyzed, and 31 cases of IPA (proven or probable) were identified. The global sensitivity of BALF GM (optical density index [ODI] 1.0) was 77.4%; sensitivity was higher in patients with immunosuppressive conditions than in patients with COPD (81.8% vs 66.7%; p: 0.38). In COPD patients, the best performance was obtained for BALF GM (ODI 0.5), although sensitivity (88.9%) was similar to that of BALF fungal culture (88.9%). The sensitivity of GM in serum was very poor in both populations (36.4% and 11.6%, respectively). Conclusions: In the present series, the diagnostic performance of BALF GM was good for IPA in non-hematological patients, especially in patients with immunosuppressive conditions. ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction The role of galactomannan (GM) in bronchoalveolar lavage fluid (BALF) in the diagnosis of invasive pulmonary aspergillosis (IPA) has been widely discussed in neutropenic and hemato-oncological patients.1,2 Most studies confirm that the sensitivity of BALF GM is higher than that of serum GM. The many groups of patients identified as being at risk for IPA include solid organ recipients, patients receiving long-term therapy with corticosteroids, patients with chronic obstructive pulmonary disease (COPD), patients admitted to intensive care units (especially patients with advanced liver cirrhosis), and patients receiving immunomodulating drugs for the treatment of autoimmune disorders and solid tumors.3 BALF GM seems to be the method of choice for diagnosis of IPA in patients who develop airwayinvasive forms,4e6 although it is difficult to know the real performance of BALF GM in non-hematological patients because of differences in immunosuppression, differences in the prevalence of IPA, and the low number of studies within this population. The objectives of the present study were to analyze the performance of BALF GM in COPD patients and in patients with immunosuppressive conditions other than oncohematological diseases.
Methods The study was approved by the Institutional Review Board of Hospital Ramon y Cajal, Madrid, Spain and supported by Ministerio de Economı´a y Competitividad, Instituto de Salud Carlos III (co-funded by the European Development Regional Fund “A way to achieve Europe” ERDF) and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). We performed an observational retrospective cohort study from 2010 to 2014 in 3 university hospitals in Madrid, Spain: Hospital Ramon y Cajal, Hospital La Paz, and Hospital 12 de Octubre. The criteria proposed by the European Organization for Research and Treatment in Cancer and the Mycoses Study Group for diagnosis of IPA were applied for patients with immunosuppressive conditions.7 As previously stated, critically ill patients with COPD, patients receiving long-term therapy with corticosteroids, solid organ recipients, HIVinfected patients with <200 CD4/mm3, patients with cirrhosis
and patients receiving immunomodulating drugs for the treatment of autoimmune disorders or solid tumors were included in the analysis as host factors.4,5 However, because the radiological consensus criteria are less specific for IPA in these groups, the presence of pulmonary infiltrates or consolidations not responding to broad-spectrum antibacterial coverage was considered a radiological criterion.3e5 This amendment adapts more favorably to the diagnostic criteria of IPA in non-hematological patients proposed by Blot et al.8 and Bulpa et al.9,10 In summary, a diagnosis of “probable IPA” was established based on the simultaneous presence of at least 1 host factor, 1 radiological criterion, and 1 mycological criterion. The modified radiological criteria respond to previous clinical experience suggesting that IPA in patients with COPD or immunosuppressive conditions may be accompanied by lung infiltrates (i.e., peribronchial consolidation or tree-in-bud pattern) that differ from the typical signs observed in hematological patients.11,12 The microbiological criteria included any of the following: a) recovery of Aspergillus spp. in culture from sputum, BALF, or bronchial brush samples; b) a positive serum GM result (ODI 0.5) confirmed in 2 samples; or c) a positive BALF GM result (ODI 1.0). The cutoff of ODI 1.0 for BALF GM was accepted because it was routinely used for the diagnosis of IPA in the 3 hospitals, according to previous reports.2,11,13e16 GM was performed as recommended by the manufacturer (Platelia Aspergillus; Sanofi Diagnostics Pasteur, Marnes-La-Coquette, France). The diagnosis of “possible IPA” was based only on host factors and radiological criteria. The initial population comprised all adult patients (age >18 years) with COPD or other immunosuppressive conditions, in the absence of neutropenia (<500 cells/ml) or hematologic diseases, with suspected IPA in whom BALF GM was available. COPD was classified following the GOLD criteria. All COPD patients had an FEV1/FVC ratio < 0.70. FEV was classified as follows: stage I, FEV1 80% of normal; stage II, FEV1 50e79% of normal; stage III, FEV1 30e49% of normal; stage IV, FEV1 < 30% of normal or <50% normal with chronic respiratory failure. Immunosuppressive conditions included any of the following: a) chronic therapy with corticosteroids (>15 mg/day, >4 weeks); b) solid tumors managed with chemotherapy or immunomodulating drugs in the absence of prolonged neutropenia (<500 cell/ml); c) solid organ transplants; and d) HIV infection with <200 CD4/mm3. A single on-line database was used. The application included epidemiological, clinical, diagnostic, imaging, therapeutic, and prognostic variables.
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Experienced personnel performed all bronchoscopies. BAL was obtained after instillation of at least 20 ml of saline 1e3 times in the affected area or, failing that, the bronchoscope was wedged into the middle lobe bronchus. Statistical analysis: The McNemar c2 test was used to compare sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) between the assays. The univariate analysis of contingency data was performed using a c2 test or Fisher exact test. Although an ODI ratio 1.0 in BALF GM was considered a priori as a reference for the diagnosis of IPA, receiver operating characteristic (ROC) curve analysis was used to establish the BALF GM that best distinguished IPA in patients with COPD and patients with immunosuppressive conditions. The analyses were performed using IBM SPSS Statistics for Windows, Version 19.0 (IBM Corp., Armonk, NY, USA).
