Cerebral aspergillosis in the era of new antifungals: The CEREALS national cohort study Nationwide CEREbral Aspergillosis Lesional study (CEREALS)

  • A. Serris
    Affiliations
    Centre for Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Université de Paris, Paris, France
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  • Author Footnotes
    ¶ Both authors contributed equally to the work.
    J. Benzakoun
    Footnotes
    ¶ Both authors contributed equally to the work.
    Affiliations
    Department of Neuroradiology, Université de Paris, INSERM UMR 1266, GHU Paris, Hôpital Sainte-Anne, DHU Neurovasc Paris Sorbonne, Paris, France
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  • Author Footnotes
    ¶ Both authors contributed equally to the work.
    F. Danion
    Footnotes
    ¶ Both authors contributed equally to the work.
    Affiliations
    Department of Infectious Diseases, Hôpital Universitaire de Strasbourg, Université de Strasbourg, Strasbourg, France
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  • R. Porcher
    Affiliations
    Clinical Epidemiology Centre, Hôpital Hôtel-Dieu, Assistance Publique Hôpitaux de Paris, and Centre of Research in Epidemiology and Statistics (CRESS), Institut National de la Santé et de la Recherche Médicale U1153; Université de Paris, Paris, France
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  • R. Sonneville
    Affiliations
    Intensive Care Medicine and Infectious Diseases, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, and UMR1148, LVTS, Sorbonne Paris Cité, INSERM, France
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  • M. Wolff
    Affiliations
    Neurological Intensive Care Unit, Hôpital Sainte-Anne, GHU Paris Psychiatrie et NeuroSciences, Paris, France
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  • S. Kremer
    Affiliations
    Department of Neuroradiology, Hôpital Universitaire de Strasbourg, Engineering science, computer science and imaging laboratory (ICube), UMR 7357, University of Strasbourg-CNRS, Strasbourg, France
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  • V Letscher-Bru
    Affiliations
    Parasitology-Mycology Laboratory, Hôpital Universitaire de Strasbourg, Strasbourg, France
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  • A Fekkar
    Affiliations
    Parasitology Mycology, hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France
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  • G. Hekimian
    Affiliations
    Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, France
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  • V. Pourcher
    Affiliations
    Infectious Diseases Department, , hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, France
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  • M-E. Bougnoux
    Affiliations
    Parasitology-Mycology Laboratory, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Paris, France
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  • S. Poirée
    Affiliations
    Department of adult radiology, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Paris, France
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  • F. Ader
    Affiliations
    Infectious Diseases department, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
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  • F. Persat
    Affiliations
    Parasitology-Mycology Laboratory, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
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  • Francois Cotton
    Affiliations
    Department of Radiology, Lyon Sud Hospital, Hospices Civils de Lyon, Lyon, France

    CREATIS, CNRS UMR 5220 & Inserm U1044, Université Claude Bernard Lyon 1, Villeurbanne, France
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  • Pierre Tattevin
    Affiliations
    Infectious Diseases and Intensive Care Unit, hôpital universitaire Pontchaillou, Rennes, France
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  • J.-P. Gangneux
    Affiliations
    Department of Mycology, Rennes University Hospital, Rennes, France
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  • L. Lelièvre
    Affiliations
    Department of Infectious and Tropical Diseases, hôpital universitaire de Toulouse, France
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  • S. Cassaing
    Affiliations
    Department of Parasitology Mycology, hôpital universitaire de Toulouse, Toulouse, France
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  • Fabrice Bonneville
    Affiliations
    Department of Neuroradiology, hôpital universitaire de Toulouse, Toulouse, France
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  • S. Houze
    Affiliations
    Mycology Parasitology Department, hôpital Bichat, Assistance Publique Hôpitaux de Paris, Paris, France
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  • Stephane Bretagne
    Affiliations
    Molecular Mycology Unit, National Reference Centre for Invasive Mycoses and Antifungals, UMR 2000, Institut Pasteur, CNRS, Université de Paris, Paris, France

