Skip to main content

Advertisement

SpringerLink
Log in

Systematic review and meta-analysis of galactomannan antigen testing in serum and bronchoalveolar lavage for the diagnosis of chronic pulmonary aspergillosis: defining a cutoff

  • Review
  • Published:
European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Background

A clear cutoff value of galactomannan (GM) has not been established for chronic pulmonary aspergillosis (CPA) and is frequently extrapolated from invasive pulmonary aspergillosis. We performed a systematic review and meta-analysis to evaluate the diagnostic performance of serum and bronchoalveolar lavage (BAL) GM, and to propose a cutoff.

Methods

We extracted from the studies the cutoff of serum or/and BAL GM associated with true positives, false positives, true negatives, and false negatives. We performed a multi-cutoff model and a non-parametric random effect model. We estimated the optimal cutoff and the area under the curve (AUC) for GM in serum and BAL samples.

Results

Nine studies from 1999 to 2021 were included. Overall, the optimal cutoff of serum GM was 0.96 with a sensitivity of 0.29 (95%CI: 0.14–0.51); specificity of 0.88 (95%CI: 0.73–0.95); and AUC of 0.529 (with a CI: [0.415–0.682] [0.307–0.713]). The AUC for the non-parametric ROC model was 0.631. For BAL GM the cutoff was 0.67 with a sensitivity of 0.68 (95%CI: 0.51–0.82), specificity of 0.84 (95%CI: 0.70–0.92), and AUC of 0.814 (with a CI: [0.696–0.895] [0.733–0.881]). The AUC for the non-parametric model was 0.789.

Conclusion

The diagnosis of CPA requires the assessment of a combination of mycological and serological factors, as no single serum and/or BAL GM antigen test is adequate. BAL GM performed better than serum, with better sensitivity and excellent accuracy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are not publicly available, because the authors elected to not share, but are available from the corresponding author on reasonable request.

References

  1. Soubani AO, Chandrasekar PH (2002) The clinical spectrum of pulmonary aspergillosis. Chest 121:1988–1999

    Article  PubMed  Google Scholar 

  2. Rozaliyani A, Rosianawati H, Handayani D, Agustin H, Zaini J, Syam R, Adawiyah R, Tugiran M, Setianingrum F, Burhan E et al (2020) Chronic pulmonary aspergillosis in post tuberculosis patients in indonesia and the role of ldbio aspergillus ICT as part of the diagnosis scheme. J Fungi 6(4):318

  3. Camara B, Reymond E, Saint-Raymond C, Roth H, Brenier-Pinchart M-P, Pinel C, Cadranel J, Ferretti G, Pelloux H, Pison C et al (2015) Characteristics and outcomes of chronic pulmonary aspergillosis: a retrospective analysis of a tertiary hospital registry. Clin Respir J 9:65–73

    Article  PubMed  Google Scholar 

  4. Barac A, Kosmidis C, Alastruey-Izquierdo A, Salzer HJF, CPA Net (2019) Chronic pulmonary aspergillosis update: A year in review. Med Mycol 57:S104–S109

    Article  CAS  PubMed  Google Scholar 

  5. Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. Sci Transl Med 4:165rv13

    Article  PubMed  Google Scholar 

  6. Denning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, Ullmann AJ, Dimopoulos G, Lange C, European Society for Clinical Microbiology and Infectious Diseases and European Respiratory Society (2016) Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J 47:45–68

    Article  CAS  PubMed  Google Scholar 

  7. Denning DW, Pleuvry A, Cole DC (2011) Global burden of chronic pulmonary aspergillosis as a sequel to pulmonary tuberculosis. Bull World Health Organ 89:864–872

    Article  PubMed  PubMed Central  Google Scholar 

  8. The Lancet Respiratory Medicine (2016) Chronic pulmonary aspergillosis: help is on the way. Lancet Respir Med 4:83

    Article  CAS  PubMed  Google Scholar 

  9. Lowes D, Al-Shair K, Newton PJ, Morris J, Harris C, Rautemaa-Richardson R, Denning DW (2017) Predictors of mortality in chronic pulmonary aspergillosis. Eur Respir J 49(2)

  10. Izumikawa K, Yamamoto Y, Mihara T, Takazono T, Morinaga Y, Kurihara S, Nakamura S, Imamura Y, Miyazaki T, Nishino T et al (2012) Bronchoalveolar lavage galactomannan for the diagnosis of chronic pulmonary aspergillosis. Med Mycol 50:811–817

    Article  CAS  PubMed  Google Scholar 

  11. Urabe N, Sakamoto S, Sano G, Suzuki J, Hebisawa A, Nakamura Y, Koyama K, Ishii Y, Tateda K, Homma S (2017) Usefulness of Two Aspergillus PCR Assays and Aspergillus Galactomannan and β-d-Glucan Testing of Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis. J Clin Microbiol 55:1738–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zou M, Tang L, Zhao S, Zhao Z, Chen L, Chen P, Huang Z, Li J, Chen L, Fan X (2012) Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for diagnosing invasive aspergillosis. PLoS ONE 7:e43347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mercier T, Castagnola E, Marr KA, Wheat LJ, Verweij PE, Maertens JA (2021) Defining galactomannan positivity in the updated EORTC/MSGERC consensus definitions of invasive fungal diseases. Clin Infect Dis 72:S89–S94

    Article  CAS  PubMed  Google Scholar 

  14. Leeflang MMG, Debets-Ossenkopp YJ, Wang J, Visser CE, Scholten RJPM, Hooft L, Bijlmer HA, Reitsma JB, Zhang M, Bossuyt PMM et al (2015) Galactomannan detection for invasive aspergillosis in immunocompromised patients. Cochrane Database Syst Rev 2017(9)