Results A total of 188 patients were analyzed during the study period. No hematological patients, neutropenic patients, or recipients of autologous or allogeneic hematopoietic progenitors were included. A total of 31 cases of proven/ probable IA (16.5%) and 34 cases of proven/probable/ possible IA (18.1%) were confirmed. BALF GM was available in all cases. COPD was recorded in 35 patients and immunosuppressive conditions in 153. The 188 patients were affected by 224 (35 þ 189) immunosuppressive conditions, because several patients shared more than 1 type of immunosuppression (Table 1). All COPD patients were included in the COPD group, although 20 shared other immunosuppressive conditions. A total of 153 patients presented 189 immunosuppressive conditions (solid tumor, 52; solid organ transplant, 41; HIV infection, 21; and chronic illnesses requiring corticosteroid maintenance of at least 15 mg/d for more than 4 weeks, 75). Table 1 shows the baseline conditions and characteristics of the patients and the frequency of IPA (proven/probable). Most cases of IPA occurred in solid organ recipients and in patients with COPD. No cases of IPA were confirmed in patients with HIV infection. All patients with COPD and IPA had advanced stages of COPD (GOLD III or IV). Overall mortality in both groups (COPD and immunosuppressive conditions) was over 40%. The sensitivity, specificity, PPV, and NPV of the different microbiologic diagnostic tests are presented in Table 2. Although BALF GM (ODI 1) and serum GM (ODI 0.5) were considered diagnostic criteria of IPA a priori, Table 2 shows the performance of BALF GM with 3 different cutoffs: ODI 0.5, ODI 1.0, and ODI 1.5. Table 2 also shows the performance of serum GM (ODI > 0.5), isolation of Aspergillus spp. in BALF culture, and isolation of Aspergillus in sputum/or bronchial wash culture. The overall prevalence of IPA (proven/probable) in this study was 16.5% (31/188), 14.4% for patients with immunosuppressive conditions, and 25.7% for patients with COPD. BALF GM (ODI 1.0) had an overall sensitivity of 77.4%, although this was higher in patients with immunosuppressive conditions (81.8%) than in patients with COPD (66.7%); p: 0.38. For patients with immunosuppressive conditions, the optimal BALF GM ODI was 1.0 (sensitivity,
3 81.8%; specificity, 93.9%; PPV, 69.2%; and NPV, 96.9%). However, for COPD patients, a BALF GM ODI 0.5 (sensitivity, 88.9%; specificity, 88.4%; PPV, 72.7%; and NPV, 95.8%) performed better than BALF GM ODI 1.0 (sensitivity, 66.7%; specificity, 96.2%; PPV, 85.7%; and NPV, 89.3%). With specificity similar to that of BALF GM ODI 1.0, BALF GM ODI 1.5 presented a lower sensitivity in all patients. The sensitivity of sputum or bronchial wash fungal culture was similar in both groups (z50%), although that of BALF fungal culture was slightly higher in patients with COPD (88.9%) than in patients with immunosuppressive conditions (63.6%); p: 0.2. On the other hand, the sensitivity of serum GM for the threshold value considered for diagnosis (ODI 0.5 in 2 samples) was very low in both groups of patients (11.1% and 36.4%, respectively). The superiority of BALF GM and the estimation of differences between the diagnostic procedures are shown using ROC curves (Fig. 1). The areas under the curve (AUC) of BALF GM and serum GM were 0.92 (95%CI: 0.86e0.97) and 0.60 (95%CI: 0.46e0.74), respectively.
Discussion This study analyzes two groups of patients: (a) a heterogeneous population of immunocompromised patients, with cellular immunosuppression, and (b) a population of patients with advanced COPD, some of whom also had other immunosuppressive conditions. Unlike neutropenic and hematological patients, in whom IPA mainly has an angio-invasive pattern, the dominating pattern in other patients is airway-invasive. Despite the presence of common airway-invasive pattern in immunosuppressed and COPD patients,12 we performed a separate analysis of both populations given the frequent colonization of the bronchial tree by Aspergillus spp. in patients with COPD. Two recent meta-analyses evaluated the performance of BALF GM in hematological patients.15,16 The more recent study analyzed 13 studies including more than 3000 patients.15 The optimal ODI of BALF GM was 1.0. For this value, the sensitivity and specificity of BALF GM in the diagnosis of IPA (proven/probable) were 86% and 95%, respectively. BALF GM was clearly superior to serum GM (ODI 0.5), which showed a sensitivity of 65% and specificity of 95%. In a large-cohort study, D’Haese et al. assessed the performance of BALF GM in a mixed population of at-risk patients (n: 251) including only 20.3% hematological patients, of whom 23.6% had a proven or probable IPA.4 Using a BALF GM ODI 0.8 (optimal optical density), sensitivity, specificity, and positive and negative predictive values were 86.4%, 90.7%, and 81% and 93.6%, respectively. Performance did not differ between neutropenic and nonneutropenic patients (p: 0.31), but no COPD patients were included.4 In contrast, culture of BAL fluid samples had a sensitivity of 72%. The same group confirmed similar results in a previous study with 110 patients,5 where the sensitivity of serum GM was only 42%.5 The sensitivity of BALF GM (ODI 1.0) in immunosuppressed patients in the current study was 81.8%. This value increased significantly by 18.2% with respect to BALF fungal
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Table 1 Baseline conditions (by patients) and type of disease and invasive pulmonary aspergillosis in patients with COPD and patients with ISC. Some patients shared more than 1 disease. Total patients: 188; total diseases: 224
IPA (PP) (n: 31)
Patients Male Hospitalization Intensive care unit admission Previous aspergillosis Systemic corticosteroids Inhaled corticosteroids Cavitary pulmonary infiltrate Concomitant bacteremia Previous antifungal therapy
121 (64.4%) 169 (89.9%) 40 (21.3%) 7 (3.7%) 163 (86.7%) 22 (11.7%) 32 (17.0%) 16 (8.5%) 4 (2.1%)
17 (54.8%) 30 (96.8%) 10 (32.3%) 4 (12.9%) 31 (100%) 9 (29.0%) 9 (29.0)% 7 (22.5%) 1 (3.2%)
Diseases COPD patients GOLD I GOLD II GOLD III GOLD IV
35 4 9 7 15
9 (25.7%) 0 0 2 (28.6%) 7 (46.6%)
ISC patients Chronic therapy with corticosteroids -Autoimmune disorder - Vasculitis - Glomerulonephritis and kidney diseases -Autoimmune hepatitis - Inflammatory bowel disease - Other Solid tumors - Lung - Skin (including melanoma and KS) - Colon - Genitourinary - Breast - Hepatocarcinoma - Other Solid organ transplants - Kidney transplant - Liver transplant HIV infection - <200 CD4/mm3 - 20e500 CD4/mm3
189 75 41 14 7 6 4 6 52 17 7 6 5 3 3 11 41 26 15 21 15 6
22 (11.6%) 11 (14.7%) 6 (14.6%) 2 (14.3%) 0 2 (33.3%) 1 (25%) 0 4 (7.7%) 1 (5.9%) 0 0 1 (20%) 0 2 (66.6%) 0 11 (26.8%) 5 (19.2%) 6 (40.0%) 0 0 0
COPD: chronic obstructive pulmonary disease. ISC: immunosuppressive conditions. PP: proven or probable. KS: Kaposi sarcoma. HIV: human immunodeficiency virus.