    Parasitology-Mycology Laboratory, Lariboisière, Saint-Louis, Fernand Widal Hospitals, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris, Paris, France
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  • R. Herbrecht
    Affiliations
    Department of Haematology, Institut de Cancérologie de Strasbourg (ICANS), Strasbourg, France
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  • Author Footnotes
    ¶ Both authors contributed equally to the work.
    O. Lortholary
    Footnotes
    ¶ Both authors contributed equally to the work.
    Affiliations
    Centre for Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Université de Paris, Paris, France

    Molecular Mycology Unit, National Reference Centre for Invasive Mycoses and Antifungals, UMR 2000, Institut Pasteur, CNRS, Université de Paris, Paris, France
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  • Author Footnotes
    ¶ Both authors contributed equally to the work.
    O. Naggara
    Footnotes
    ¶ Both authors contributed equally to the work.
    Affiliations
    Department of Neuroradiology, Université de Paris, INSERM UMR 1266, GHU Paris, Hôpital Sainte-Anne, DHU Neurovasc Paris Sorbonne, Paris, France
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  • F. Lanternier
    Correspondence
    Corresponding author.
    Affiliations
    Centre for Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique – Hôpitaux de Paris, Université de Paris, Paris, France

    Molecular Mycology Unit, National Reference Centre for Invasive Mycoses and Antifungals, UMR 2000, Institut Pasteur, CNRS, Université de Paris, Paris, France
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  • the CEREAL study group
    Author Footnotes
    # CEREAL Study Group: Samy Ammari (Villejuif), Adela Angoulvant (Kremlin-Bicêtre), René Anxionnat (Nancy), Charlotte Barbier (Caen), Philippe Blanche (Hôpital Cochin, Paris), Julie Bonhomme (Caen), Françoise Botterel (Créteil), Thorsten Braun (Bobigny), Pierre-Yves Brillet (Bobigny), Sophie Brun (Bobigny), Clémentine Charles (Lille), Cyril Chivot (Amiens), Taieb Chouaki (Amiens), Jean Michel Colombani (Clichy), Jean-Philippe Cottier (Tours), Eric Dannaoui (Hôpital Pitié Salpétrière, Paris), Guillaume Desoubeaux (Tours), Denis Ducreux (Kremlin-Bicêtre), Mathieu Dupont (St Malo), Odile Eloy (Versailles), François Eugene (Rennes), Loïc Favennec (Rouen), Jamilé Frayer (Meaux), Sophie Gallas (Créteil), Jean-Pierre Gangneux (Rennes), David Guez (Villejuif), Gaëlle Guillerm (Brest), Elie Haddad (Hôpital Pitié Salpétrière, Paris), Philippe Halimi (Paris), Lilia Hasseine (Nice), Gregory Kuchcinski (Lille), Jean-Philippe Lanoix (Amiens), Marie-Pierre Ledoux (Strasbourg), Agnès Lefort (Clichy), Liem Binh Luong Nguyen (Hôpital Cochin, Paris), Elias Mahdjoub (Hôpital Bichat, Paris), Aude Marie-Cardine (Rouen), Armand Mekontso Dessap (Créteil), André Paugam (hôpital Cochin, Paris), Juliette Pavie (Hôpital Européen Georges Pompidou, Paris), Nadya Pyatigorskaya (Paris), Marie-Pierre Revel (Hôpital Cochin, Paris), Christine Robin (Créteil), Boualem Sendid (Lille), Jean-Philippe Talarmin (Quimper), Yacine Tandjaoui (Bobigny), Benjamin Terrier (Hôpital Cochin, Paris), Dominique Toubas (Reims), Renaud Vernon (Caen), Fanny Vuotto (Lille), Martine Wallon (Lyon), Benjamin Wyplosz (Bobigny).
  • Author Footnotes
    ¶ Both authors contributed equally to the work.
    # CEREAL Study Group: Samy Ammari (Villejuif), Adela Angoulvant (Kremlin-Bicêtre), René Anxionnat (Nancy), Charlotte Barbier (Caen), Philippe Blanche (Hôpital Cochin, Paris), Julie Bonhomme (Caen), Françoise Botterel (Créteil), Thorsten Braun (Bobigny), Pierre-Yves Brillet (Bobigny), Sophie Brun (Bobigny), Clémentine Charles (Lille), Cyril Chivot (Amiens), Taieb Chouaki (Amiens), Jean Michel Colombani (Clichy), Jean-Philippe Cottier (Tours), Eric Dannaoui (Hôpital Pitié Salpétrière, Paris), Guillaume Desoubeaux (Tours), Denis Ducreux (Kremlin-Bicêtre), Mathieu Dupont (St Malo), Odile Eloy (Versailles), François Eugene (Rennes), Loïc Favennec (Rouen), Jamilé Frayer (Meaux), Sophie Gallas (Créteil), Jean-Pierre Gangneux (Rennes), David Guez (Villejuif), Gaëlle Guillerm (Brest), Elie Haddad (Hôpital Pitié Salpétrière, Paris), Philippe Halimi (Paris), Lilia Hasseine (Nice), Gregory Kuchcinski (Lille), Jean-Philippe Lanoix (Amiens), Marie-Pierre Ledoux (Strasbourg), Agnès Lefort (Clichy), Liem Binh Luong Nguyen (Hôpital Cochin, Paris), Elias Mahdjoub (Hôpital Bichat, Paris), Aude Marie-Cardine (Rouen), Armand Mekontso Dessap (Créteil), André Paugam (hôpital Cochin, Paris), Juliette Pavie (Hôpital Européen Georges Pompidou, Paris), Nadya Pyatigorskaya (Paris), Marie-Pierre Revel (Hôpital Cochin, Paris), Christine Robin (Créteil), Boualem Sendid (Lille), Jean-Philippe Talarmin (Quimper), Yacine Tandjaoui (Bobigny), Benjamin Terrier (Hôpital Cochin, Paris), Dominique Toubas (Reims), Renaud Vernon (Caen), Fanny Vuotto (Lille), Martine Wallon (Lyon), Benjamin Wyplosz (Bobigny).
Published:November 24, 2021DOI:https://doi.org/10.1016/j.jinf.2021.11.014