  15. Arvanitis M, Anagnostou T, Mylonakis E (2015) Galactomannan and Polymerase Chain Reaction-Based Screening for Invasive Aspergillosis Among High-Risk Hematology Patients: A Diagnostic Meta-analysis. Clin Infect Dis 61:1263–1272

    Article  CAS  PubMed  Google Scholar 

  16. Pfeiffer CD, Fine JP, Safdar N (2006) Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 42:1417–1427

    Article  CAS  PubMed  Google Scholar 

  17. Ohba H, Miwa S, Shirai M, Kanai M, Eifuku T, Suda T, Hayakawa H, Chida K (2012) Clinical characteristics and prognosis of chronic pulmonary aspergillosis. Respir Med 106:724–729

    Article  PubMed  Google Scholar 

  18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71

    Article  PubMed  PubMed Central  Google Scholar 

  19. McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM, the PRISMA-DTA Group, Clifford T, Cohen JF, Deeks JJ, Gatsonis C et al (2018) Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement. JAMA 319:388–396

    Article  PubMed  Google Scholar 

  20. Martínez-Camblor P (2017) Fully non-parametric receiver operating characteristic curve estimation for random-effects meta-analysis. Stat Methods Med Res 26:5–20

    Article  PubMed  Google Scholar 

  21. Steinhauser S, Schumacher M, Rücker G (2016) Modelling multiple thresholds in meta-analysis of diagnostic test accuracy studies. BMC Med Res Methodol 16:97

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kawamura S, Maesaki S, Noda T, Hirakata Y, Tomono K, Tashiro T, Kohno S (1999) Comparison between PCR and detection of antigen in sera for diagnosis of pulmonary aspergillosis. J Clin Microbiol 37:218–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shin B, Koh W-J, Jeong B-H, Yoo H, Park HY, Suh GY, Kwon OJ, Jeon K (2014) Serum galactomannan antigen test for the diagnosis of chronic pulmonary aspergillosis. J Infect 68:494–499

    Article  PubMed  Google Scholar 

  24. Salzer HJF, Prattes J, Flick H, Reimann M, Heyckendorf J, Kalsdorf B, Obersteiner S, Gaede KI, Herzmann C, Johnson GL et al (2018) Evaluation of Galactomannan Testing, the Aspergillus-Specific Lateral-Flow Device Test and Levels of Cytokines in Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis. Front Microbiol 9:2223

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sehgal IS, Dhooria S, Choudhary H, Aggarwal AN, Garg M, Chakrabarti A, Agarwal R (2019) Efficiency of A fumigatus-specific IgG and galactomannan testing in the diagnosis of simple aspergilloma. Mycoses 62:1108–1115

    Article  CAS  PubMed  Google Scholar 

  26. Sehgal IS, Dhooria S, Choudhary H, Aggarwal AN, Garg M, Chakrabarti A, Agarwal R (2019) Utility of serum and bronchoalveolar lavage fluid galactomannan in diagnosis of chronic pulmonary aspergillosis. J Clin Microbiol 57:10

    Article  Google Scholar 

  27. Takazono T, Ito Y, Tashiro M, Nishimura K, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Mukae H et al (2019) Evaluation of Aspergillus-Specific Lateral-Flow Device Test Using Serum and Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis. J Clin Microbiol 57:10

    Article  Google Scholar 

  28. Ye F, Zeng P, Li Z, Tang C, Liu W, Su D, Zhan Y, Li S (2021) Detection of aspergillus DNA in BALF by Real-time PCR and galactomannan antigen for the early diagnosis of chronic pulmonary aspergillosis. Ann Clin Lab Sci 51(5):698–704

    CAS  PubMed  Google Scholar 

  29. Denning DW, Riniotis K, Dobrashian R, Sambatakou H (2003) Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review. Clin Infect Dis 37 (Suppl 3):S265–S280

  30. Sehgal IS, Dhooria S, Muthu V, Prasad KT, Agarwal R (2020) An overview of the available treatments for chronic cavitary pulmonary aspergillosis. Expert Rev Respir Med 14:715–727

    Article  CAS  PubMed  Google Scholar 

  31. de Oliveira VF, Viana JA, Sawamura MVY, Magri ASGK, Costa N, Abdala E et al (2022) Sensitivity of antigen, serology, and microbiology assays for diagnosis of the subtypes of chronic pulmonary aspergillosis at a teaching hospital in São Paulo, Brazil. Am J Trop Med Hygiene 108(1):22–26

Download references

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Department of Infectious and Parasitic Diseases, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

    Vítor Falcão de Oliveira, Mariane Taborda, Anna S. Levin & Marcello Mihailenko Chaves Magri

  2. Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

    Guilherme Diogo Silva

Authors
  1. Vítor Falcão de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guilherme Diogo Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mariane Taborda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna S. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marcello Mihailenko Chaves Magri
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Vítor Falcão de Oliveira and Guilherme Diogo Silva. The first draft of the manuscript was written by Vítor Falcão de Oliveira and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Vítor Falcão de Oliveira.

Ethics declarations

Ethics approval

Our study did not require ethics approval.

Conflict of interest

All authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Oliveira, V.F., Silva, G.D., Taborda, M. et al. Systematic review and meta-analysis of galactomannan antigen testing in serum and bronchoalveolar lavage for the diagnosis of chronic pulmonary aspergillosis: defining a cutoff. Eur J Clin Microbiol Infect Dis 42, 1047–1054 (2023). https://doi.org/10.1007/s10096-023-04639-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-023-04639-0

Keywords

Search

Navigation