culture. These results are in line with those reported elsewhere, especially in solid organ transplant, where BALF GM is a valid tool for the diagnosis of IPA. In a study of 116 lung transplants, BALF GM (ODI 0.5) had a sensitivity of 67% and a specificity of 95%; when the ODI was raised to 1.0, sensitivity and specificity were 60% and 98%, respectively.17 Another study of lung transplants confirmed a sensitivity and specificity for BALF GM (ODI 1.0) of 100% and 91%, respectively.14 The present study did not examine lung transplantation, in which IPA is more prevalent. Only liver and kidney transplant are represented. Experience with BALF GM is scarce in patients with COPD, and threshold values are not clearly
established.13,14,18 Given the high degree of colonization by Aspergillus spp. in the airways of patients with COPD, the specificity and PPV of sputum/bronchial wash fungal culture were only 65.4% and 35.7%, respectively, in this series. Prattes et al.6 analyzed the role of BALF GM in 221 patients with no hematological malignancy or previous solid organ transplantation and a 14% frequency of proven/probable IPA. The performance of BALF GM (ODI 1.0) confirmed a sensitivity, specificity, and PPV and NPV of 97%, 93%, and 68% and 99%, respectively. These results were better than those obtained for b-D-glucan and lateral flow devices.6 A total of 67 patients (30%) had COPD, but no data were provided on performance of BALF GM in this
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Table 2 Performance of GM in BAL, GM in serum, BAL culture and sputum/bronchial wash culture in the diagnosis of IPA in patients with COPD and patients with ISC. Sensitivity (95%CI)
Specificity (95%CI)
PPV (95%CI)
NPV (95%CI)
COPD patients (n Z 35; IA Z 9) (prevalence: 25.7%)
(a) (b) (c) (d) (e) (f)
88.9% 66.7% 66.7% 11.1% 88.9% 55.6%
(68.4e100) (35.9e97.5) (35.9e97.5) (0e31.6) (68.4e100) (23.1e88.0)
88.4% 96.2% 96.0% 96.2% 96.2% 65.4%
(76.2e100) (88.8e100) (88.3e100) (88.8e100) (88.8e100) (47.1e83.7)
72.7% 85.7% 85.7% 50% 88.9% 35.7%
(46.4e99.0) (59.8e100) (59.8e100) (0e100) (68.4e100) (10.6e60.8)
95.8% 89.3% 88.9% 75.8% 96.2% 81.0%
(87.8e100) (77.8e100) (77.0e100) (61.1e90.4) (88.8e100) (64.2e97.7)
ISC patients (n Z 153; IA Z 22) (prevalence: 14.4%)
(a) (b) (c) (d) (e) (f)
86.4% 81.8% 72.7% 36.4% 63.6% 50.0%
(72.0e100) (65.7e97.9) (54.1e91.3) (16.3e56.5) (43.5e83.7) (29.1e70.9)
83.9% 93.9% 93.9% 93.9% 95.4% 91.6%
(78.6e90.9) (89.8e98.0) (89.8e98.0) (89.8e98.0) (91.8e99.0) (86.9e96.4)
48.7% 69.2% 66.7% 50% 70% 50%
(33.0e64.4) (51.5e87.0) (47.8e85.5) (25.5e74.5) (49.9e90.1) (29.1e70.9)
97.3% 96.9% 95.3% 89.8% 94.0% 91.6%
(94.4e100) (93.8e99.9) (91.7e99.0) (84.7e94.9) (89.9e98.0) (86.9e96.4)
(a) GM in BAL (ODI 0.5); (b) GM in BAL (ODI 1.0); (c) GM in BAL (ODI 1.5); (d) GM in serum (ODI 0.5); (e) Isolation of Aspergillus spp. in BAL culture; (f) Isolation of Aspergillus spp. in sputum or bronchial wash culture. GM: galactomannan. BAL: bronchoalveolar lavage. IPA: invasive pulmonary aspergillosis. PP: proven or probable. COPD: chronic obstructive pulmonary disease. ISC: immunosuppressive conditions. PPV: positive predictive value. NPV: negative predictive value.
group. In a study of 34 COPD patients admitted to the ICU with suspected IPA in Korea, He et al.14 confirmed the superiority of BALF GM over serum GM and lower respiratory tract culture. The optimal ODI for BALF GM was 0.8, with sensitivity, specificity, and positive and negative predictive values of 88.9%, 100%, and 100% and 94.4%, respectively.14 Lower respiratory tract fungal culture (including sputum and endotracheal aspiration) revealed sensitivity for IPA of 67% and a diagnostic delay of 3 days with respect to BALF GM.14 Similarly, in the present study, the sensitivity of sputum/tracheo-bronchial wash culture in COPD patients was lower (55.6%) than that of BALF GM. However, selective culture of BALF in COPD patients (not expressed in the
study by He et al.) revealed a sensitivity of 88.9%, which is higher than that obtained with BALF GM (ODI 1.0) (66.7%) and comparable to that of BALF GM (ODI 0.5) (88.9%). This high performance of BALF fungal culture in COPD patients in the present study may be clinically relevant, because the classic poor positive predictive value associated with respiratory tract culture in this group in many studies is probably not applicable to BALF, in which the finding of Aspergillus is associated with IPA. In fact, in the present study a lower ODI for BALF GM (0.5 vs 1.0) increased sensitivity in COPD patients, with similar specificity and positive predictive values. Studies performed in patients with aspergilloma have also documented a higher
Figure 1 Receiver operating characteristic curves for BALF GM (1a) and serum GM (1b). The area under the curve was 0.92 (95% Q5 CI, 0.86e0.97) for BALF GM and 0.60 (95%CI: 0.46e0.74) for serum GM. n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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sensitivity of BALF GM, although pathogenicity was different and a high inoculum of Aspergillus was demonstrated in BALF in the absence of invasion.20 Our findings for serum GM confirm a lower sensitivity in patients with immunosuppressive conditions and in COPD patients than in hematological patients. We previously confirmed a sensitivity of only 56% in the diagnosis of IPA in liver recipients,21 and a sensitivity <50% has been reported in a systematic review of the literature for non-hematologyeoncology patients.22 The value of serum GM in patients with COPD and a risk of IPA has been evaluated in several studies,23e25 with sensitivity ranging between 30% and 60%. This reduced sensitivity has been linked to two factors: increased clearance of GM by circulating neutrophils and lower angio-invasiveness of Aspergillus spp.26 Studies performed in hematological patients have shown a lower sensitivity of BALF GM in patients with a high degree of antifungal exposure.27,28 Given the lower suspicion of IPA, the number of patients receiving antifungal therapy in this series when BALF was obtained was low (<10%), with a minimal impact on the performance of diagnostic procedures. The present study is subject to a series of limitations. First, it was retrospective. Second, the collection and processing of BALF samples has not yet been standardized. The volume of BALF usually retrieved after successive instillations of 20 ml of saline is low, especially for COPD patients. In addition, the variation in the volume retrieved is considerable and may influence the final concentration. Third, the number of patients included is low, especially COPD patients, since