The role of galactomannan testing to diagnose invasive pulmonary aspergillosis in critically ill patients
Editorial

The role of galactomannan testing to diagnose invasive pulmonary aspergillosis in critically ill patients

Maya Hites1, Eduardo Wilfrido Goicoechea Turcott2, Fabio Silvio Taccone2

1Department of Infectious Diseases, 2Department of Intensive Care Unit, Hopital Erasme, Université Libre de Bruxelles, Brussels, Belgium

Correspondence to: Prof. Fabio Silvio Taccone. Department of Intensive Care Unit, Hopital Erasme, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Email: ftaccone@ulb.ac.be.

Submitted Jul 18, 2016. Accepted for publication Jul 20, 2016.

doi: 10.21037/atm.2016.08.32


Invasive aspergillosis (IA) is an opportunistic infection caused by Aspergillus spp., a saprophytic filamentous fungus that is frequently isolated in the environment. The infection occurs most frequently in the lower respiratory tract (LRT) of immunocompromised patients with prolonged neutropenia or hematopoietic organ transplants (1,2). Significant progress has been made over the last 20 years in the development of diagnostic tools and decision algorithms as well as of effective antifungal drugs for IA (3), allowing for improved outcomes in non-critically ill immunocompromised patients due to the rapid initiation of appropriate therapy (4).

Symptoms or signs suggestive of invasive pulmonary aspergillosis (IPA) are fever refractory to at least 3 days of appropriate antibiotic therapy, recrudescent fever after a period of defervescence of at least 48 hours while still on antibiotics, pleuritic chest pain or rub, dyspnea, hemoptysis, or worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilatory support (5). Nevertheless, these symptoms are not specific for IPA and may result in under-diagnosing of this infectious disease, in particular in those patients without evidence of Aspergillus from tracheal aspirate or sputum. Thus, the European Organization for the Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) has developed a combination of diagnostic criteria that can differentiate patients with “proven”, “probable”, and “possible” IPA from those with Aspergillus colonization (5). These criteria include chest imaging based on computed tomography (CT-scan), the presence of “host factors”, direct and indirect positive mycological tests and positive histopathology results. In particular, the “typical” signs of IPA on chest CT-scan are dense, well-circumscribed lesions with or without a “halo” sign (e.g., a region of ground-glass attenuation surrounding a pulmonary nodule), an air-crescent sign or pulmonary cavity. Host factors are a history of severe neutropenia (less than 500 neutrophils/mm3) for at least 10 days, allogenic stem-cell transplant recipient, prolonged corticosteroids use (≥20 mg/day of prednisolone or equivalent for at least 3 weeks), T-cell immunosuppressant treatment during the previous 3 months and inherited severe immunodeficiency. Positive mycology results refer to positive direct (e.g., identification of Aspergillus spp. by direct microscopy, culture, or cytology on LRT or sterile pulmonary samples) and indirect tests (e.g., high levels of detect antigen or cell-wall constituents either in blood or LRT sampling). Histo-pathological evidence of IPA must show tissue invasion branching filamentous fungi with septae on lung or tracheal biopsy. As such, proven IPA refers to a patient with histopathological evidence of IPA; probable IPA requires the simultaneous presence of at least one host factor, one clinical feature and the mycological evidence of Aspergillus in the LRT; possible IPA requires that a host factor and clinical features are present, without mycological positive tests (5).

Recently, IA has also been recognized as an emerging infectious disease associated with high morbidity, mortality and healthcare costs in critically ill patients without traditional risk factors for the disease (6-9). This issue was well depicted by the increase in the prevalence of invasive fungal infections from 2.2% to 5.1% over a 12-year period, mostly due to an increase in the rate of Aspergillus infection, reported in a non-selected patient population at an academic hospital (10). Currently, incidence and mortality rates due to IA in critically ill patients vary widely from 0.02% to 19%, and from 46% to 95%, respectively (7,11). This large variability is probably due to the great heterogeneity of the different patient populations included in these studies as well as the poor performance of diagnostic criteria that were applied in these patients. Indeed, post-mortem samplings are sometimes the only proof of IPA in critically ill non-survivors and several studies have shown that invasive fungal infections are the most commonly missed diagnoses in ICU patients (12-14). These data clearly underline a knowledge gap in the accuracy of diagnostic algorithms used in this setting. As such, clinical and radiological presentation of IPA is often non-specific and lung biopsy is frequently contraindicated in critically ill patients (7,15). Also, risk factors for IPA in these patients include chronic obstructive pulmonary disease (COPD), short-term corticosteroid use, acute respiratory distress syndrome (ARDS), severe sepsis, H1N1 virus infection, decompensated chronic liver disease and acute renal failure (7-9). However, as these conditions are not recognized among the EORTC/MSG diagnostic criteria, most of IPA in critically ill patients is considered as “non-classifiable” (15).