      Highlights

      • Characteristics of cerebral aspergillosis vary according to the presumed route of Aspergillus dissemination to the brain.
      • Galactommanan antigen is positive in the sera in 61% of the patients and in the CSF in 69%.
      • CSF analysis is often informative and should be formed systematically if possible.
      • Cerebral ischemic events are reported in 2/3 of patients with cerebral aspergillosis with contiguous extension.
      • Cerebral aspergillosis mortality remains high (45% at W6 and 63% at M12).

      Summary

      Background

      Cerebral aspergillosis (CA) is a life-threatening disease for which diagnosis and management remain challenging. Detailed analyses from large cohorts are lacking.

      Methods

      We included 119 cases of proven (n = 54) or probable (n = 65) CA diagnosed between 2006 and 2018 at 20 French hospitals. Data were collected at baseline and during follow-up. Cerebral imaging was reviewed centrally by two neuroradiologists.

      Results

      The most frequent underlying conditions were hematological malignancy (40%) and solid organ transplantation (29%). Galactomannan was detected in the serum of 64% of patients. In 75% of cases, at least one of galactomannan, Aspergillus PCR, and β-d-glucan was positive in the cerebrospinal fluid. Six-week mortality was 45%. Two distinct patterns of disease were identified according to presumed route of dissemination. Presumed haematogenous dissemination (n = 88) was associated with a higher frequency of impaired consciousness (64%), shorter time to diagnosis, the presence of multiple abscesses (70%), microangiopathy (52%), detection of serum galactomannan (69%) and Aspergillus PCR (68%), and higher six-week mortality (54%). By contrast, contiguous dissemination from the paranasal sinuses (n = 31) was associated with a higher frequency of cranial nerve palsy (65%), evidence of meningitis on cerebral imaging (83%), macrovascular lesions (61%), delayed diagnosis, and lower six-week mortality (30%). In multivariate analysis and in a risk prediction model, haematogenous dissemination, hematological malignancy and the detection of serum galactomannan were associated with higher six-week mortality.

      Conclusion

      Distinguishing between hematogenous and contiguous dissemination patterns appears to be critical in the workup for CA, as they are associated with significant differences in clinical presentation and outcome.

      Graphical abstract

      Keywords

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