fiberoptic bronchoscopy is difficult to perform in severely ill COPD patients. Fourth, prioritization of cases meant that the prevalence of IPA in this study was artificially high (25.7% and 14.4% for COPD and immunosuppressed patients, respectively); therefore, predictive values should be interpreted with caution. Fifth, there is no guarantee that all patients correctly assessed by expert radiologists will fulfill the criteria for the airway pattern of IPA. Finally, our results may be subject to bias, since BALF GM, serum GM, and isolation of Aspergillus in the lower respiratory tract were included in the criteria to define IPA. By incorporating the test(s) under evaluation in the reference standard, sensitivity and specificity may appear to be higher than they really are. In summary, this multicenter, retrospective study suggests that BALF GM ODI 1.0 performed well in the diagnosis of IPA, especially in immunosuppressed patients. In COPD patients, BALF GM ODI 0.5 performed better than ODI 1.0. The sensitivity of serum GM is significantly low in both populations.
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Disclaimer The funding bodies had no involvement in the preparation of the manuscript.
Financial support Q7
This study was funded by a research grant from Pfizer.
Potential conflicts of interest The authors declare that they have no potential conflicts of interest.
Uncited reference
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19.
Acknowledgments We thank Thomas O’Boyle for his assistance in writing the manuscript.
References 1. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 2005;5(10):609e22. 2. Maertens J, Maertens V, Theunissen K, Meersseman W, Meersseman P, Meers S, et al. Bronchoalveolar lavage fluid galactomannan for the diagnosis of invasive pulmonary aspergillosis in patients with hematologic diseases. Clin Infect Dis 2009;49(11):1688e93. 3. Kousha M, Tadi R, Soubani AO. Pulmonary aspergillosis: a clinical review. Eur Respir Rev 2011;2011(20):156e74. 4. 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(4):1258e63. 5. Meersseman W, Lagrou K, Maertens J, Wilmer A, Hermans G, Vanderschueren S, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med 2008;177:27e34. €ller F, Koidl C, Raggam RB, Palfner M, 6. Prattes J, Flick H, Pru et al. Novel tests for diagnosis of invasive aspergillosis in patients with underlying respiratory diseases. Am J Respir Crit Care Med 2014;190(8):922e9. 7. EORTC Criteria, De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, et alEuropean Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative GroupNational Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. 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 Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008;46(12):1813e21. 8. Blot SI, Taccone FS, Van den Abeele AM, Bulpa P, Meersseman W, Brusselaers N, et alStudy Investigators. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012 Jul 1; 186(1):56e64. 9. Bulpa P, Dive A. Diagnosis of invasive bronchial-pulmonary aspergillosis in patients with chronic obstructive respiratory diseases. Crit Care 2011;15(2):420. 10. Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Respir J 2007 Oct;30(4):782e800. Review. Erratum in: Eur Respir Q8 J. 2007 Dec;30(6):1236. 11. Gavalda J, Len O, San Juan R, Aguado JM, Fortun J, Lumbreras C, et al. Risk factors for invasive aspergillosis in solid-organ transplant recipients: a case-control study. Clin Infect Dis 2005;41:52e9.
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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12. Munoz P, Vena A, Ceron I, Valerio M, Palomo J, Guinea J, et al. Invasive pulmonary aspergillosis in heart transplant recipients: two radiologic patterns with a different prognosis. J Heart Lung Transpl 2014;33:1034e40. 13. Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van Wijngaerden E. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004;170(6):621e5. 14. He H, Ding L, Sun B, Li F, Zhan Q. Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. Crit Care 2012;16(4):R138. 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(8):e43347. doi. 16. Guo YL, Chen YQ, Wang K, Qin SM, Wu C, Kong JL. Accuracy of BAL galactomannan in diagnosing invasive aspergillosis: a bivariate metaanalysis and systematic review. Chest 2010; 138(4):817e24. 17. Husain S, Paterson DL, Studer SM, Crespo M, Pilewski J, Durkin M, et al. Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients. Transplantation 2007; 83(10):1330e6. 18. Ader F. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: an emerging fungal disease. Curr Infect Dis Rep 2010;12(6):409e16. 19. Clancy CJ, Jaber RA, Leather HL, Wingard JR, Staley B, Wheat LJ, et al. Bronchoalveolar lavage galactomannan in diagnosis of invasive pulmonary aspergillosis among solidorgan transplant recipients. J Clin Microbiol 2007 Jun;45(6): 1759e65. 20. Park SY, Lee SO, Choi SH, Jeong JY, Sung H, Kim MN, et al. Serum and bronchoalveolar lavage fluid galactomannan assays
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in patients with pulmonary aspergilloma. Clin Infect Dis 2011; 52(7):e149e52. Fortun J, Martin-Davila P, Alvarez ME, Sanchez-Sousa A, Quereda C, Navas E, et al. Aspergillus antigenemia sandwichenzyme immunoassay test as a serodiagnostic method for invasive aspergillosis in liver transplant recipients. Transplantation 2001 Jan 15;71(1):145e9. 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 Oct 8;(4). CD007394. He H, Ding L, Chang S, Li F, Zhan Q. Value of consecutive galactomannan determinations for the diagnosis and prognosis of invasive pulmonary aspergillosis in critically ill chronic obstructive pulmonary disease. Med Mycol 2011;49(4):345e51. He H, Ding L, Li F, Zhan Q. Clinical features of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive respiratory diseases: a prospective study. Crit Care 2011;15(1):R5. http://dx.doi.org/10.1186/cc9402. n P, Mun ~oz P, Pozo F, Guinea J, Torres-Narbona M, Gijo ez T, et al. Pulmonary aspergillosis in patients with chronic Pela obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010;16(7):870e7. Mennink-Kersten MA, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis 2004;4(6):349e57. Affolter K, Tamm M, Jahn K, Halter J, Passweg J, Hirsch HH, et al. Galactomannan in bronchoalveolar lavage for diagnosing invasive fungal disease. Am J Respir Crit Care Med 2014 Aug 1; 190(3):309e17. Fisher CE, Stevens AM, Leisenring W, Pergam SA, Boeckh M, Hohl TM. Independent contribution of bronchoalveolar lavage and serum galactomannan in the diagnosis of invasive pulmoQ1 nary aspergillosis. Transpl Infect Dis 2014;16(3):505e10.