A significant improvement in IPA has been recently made by the development of an “easy-to-use” decisional algorithm (the “AspICU” decision tree), which showed a high predictive negative value for IPA and could help clinicians to distinguish colonization from IPA (15). Moreover, the definition of “putative” IPA was created to classify those patients who had Aspergillus positive LRT samples, compatible clinical symptoms, an abnormal chest X-ray or CT-scan and either typical host factors or positive Aspergillus culture in the broncho-alveolar lavage (BAL) sampling. Despite this diagnostic approach performed much better than the EORTC/MSG diagnostic criteria to diagnose IPA, it was limited by the necessity to have a positive LRT sample for Aspergillus spp.; however, IPA may evolve without a positive respiratory culture, which is present in only 40–50% of patients with the disease (16), and the need for further improvement of diagnostic criteria of IPA in critically ill patients is warranted.

The measurement of the cell-wall constituent galactomannans (GM), a [1-3]-β-D-glucan (BD) that is released during fungal growth, has been widely used as a biomarker for early diagnosis of IPA in neutropenic patients, together with polymerase chain reaction (PCR) assay. GM and BD are polysaccharide of the Aspergillus wall that can be detected during the invasive disease in different body fluids (e.g., serum, BAL and cerebrospinal fluid). In a recent Cochrane Review, the sensitivity and the specificity of the GM assay measured in the serum with a cut-off of 0.5 optical density index was 82% and 81%, respectively, to detect IPA in neutropenic patients where the prevalence of the disease is estimated around 10% (17). Nevertheless, in non-neutropenic patients, serum GM assays result in significantly poorer results because these molecules are cleared by neutrophils, thus limiting the diagnostic value of this test to detect IPA in such population. Thus, in a retrospective study evaluating critically ill patients, serum GM was increased in only 53% of patients with IPA (18). The accuracy of GM to diagnose IPA in this setting could be increased by performing consecutive serum GM determinations. In one study including critically ill COPD patients (n=90), two consecutive positive serum GM tests were performed on the first and fourth day after ICU admission had positive and negative predictive values of 89% and 85% to diagnose IPA (19). In another study (n=110) a GM cut-off of 0.5 into the BAL showed a sensitivity and specificity of 88% and 87% to diagnose IPA in critically ill patients, while the sensitivity of serum GM was only 42% (20).

In a recent issue of Critical Care, Schroeder et al. evaluated for the first time the AspICU algorithm to diagnose IPA in critically ill patients in patients with both positive (n=43) and negative (n=42) LRT cultures for Aspergillus spp. (21). The authors observed that the two groups of patients had similar demographic and clinical characteristics. The median GM titre in BAL fluid was significantly higher in patients with positive Aspergillus cultures than others [5.9 (3.2–5.7) vs. 1.7 (0.9–4.5); P<0.001]. Interestingly, when a modified AspICU algorithm including positive (>0.5) GM assessment on BAL fluid was applied in those patients with negative LRT cultures, the proportion of patients with proven/putative IPA was similar in the groups (36/43 if positive cultures vs. 33/42 if negative cultures). According to the authors, without the use of GM assessment as an additional entry point to the decision tree, these patients would have considered as “non-classifiable” and therefore not treated thereafter.

