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Clinical impact of polymerase chain reaction-based Aspergillus and azole resistance detection in invasive aspergillosis : a prospective multicenter study

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Abstract
This prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not associated with mortality. Its place in the current EORTC/MSGERC definitions should be reconsidered. Background Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. Methods In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. Results Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). Conclusions Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).
Keywords
invasive aspergillosis, azole resistance, Aspergillus PCR, clinical impact, BRONCHOALVEOLAR LAVAGE, FUMIGATUS, VORICONAZOLE, VALIDATION

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MLA
Huygens, Sammy, et al. “Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis : A Prospective Multicenter Study.” CLINICAL INFECTIOUS DISEASES, vol. 77, no. 1, Oxford Univ Press Inc, 2023, pp. 38–45, doi:10.1093/cid/ciad141.
APA
Huygens, S., Dunbar, A., Buil, J. B., Klaassen, C. H. W., Verweij, P. E., van Dijk, K., … Rijnders, B. J. A. (2023). Clinical impact of polymerase chain reaction-based Aspergillus and azole resistance detection in invasive aspergillosis : a prospective multicenter study. CLINICAL INFECTIOUS DISEASES, 77(1), 38–45. https://doi.org/10.1093/cid/ciad141
Chicago author-date
Huygens, Sammy, Albert Dunbar, Jochem B. Buil, Corne H. W. Klaassen, Paul E. Verweij, Karin van Dijk, Nick de Jonge, et al. 2023. “Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis : A Prospective Multicenter Study.” CLINICAL INFECTIOUS DISEASES 77 (1): 38–45. https://doi.org/10.1093/cid/ciad141.
Chicago author-date (all authors)
Huygens, Sammy, Albert Dunbar, Jochem B. Buil, Corne H. W. Klaassen, Paul E. Verweij, Karin van Dijk, Nick de Jonge, Jeroen J. W. M. Janssen, Walter J. F. M. van der Velden, Bart J. Biemond, Aldert Bart, Anke H. W. Bruns, Pieter-Jan A. Haas, Astrid M. P. Demandt, Guy Oudhuis, Peter von dem Borne, Martha T. van der Beek, Saskia K. Klein, Peggy Godschalk, Lambert F. R. Span, Douwe F. Postma, Greetje A. Kampinga, Johan Maertens, Katrien Lagrou, Toine Mercier, Ine Moors, Jerina Boelens, Dominik Selleslag, Marijke Reynders, Willemien Zandijk, Jeanette K. Doorduijn, Jan J. Cornelissen, Alexander F. A. D. Schauwvlieghe, and Bart J. A. Rijnders. 2023. “Clinical Impact of Polymerase Chain Reaction-Based Aspergillus and Azole Resistance Detection in Invasive Aspergillosis : A Prospective Multicenter Study.” CLINICAL INFECTIOUS DISEASES 77 (1): 38–45. doi:10.1093/cid/ciad141.
Vancouver
1.
Huygens S, Dunbar A, Buil JB, Klaassen CHW, Verweij PE, van Dijk K, et al. Clinical impact of polymerase chain reaction-based Aspergillus and azole resistance detection in invasive aspergillosis : a prospective multicenter study. CLINICAL INFECTIOUS DISEASES. 2023;77(1):38–45.
IEEE
[1]
S. Huygens et al., “Clinical impact of polymerase chain reaction-based Aspergillus and azole resistance detection in invasive aspergillosis : a prospective multicenter study,” CLINICAL INFECTIOUS DISEASES, vol. 77, no. 1, pp. 38–45, 2023.
@article{01HPHHYSNVS1GFD3T0AJ07HRAC,
  abstract     = {{This prospective multicenter study showed that real-time resistance testing may limit the impact of azole resistance on mortality. An isolated positive polymerase chain reaction assay was not associated with mortality. Its place in the current EORTC/MSGERC definitions should be reconsidered.

 Background Invasive aspergillosis (IA) by a triazole-resistant Aspergillus fumigatus is associated with high mortality. Real-time resistance detection will result in earlier initiation of appropriate therapy. Methods In a prospective study, we evaluated the clinical value of the AsperGenius polymerase chain reaction (PCR) assay in hematology patients from 12 centers. This PCR assay detects the most frequent cyp51A mutations in A. fumigatus conferring azole resistance. Patients were included when a computed tomography scan showed a pulmonary infiltrate and bronchoalveolar fluid (BALf) sampling was performed. The primary end point was antifungal treatment failure in patients with azole-resistant IA. Results Of 323 patients enrolled, complete mycological and radiological information was available for 276 (94%), and probable IA was diagnosed in 99/276 (36%). Sufficient BALf for PCR testing was available for 293/323 (91%). Aspergillus DNA was detected in 116/293 (40%) and A. fumigatus DNA in 89/293 (30%). The resistance PCR was conclusive in 58/89 (65%) and resistance detected in 8/58 (14%). Two had a mixed azole-susceptible/azole-resistant infection. In the 6 remaining patients, treatment failure was observed in 1. Galactomannan positivity was associated with mortality (P = .004) while an isolated positive Aspergillus PCR was not (P = .83). Conclusions Real-time PCR-based resistance testing may help to limit the clinical impact of triazole resistance. In contrast, the clinical impact of an isolated positive Aspergillus PCR on BALf seems limited. The interpretation of the EORTC/MSGERC PCR criterion for BALf may need further specification (eg, minimum cycle threshold value and/or PCR positive on >1 BALf sample).}},
  author       = {{Huygens, Sammy and Dunbar, Albert and  Buil, Jochem B. and  Klaassen, Corne H. W. and  Verweij, Paul E. and  van Dijk, Karin and  de Jonge, Nick and  Janssen, Jeroen J. W. M. and  van der Velden, Walter J. F. M. and  Biemond, Bart J. and  Bart, Aldert and  Bruns, Anke H. W. and  Haas, Pieter-Jan A. and  Demandt, Astrid M. P. and  Oudhuis, Guy and  von dem Borne, Peter and  van der Beek, Martha T. and  Klein, Saskia K. and  Godschalk, Peggy and  Span, Lambert F. R. and  Postma, Douwe F. and  Kampinga, Greetje A. and  Maertens, Johan and Lagrou, Katrien and  Mercier, Toine and Moors, Ine and Boelens, Jerina and  Selleslag, Dominik and  Reynders, Marijke and  Zandijk, Willemien and  Doorduijn, Jeanette K. and  Cornelissen, Jan J. and  Schauwvlieghe, Alexander F. A. D. and  Rijnders, Bart J. A.}},
  issn         = {{1058-4838}},
  journal      = {{CLINICAL INFECTIOUS DISEASES}},
  keywords     = {{invasive aspergillosis,azole resistance,Aspergillus PCR,clinical impact,BRONCHOALVEOLAR LAVAGE,FUMIGATUS,VORICONAZOLE,VALIDATION}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{38--45}},
  publisher    = {{Oxford Univ Press Inc}},
  title        = {{Clinical impact of polymerase chain reaction-based Aspergillus and azole resistance detection in invasive aspergillosis : a prospective multicenter study}},
  url          = {{http://doi.org/10.1093/cid/ciad141}},
  volume       = {{77}},
  year         = {{2023}},
}

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