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in non-hematological patients* vila a, E. Gomez Garcia de la Pedrosa b, n a,*, P. Martı´n-Da J. Fortu J.T. Silva c, J. Garcia-Rodrı´guez d, D. Benito a, E. Venanzi a, ~ o a, M. Ferna ndez-Ruiz c, F. Lazaro d, R. Garcı´a-Luja n e, F. Castan d f a c I. Quiles , J.J. Cabanillas , S. Moreno , J.M. Aguado Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Instituto de Investigacion Ramon y Cajal (IRYCIS), Universidad de Alcala, Madrid, Spain b Department of Microbiology, Hospital Universitario Ramon y Cajal, Instituto de Investigacion Ramon y Cajal (IRYCIS), Universidad de Alcala, Madrid, Spain c Unit of Infectious Diseases, Hospital Universitario “12 de Octubre”, Instituto de Investigacion Hospital “12 de Octubre”, Universidad Complutense, Madrid, Spain d Department of Microbiology, Hospital Universitario La Paz, Instituto de Investigacion Hospital Universitario La Paz (IdiPAZ), Universidad Autonoma, Madrid, Spain e Department of Pneumology, Hospital Universitario “12 de Octubre”, Instituto de Investigacion Hospital “12 de Octubre”, Universidad Complutense, Madrid, Spain f Department of Pneumology, Hospital Universitario La Paz, Instituto de Investigacion Hospital Universitario La Paz (IdiPAZ), Universidad Autonoma, Madrid, Spain a
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Accepted 26 February 2016 Available online - - -
KEYWORDS Galactomannan; Bronchoalveolar lavage fluid; Invasive aspergillosis
Summary Background: The role of galactomannan (GM) in serum or bronchoalveolar lavage fluid (BALF) for the diagnosis of invasive pulmonary aspergillosis (IPA) has been extensively evaluated in hematological patients, however its performance in non-hematological patients is not well established. Methods: We performed a multicenter retrospective study in 3 university hospitals in Madrid, Spain between 2010 and 2014. The study population comprised patients with chronic obstructive pulmonary disease (COPD) and patients with immunosuppressive conditions in whom IPA
~ ola de Investigacio n en Patologı´a Infecciosa; SEIMC, Sociedad Espan ~ola de Enfermedades Infecciosas y MiAbbreviations: REIPI, Red Espan crobiologı´a Clı´nica. * The study was presented in part at ICAAC 2015, San Diego, California (USA), 17e21 September, 2015. Q3 * Corresponding author. Department of Infectious Diseases, Hospital Universitario Ramon y Cajal, Carretera Colmenar km 9,1, 28034 Madrid, Spain. n). E-mail address: [email protected] (J. Fortu http://dx.doi.org/10.1016/j.jinf.2016.02.019 0163-4453/ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association. n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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was suspected and for whom BALF GM was available. Patients with hematological disorders were excluded. Results: A total of 188 patients (35 with COPD and 153 with immunosuppressive conditions) were analyzed, and 31 cases of IPA (proven or probable) were identified. The global sensitivity of BALF GM (optical density index [ODI] 1.0) was 77.4%; sensitivity was higher in patients with immunosuppressive conditions than in patients with COPD (81.8% vs 66.7%; p: 0.38). In COPD patients, the best performance was obtained for BALF GM (ODI 0.5), although sensitivity (88.9%) was similar to that of BALF fungal culture (88.9%). The sensitivity of GM in serum was very poor in both populations (36.4% and 11.6%, respectively). Conclusions: In the present series, the diagnostic performance of BALF GM was good for IPA in non-hematological patients, especially in patients with immunosuppressive conditions. ª 2016 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction The role of galactomannan (GM) in bronchoalveolar lavage fluid (BALF) in the diagnosis of invasive pulmonary aspergillosis (IPA) has been widely discussed in neutropenic and hemato-oncological patients.1,2 Most studies confirm that the sensitivity of BALF GM is higher than that of serum GM. The many groups of patients identified as being at risk for IPA include solid organ recipients, patients receiving long-term therapy with corticosteroids, patients with chronic obstructive pulmonary disease (COPD), patients admitted to intensive care units (especially patients with advanced liver cirrhosis), and patients receiving immunomodulating drugs for the treatment of autoimmune disorders and solid tumors.3 BALF GM seems to be the method of choice for diagnosis of IPA in patients who develop airwayinvasive forms,4e6 although it is difficult to know the real performance of BALF GM in non-hematological patients because of differences in immunosuppression, differences in the prevalence of IPA, and the low number of studies within this population. The objectives of the present study were to analyze the performance of BALF GM in COPD patients and in patients with immunosuppressive conditions other than oncohematological diseases.