Although interesting, the results of the study must however be interpreted with caution. First, there were more neutropenic patients in the group of patients with Aspergillus-negative respiratory samples than in the group of patients with positive cultures (6/42 vs. 0/43; P=0.012), which increased the risk for IPA independently from the results of LRT samples. Thus, the question about the effectiveness of biomarkers to increase the detection of IPA in a completely non-neutropenic critically ill population remains unsolved. Second, clinical diagnosis of IPA was based on the decision of the attending physician to start antifungal treatment, but treatment was very short in the majority of cases (the majority of patients received treatment for 3 weeks or less). As length of treatment of IA is usually around 6 weeks (5), it is possible that some of the diagnoses of IPA would have revised or infirmed thereafter. Finally, only 4/25 and 8/25 patients who died in the group of patients with a positive and negative Aspergillus cultures, respectively, had a post-mortem examination that could confirm IPA. Thus, in the absence of direct tissue invasion demonstrated on specific assays, it remains unclear the accuracy of this modified AspICU algorithm to diagnose IPA in critically ill patients.

How the results of these studies can be compared with other investigations on GM measurement in ICU patients? The optimal cut-off of GM assessment in the BAL fluid has been widely debated. In the present study, the receiver operating characteristics curve (ROC) analyses for GM to predict positive Aspergillus cultures was 0.71 for an index of 0.5 and was not significantly improved for higher values (21). In previous studies, a GM cut-off of 0.8 for BAL fluid was associated with a high sensitivity and specificity (89% and 100%, respectively) and an AUC of 0.91 to diagnose IPA in COPD patients (22). Other studies showed that a cut-off of 0.5 was accurate to diagnose IPA in critically ill non-neutropenic patients (20,23). Moreover, GM assay in the BAL fluid could become positive earlier than the Aspergillus LRT culture by 2 to 10 days, which could have a significant impact on the timing of initiation of therapy (24). However, the time from positive test to initiation of therapy was not evaluated in the Schroeder’s study. Finally, the combination of several biomarkers could provide an even more accurate diagnostic approach to identify IPA in such patients. [1-3]-β-D-glucan offered similar diagnostic accuracy as serum GM in two different studies, but lower accuracy than the GM BAL detection (25,26) and cannot be considered as a valuable alternative in this setting. Although promising, PCR techniques showed only moderate diagnostic accuracy when used as screening tests for IPA in high-risk patients and could be integrated in a diagnostic algorithm to exclude the diagnosis of IPA only when repeated at least twice, as a single PCR test may have around 20% of missed diagnosis (27). As only few patients had concomitant PCR assessment in the Schroeder’s study, this issue remains to be further evaluated.

In conclusion, Schroeder et al. have provided promising results concerning the utilization of GM determination to identify critically ill patients at risk of IPA. The results suggest that by using the modified AspICU clinical algorithm with positive GM in the BAL fluid as an additional entry point may increase the diagnostic detection of IPA in ICU patients. More studies including proven IPA from post-mortem or biopsy tests should be performed to confirm these preliminary results. Furthermore, the use of other biomarkers (either in combination with GM or to replace GM detection) should be considered as well.


Acknowledgements

None.


Footnote

Provenance: This is a Guest Editorial commissioned by Section Editor Zhi Mao, MD (Department of Critical Care Medicine, Chinese People’s Liberation Army General Hospital, Beijing, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.

Comment on: Schroeder M, Simon M, Katchanov J, et al. Does galactomannan testing increase diagnostic accuracy for IPA in the ICU? A prospective observational study. Crit Care 2016;20:139.