Methods The study was approved by the Institutional Review Board of Hospital Ramon y Cajal, Madrid, Spain and supported by Ministerio de Economı´a y Competitividad, Instituto de Salud Carlos III (co-funded by the European Development Regional Fund “A way to achieve Europe” ERDF) and the Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015). We performed an observational retrospective cohort study from 2010 to 2014 in 3 university hospitals in Madrid, Spain: Hospital Ramon y Cajal, Hospital La Paz, and Hospital 12 de Octubre. The criteria proposed by the European Organization for Research and Treatment in Cancer and the Mycoses Study Group for diagnosis of IPA were applied for patients with immunosuppressive conditions.7 As previously stated, critically ill patients with COPD, patients receiving long-term therapy with corticosteroids, solid organ recipients, HIVinfected patients with <200 CD4/mm3, patients with cirrhosis
and patients receiving immunomodulating drugs for the treatment of autoimmune disorders or solid tumors were included in the analysis as host factors.4,5 However, because the radiological consensus criteria are less specific for IPA in these groups, the presence of pulmonary infiltrates or consolidations not responding to broad-spectrum antibacterial coverage was considered a radiological criterion.3e5 This amendment adapts more favorably to the diagnostic criteria of IPA in non-hematological patients proposed by Blot et al.8 and Bulpa et al.9,10 In summary, a diagnosis of “probable IPA” was established based on the simultaneous presence of at least 1 host factor, 1 radiological criterion, and 1 mycological criterion. The modified radiological criteria respond to previous clinical experience suggesting that IPA in patients with COPD or immunosuppressive conditions may be accompanied by lung infiltrates (i.e., peribronchial consolidation or tree-in-bud pattern) that differ from the typical signs observed in hematological patients.11,12 The microbiological criteria included any of the following: a) recovery of Aspergillus spp. in culture from sputum, BALF, or bronchial brush samples; b) a positive serum GM result (ODI 0.5) confirmed in 2 samples; or c) a positive BALF GM result (ODI 1.0). The cutoff of ODI 1.0 for BALF GM was accepted because it was routinely used for the diagnosis of IPA in the 3 hospitals, according to previous reports.2,11,13e16 GM was performed as recommended by the manufacturer (Platelia Aspergillus; Sanofi Diagnostics Pasteur, Marnes-La-Coquette, France). The diagnosis of “possible IPA” was based only on host factors and radiological criteria. The initial population comprised all adult patients (age >18 years) with COPD or other immunosuppressive conditions, in the absence of neutropenia (<500 cells/ml) or hematologic diseases, with suspected IPA in whom BALF GM was available. COPD was classified following the GOLD criteria. All COPD patients had an FEV1/FVC ratio < 0.70. FEV was classified as follows: stage I, FEV1 80% of normal; stage II, FEV1 50e79% of normal; stage III, FEV1 30e49% of normal; stage IV, FEV1 < 30% of normal or <50% normal with chronic respiratory failure. Immunosuppressive conditions included any of the following: a) chronic therapy with corticosteroids (>15 mg/day, >4 weeks); b) solid tumors managed with chemotherapy or immunomodulating drugs in the absence of prolonged neutropenia (<500 cell/ml); c) solid organ transplants; and d) HIV infection with <200 CD4/mm3. A single on-line database was used. The application included epidemiological, clinical, diagnostic, imaging, therapeutic, and prognostic variables.
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Experienced personnel performed all bronchoscopies. BAL was obtained after instillation of at least 20 ml of saline 1e3 times in the affected area or, failing that, the bronchoscope was wedged into the middle lobe bronchus. Statistical analysis: The McNemar c2 test was used to compare sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) between the assays. The univariate analysis of contingency data was performed using a c2 test or Fisher exact test. Although an ODI ratio 1.0 in BALF GM was considered a priori as a reference for the diagnosis of IPA, receiver operating characteristic (ROC) curve analysis was used to establish the BALF GM that best distinguished IPA in patients with COPD and patients with immunosuppressive conditions. The analyses were performed using IBM SPSS Statistics for Windows, Version 19.0 (IBM Corp., Armonk, NY, USA).
Results A total of 188 patients were analyzed during the study period. No hematological patients, neutropenic patients, or recipients of autologous or allogeneic hematopoietic progenitors were included. A total of 31 cases of proven/ probable IA (16.5%) and 34 cases of proven/probable/ possible IA (18.1%) were confirmed. BALF GM was available in all cases. COPD was recorded in 35 patients and immunosuppressive conditions in 153. The 188 patients were affected by 224 (35 þ 189) immunosuppressive conditions, because several patients shared more than 1 type of immunosuppression (Table 1). All COPD patients were included in the COPD group, although 20 shared other immunosuppressive conditions. A total of 153 patients presented 189 immunosuppressive conditions (solid tumor, 52; solid organ transplant, 41; HIV infection, 21; and chronic illnesses requiring corticosteroid maintenance of at least 15 mg/d for more than 4 weeks, 75). Table 1 shows the baseline conditions and characteristics of the patients and the frequency of IPA (proven/probable). Most cases of IPA occurred in solid organ recipients and in patients with COPD. No cases of IPA were confirmed in patients with HIV infection. All patients with COPD and IPA had advanced stages of COPD (GOLD III or IV). Overall mortality in both groups (COPD and immunosuppressive conditions) was over 40%. The sensitivity, specificity, PPV, and NPV of the different microbiologic diagnostic tests are presented in Table 2. Although BALF GM (ODI 1) and serum GM (ODI 0.5) were considered diagnostic criteria of IPA a priori, Table 2 shows the performance of BALF GM with 3 different cutoffs: ODI 0.5, ODI 1.0, and ODI 1.5. Table 2 also shows the performance of serum GM (ODI > 0.5), isolation of Aspergillus spp. in BALF culture, and isolation of Aspergillus in sputum/or bronchial wash culture. The overall prevalence of IPA (proven/probable) in this study was 16.5% (31/188), 14.4% for patients with immunosuppressive conditions, and 25.7% for patients with COPD. BALF GM (ODI 1.0) had an overall sensitivity of 77.4%, although this was higher in patients with immunosuppressive conditions (81.8%) than in patients with COPD (66.7%); p: 0.38. For patients with immunosuppressive conditions, the optimal BALF GM ODI was 1.0 (sensitivity,
3 81.8%; specificity, 93.9%; PPV, 69.2%; and NPV, 96.9%). However, for COPD patients, a BALF GM ODI 0.5 (sensitivity, 88.9%; specificity, 88.4%; PPV, 72.7%; and NPV, 95.8%) performed better than BALF GM ODI 1.0 (sensitivity, 66.7%; specificity, 96.2%; PPV, 85.7%; and NPV, 89.3%). With specificity similar to that of BALF GM ODI 1.0, BALF GM ODI 1.5 presented a lower sensitivity in all patients. The sensitivity of sputum or bronchial wash fungal culture was similar in both groups (z50%), although that of BALF fungal culture was slightly higher in patients with COPD (88.9%) than in patients with immunosuppressive conditions (63.6%); p: 0.2. On the other hand, the sensitivity of serum GM for the threshold value considered for diagnosis (ODI 0.5 in 2 samples) was very low in both groups of patients (11.1% and 36.4%, respectively). The superiority of BALF GM and the estimation of differences between the diagnostic procedures are shown using ROC curves (Fig. 1). The areas under the curve (AUC) of BALF GM and serum GM were 0.92 (95%CI: 0.86e0.97) and 0.60 (95%CI: 0.46e0.74), respectively.