References

  1. Patterson TF. Advances and challenges in management of invasive mycoses. Lancet 2005;366:1013-25. [Crossref] [PubMed]
  2. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26:781-803. [Crossref] [PubMed]
  3. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-15. [Crossref] [PubMed]
  4. Auberger J, Lass-Flörl C, Ulmer H, et al. Significant alterations in the epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. Int J Hematol 2008;88:508-15. [Crossref] [PubMed]
  5. De Pauw B, Walsh TJ, Donnelly JP, et al. 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;46:1813-21. [Crossref] [PubMed]
  6. Montagna MT, Lovero G, Coretti C, et al. SIMIFF study: Italian fungal registry of mold infections in hematological and non-hematological patients. Infection 2014;42:141-51. [Crossref] [PubMed]
  7. Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit. Clin Infect Dis 2007;45:205-16. [Crossref] [PubMed]
  8. Baddley JW, Stephens JM, Ji X, et al. Aspergillosis in Intensive Care Unit (ICU) patients: epidemiology and economic outcomes. BMC Infect Dis 2013;13:29. [Crossref] [PubMed]
  9. Taccone FS, Van den Abeele AM, et al. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care 2015;19:7. [Crossref] [PubMed]
  10. Groll AH, Shah PM, Mentzel C, et al. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996;33:23-32. [Crossref] [PubMed]
  11. Koulenti D, Vogelaers D, Blot S. What's new in invasive pulmonary aspergillosis in the critically ill. Intensive Care Med 2014;40:723-6. [Crossref] [PubMed]
  12. Silfvast T, Takkunen O, Kolho E, et al. Characteristics of discrepancies between clinical and autopsy diagnoses in the intensive care unit: a 5-year review. Intensive Care Med 2003;29:321-4. [Crossref] [PubMed]
  13. Mort TC, Yeston NS. The relationship of pre mortem diagnoses and post mortem findings in a surgical intensive care unit. Crit Care Med 1999;27:299-303. [Crossref] [PubMed]
  14. Combes A, Mokhtari M, Couvelard A, et al. Clinical and autopsy diagnoses in the intensive care unit: a prospective study. Arch Intern Med 2004;164:389-92. [Crossref] [PubMed]
  15. Blot SI, Taccone FS, Van den Abeele AM, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012;186:56-64. [Crossref] [PubMed]
  16. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis 2005;5:609-22. [Crossref] [PubMed]
  17. Leeflang MM, Debets-Ossenkopp YJ, Wang J, et al. Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev 2015.CD007394. [PubMed]
  18. Meersseman W, Vandecasteele SJ, Wilmer A, et al. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004;170:621-5. [Crossref] [PubMed]
  19. He H, Ding L, Chang S, et al. Value of consecutive galactomannan determinations for the diagnosis and prognosis of invasive pulmonary aspergillosis in critically ill chronic obstructive pulmonary disease. Med Mycol 2011;49:345-51. [Crossref] [PubMed]
  20. Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar lavage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am J Respir Crit Care Med 2008;177:27-34. [Crossref] [PubMed]
  21. Schroeder M, Simon M, Katchanov J, et al. Does galactomannan testing increase diagnostic accuracy for IPA in the ICU? A prospective observational study. Crit Care 2016;20:139. [Crossref] [PubMed]
  22. He H, Ding L, Sun B, et al. 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:R138. [Crossref] [PubMed]
  23. Khorvash F, Meidani M, Babaei L, et al. Galactomannan antigen assay from bronchoalveolar lavage fluid in diagnosis of invasive pulmonary aspergillosis in intensive care units patients. Adv Biomed Res 2014;3:68. [Crossref] [PubMed]
  24. Shi Y, Liu DW, Long Y, et al. The role of galactomannan detection in the diagnosis of invasive pulmonary aspergillosis in critically ill patients. Zhonghua Nei Ke Za Zhi 2009;48:225-30. [PubMed]
  25. Cai X, Ni W, Wei C, et al. Diagnostic value of the serum galactomannan and (1, 3)-β-D-glucan assays for invasive pulmonary aspergillosis in non-neutropenic patients. Intern Med 2014;53:2433-7. [Crossref] [PubMed]
  26. Acosta J, Catalan M, del Palacio-Peréz-Medel A, et al. A prospective comparison of galactomannan in bronchoalveolar lavage fluid for the diagnosis of pulmonary invasive aspergillosis in medical patients under intensive care: comparison with the diagnostic performance of galactomannan and of (1→ 3)-β-d-glucan chromogenic assay in serum samples. Clin Microbiol Infect 2011;17:1053-60. [Crossref] [PubMed]
  27. Cruciani M, Mengoli C, Loeffler J, et al. Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people. Cochrane Database Syst Rev 2015.CD009551. [PubMed]
Cite this article as: Hites M, Goicoechea Turcott EW, Taccone FS. The role of galactomannan testing to diagnose invasive pulmonary aspergillosis in critically ill patients. Ann Transl Med 2016;4(18):353. doi: 10.21037/atm.2016.08.32

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