Discussion This study analyzes two groups of patients: (a) a heterogeneous population of immunocompromised patients, with cellular immunosuppression, and (b) a population of patients with advanced COPD, some of whom also had other immunosuppressive conditions. Unlike neutropenic and hematological patients, in whom IPA mainly has an angio-invasive pattern, the dominating pattern in other patients is airway-invasive. Despite the presence of common airway-invasive pattern in immunosuppressed and COPD patients,12 we performed a separate analysis of both populations given the frequent colonization of the bronchial tree by Aspergillus spp. in patients with COPD. Two recent meta-analyses evaluated the performance of BALF GM in hematological patients.15,16 The more recent study analyzed 13 studies including more than 3000 patients.15 The optimal ODI of BALF GM was 1.0. For this value, the sensitivity and specificity of BALF GM in the diagnosis of IPA (proven/probable) were 86% and 95%, respectively. BALF GM was clearly superior to serum GM (ODI 0.5), which showed a sensitivity of 65% and specificity of 95%. In a large-cohort study, D’Haese et al. assessed the performance of BALF GM in a mixed population of at-risk patients (n: 251) including only 20.3% hematological patients, of whom 23.6% had a proven or probable IPA.4 Using a BALF GM ODI 0.8 (optimal optical density), sensitivity, specificity, and positive and negative predictive values were 86.4%, 90.7%, and 81% and 93.6%, respectively. Performance did not differ between neutropenic and nonneutropenic patients (p: 0.31), but no COPD patients were included.4 In contrast, culture of BAL fluid samples had a sensitivity of 72%. The same group confirmed similar results in a previous study with 110 patients,5 where the sensitivity of serum GM was only 42%.5 The sensitivity of BALF GM (ODI 1.0) in immunosuppressed patients in the current study was 81.8%. This value increased significantly by 18.2% with respect to BALF fungal
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Table 1 Baseline conditions (by patients) and type of disease and invasive pulmonary aspergillosis in patients with COPD and patients with ISC. Some patients shared more than 1 disease. Total patients: 188; total diseases: 224
IPA (PP) (n: 31)
Patients Male Hospitalization Intensive care unit admission Previous aspergillosis Systemic corticosteroids Inhaled corticosteroids Cavitary pulmonary infiltrate Concomitant bacteremia Previous antifungal therapy
121 (64.4%) 169 (89.9%) 40 (21.3%) 7 (3.7%) 163 (86.7%) 22 (11.7%) 32 (17.0%) 16 (8.5%) 4 (2.1%)
17 (54.8%) 30 (96.8%) 10 (32.3%) 4 (12.9%) 31 (100%) 9 (29.0%) 9 (29.0)% 7 (22.5%) 1 (3.2%)
Diseases COPD patients GOLD I GOLD II GOLD III GOLD IV
35 4 9 7 15
9 (25.7%) 0 0 2 (28.6%) 7 (46.6%)
ISC patients Chronic therapy with corticosteroids -Autoimmune disorder - Vasculitis - Glomerulonephritis and kidney diseases -Autoimmune hepatitis - Inflammatory bowel disease - Other Solid tumors - Lung - Skin (including melanoma and KS) - Colon - Genitourinary - Breast - Hepatocarcinoma - Other Solid organ transplants - Kidney transplant - Liver transplant HIV infection - <200 CD4/mm3 - 20e500 CD4/mm3
189 75 41 14 7 6 4 6 52 17 7 6 5 3 3 11 41 26 15 21 15 6
22 (11.6%) 11 (14.7%) 6 (14.6%) 2 (14.3%) 0 2 (33.3%) 1 (25%) 0 4 (7.7%) 1 (5.9%) 0 0 1 (20%) 0 2 (66.6%) 0 11 (26.8%) 5 (19.2%) 6 (40.0%) 0 0 0
COPD: chronic obstructive pulmonary disease. ISC: immunosuppressive conditions. PP: proven or probable. KS: Kaposi sarcoma. HIV: human immunodeficiency virus.
culture. These results are in line with those reported elsewhere, especially in solid organ transplant, where BALF GM is a valid tool for the diagnosis of IPA. In a study of 116 lung transplants, BALF GM (ODI 0.5) had a sensitivity of 67% and a specificity of 95%; when the ODI was raised to 1.0, sensitivity and specificity were 60% and 98%, respectively.17 Another study of lung transplants confirmed a sensitivity and specificity for BALF GM (ODI 1.0) of 100% and 91%, respectively.14 The present study did not examine lung transplantation, in which IPA is more prevalent. Only liver and kidney transplant are represented. Experience with BALF GM is scarce in patients with COPD, and threshold values are not clearly
established.13,14,18 Given the high degree of colonization by Aspergillus spp. in the airways of patients with COPD, the specificity and PPV of sputum/bronchial wash fungal culture were only 65.4% and 35.7%, respectively, in this series. Prattes et al.6 analyzed the role of BALF GM in 221 patients with no hematological malignancy or previous solid organ transplantation and a 14% frequency of proven/probable IPA. The performance of BALF GM (ODI 1.0) confirmed a sensitivity, specificity, and PPV and NPV of 97%, 93%, and 68% and 99%, respectively. These results were better than those obtained for b-D-glucan and lateral flow devices.6 A total of 67 patients (30%) had COPD, but no data were provided on performance of BALF GM in this
n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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Table 2 Performance of GM in BAL, GM in serum, BAL culture and sputum/bronchial wash culture in the diagnosis of IPA in patients with COPD and patients with ISC. Sensitivity (95%CI)
Specificity (95%CI)
PPV (95%CI)
NPV (95%CI)
COPD patients (n Z 35; IA Z 9) (prevalence: 25.7%)
(a) (b) (c) (d) (e) (f)
88.9% 66.7% 66.7% 11.1% 88.9% 55.6%
(68.4e100) (35.9e97.5) (35.9e97.5) (0e31.6) (68.4e100) (23.1e88.0)
88.4% 96.2% 96.0% 96.2% 96.2% 65.4%
(76.2e100) (88.8e100) (88.3e100) (88.8e100) (88.8e100) (47.1e83.7)
72.7% 85.7% 85.7% 50% 88.9% 35.7%
(46.4e99.0) (59.8e100) (59.8e100) (0e100) (68.4e100) (10.6e60.8)
95.8% 89.3% 88.9% 75.8% 96.2% 81.0%
(87.8e100) (77.8e100) (77.0e100) (61.1e90.4) (88.8e100) (64.2e97.7)
ISC patients (n Z 153; IA Z 22) (prevalence: 14.4%)
(a) (b) (c) (d) (e) (f)
86.4% 81.8% 72.7% 36.4% 63.6% 50.0%
(72.0e100) (65.7e97.9) (54.1e91.3) (16.3e56.5) (43.5e83.7) (29.1e70.9)
83.9% 93.9% 93.9% 93.9% 95.4% 91.6%
(78.6e90.9) (89.8e98.0) (89.8e98.0) (89.8e98.0) (91.8e99.0) (86.9e96.4)
48.7% 69.2% 66.7% 50% 70% 50%
(33.0e64.4) (51.5e87.0) (47.8e85.5) (25.5e74.5) (49.9e90.1) (29.1e70.9)
97.3% 96.9% 95.3% 89.8% 94.0% 91.6%
(94.4e100) (93.8e99.9) (91.7e99.0) (84.7e94.9) (89.9e98.0) (86.9e96.4)
(a) GM in BAL (ODI 0.5); (b) GM in BAL (ODI 1.0); (c) GM in BAL (ODI 1.5); (d) GM in serum (ODI 0.5); (e) Isolation of Aspergillus spp. in BAL culture; (f) Isolation of Aspergillus spp. in sputum or bronchial wash culture. GM: galactomannan. BAL: bronchoalveolar lavage. IPA: invasive pulmonary aspergillosis. PP: proven or probable. COPD: chronic obstructive pulmonary disease. ISC: immunosuppressive conditions. PPV: positive predictive value. NPV: negative predictive value.
group. In a study of 34 COPD patients admitted to the ICU with suspected IPA in Korea, He et al.14 confirmed the superiority of BALF GM over serum GM and lower respiratory tract culture. The optimal ODI for BALF GM was 0.8, with sensitivity, specificity, and positive and negative predictive values of 88.9%, 100%, and 100% and 94.4%, respectively.14 Lower respiratory tract fungal culture (including sputum and endotracheal aspiration) revealed sensitivity for IPA of 67% and a diagnostic delay of 3 days with respect to BALF GM.14 Similarly, in the present study, the sensitivity of sputum/tracheo-bronchial wash culture in COPD patients was lower (55.6%) than that of BALF GM. However, selective culture of BALF in COPD patients (not expressed in the
study by He et al.) revealed a sensitivity of 88.9%, which is higher than that obtained with BALF GM (ODI 1.0) (66.7%) and comparable to that of BALF GM (ODI 0.5) (88.9%). This high performance of BALF fungal culture in COPD patients in the present study may be clinically relevant, because the classic poor positive predictive value associated with respiratory tract culture in this group in many studies is probably not applicable to BALF, in which the finding of Aspergillus is associated with IPA. In fact, in the present study a lower ODI for BALF GM (0.5 vs 1.0) increased sensitivity in COPD patients, with similar specificity and positive predictive values. Studies performed in patients with aspergilloma have also documented a higher
Figure 1 Receiver operating characteristic curves for BALF GM (1a) and serum GM (1b). The area under the curve was 0.92 (95% Q5 CI, 0.86e0.97) for BALF GM and 0.60 (95%CI: 0.46e0.74) for serum GM. n J, et al., Galactomannan in bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis in Please cite this article in press as: Fortu non-hematological patients, J Infect (2016), http://dx.doi.org/10.1016/j.jinf.2016.02.019
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sensitivity of BALF GM, although pathogenicity was different and a high inoculum of Aspergillus was demonstrated in BALF in the absence of invasion.20 Our findings for serum GM confirm a lower sensitivity in patients with immunosuppressive conditions and in COPD patients than in hematological patients. We previously confirmed a sensitivity of only 56% in the diagnosis of IPA in liver recipients,21 and a sensitivity <50% has been reported in a systematic review of the literature for non-hematologyeoncology patients.22 The value of serum GM in patients with COPD and a risk of IPA has been evaluated in several studies,23e25 with sensitivity ranging between 30% and 60%. This reduced sensitivity has been linked to two factors: increased clearance of GM by circulating neutrophils and lower angio-invasiveness of Aspergillus spp.26 Studies performed in hematological patients have shown a lower sensitivity of BALF GM in patients with a high degree of antifungal exposure.27,28 Given the lower suspicion of IPA, the number of patients receiving antifungal therapy in this series when BALF was obtained was low (<10%), with a minimal impact on the performance of diagnostic procedures. The present study is subject to a series of limitations. First, it was retrospective. Second, the collection and processing of BALF samples has not yet been standardized. The volume of BALF usually retrieved after successive instillations of 20 ml of saline is low, especially for COPD patients. In addition, the variation in the volume retrieved is considerable and may influence the final concentration. Third, the number of patients included is low, especially COPD patients, since fiberoptic bronchoscopy is difficult to perform in severely ill COPD patients. Fourth, prioritization of cases meant that the prevalence of IPA in this study was artificially high (25.7% and 14.4% for COPD and immunosuppressed patients, respectively); therefore, predictive values should be interpreted with caution. Fifth, there is no guarantee that all patients correctly assessed by expert radiologists will fulfill the criteria for the airway pattern of IPA. Finally, our results may be subject to bias, since BALF GM, serum GM, and isolation of Aspergillus in the lower respiratory tract were included in the criteria to define IPA. By incorporating the test(s) under evaluation in the reference standard, sensitivity and specificity may appear to be higher than they really are. In summary, this multicenter, retrospective study suggests that BALF GM ODI 1.0 performed well in the diagnosis of IPA, especially in immunosuppressed patients. In COPD patients, BALF GM ODI 0.5 performed better than ODI 1.0. The sensitivity of serum GM is significantly low in both populations.
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Disclaimer The funding bodies had no involvement in the preparation of the manuscript.
Financial support Q7
This study was funded by a research grant from Pfizer.
Potential conflicts of interest The authors declare that they have no potential conflicts of interest.
Uncited reference
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19.
Acknowledgments We thank Thomas O’Boyle for his assistance in writing the manuscript.
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