Invasive pulmonary aspergillosis among intubated patients with SARS-CoV-2 or influenza pneumonia: a European multicenter comparative cohort study

Anahita Rouzé, Elise Lemaitre, Ignacio Martin-Loeches, Pedro Povoa, Emili Diaz, Rémy Nyga, Antoni Torres, Matthieu Metzelard, Damien Du Cheyron, Fabien Lambiotte, Fabienne Tamion, Marie Labruyere, Claire Boulle Geronimi, Charles-Edouard Luyt, Martine Nyunga, Olivier Pouly, Arnaud W Thille, Bruno Megarbane, Anastasia Saade, Eleni Magira, Jean-François Llitjos, Iliana Ioannidou, Alexandre Pierre, Jean Reignier, Denis Garot, Louis Kreitmann, Jean-Luc Baudel, Guillaume Voiriot, Gaëtan Plantefeve, Elise Morawiec, Pierre Asfar, Alexandre Boyer, Armand Mekontso-Dessap, Demosthenes Makris, Christophe Vinsonneau, Pierre-Edouard Floch, Clémence Marois, Adrian Ceccato, Antonio Artigas, Alexandre Gaudet, David Nora, Marjorie Cornu, Alain Duhamel, Julien Labreuche, Saad Nseir, coVAPid study group, Mathilde Bouchereau, Boualem Sendid, Sean Boyd, Luis Coelho, Julien Maizel, Pierre Cuchet, Wafa Zarrougui, Déborah Boyer, Jean-Pierre Quenot, Mehdi Imouloudene, Marc Pineton de Chambrun, Thierry Van Der Linden, François Arrive, Sebastian Voicu, Elie Azoulay, Edgard Moglia, Frédéric Pene, Catia Cilloniz, Didier Thevenin, Charlotte Larrat, Laurent Argaud, Bertrand Guidet, Matthieu Turpin, Damien Contou, Alexandra Beurton, Julien Demiselle, David Meguerditchian, Keyvan Razazi, Romain Arrestier, Vassiliki Tsolaki, Mehdi Marzouk, Guillaume Brunin, Nicolas Weiss, Luis Morales, Anahita Rouzé, Elise Lemaitre, Ignacio Martin-Loeches, Pedro Povoa, Emili Diaz, Rémy Nyga, Antoni Torres, Matthieu Metzelard, Damien Du Cheyron, Fabien Lambiotte, Fabienne Tamion, Marie Labruyere, Claire Boulle Geronimi, Charles-Edouard Luyt, Martine Nyunga, Olivier Pouly, Arnaud W Thille, Bruno Megarbane, Anastasia Saade, Eleni Magira, Jean-François Llitjos, Iliana Ioannidou, Alexandre Pierre, Jean Reignier, Denis Garot, Louis Kreitmann, Jean-Luc Baudel, Guillaume Voiriot, Gaëtan Plantefeve, Elise Morawiec, Pierre Asfar, Alexandre Boyer, Armand Mekontso-Dessap, Demosthenes Makris, Christophe Vinsonneau, Pierre-Edouard Floch, Clémence Marois, Adrian Ceccato, Antonio Artigas, Alexandre Gaudet, David Nora, Marjorie Cornu, Alain Duhamel, Julien Labreuche, Saad Nseir, coVAPid study group, Mathilde Bouchereau, Boualem Sendid, Sean Boyd, Luis Coelho, Julien Maizel, Pierre Cuchet, Wafa Zarrougui, Déborah Boyer, Jean-Pierre Quenot, Mehdi Imouloudene, Marc Pineton de Chambrun, Thierry Van Der Linden, François Arrive, Sebastian Voicu, Elie Azoulay, Edgard Moglia, Frédéric Pene, Catia Cilloniz, Didier Thevenin, Charlotte Larrat, Laurent Argaud, Bertrand Guidet, Matthieu Turpin, Damien Contou, Alexandra Beurton, Julien Demiselle, David Meguerditchian, Keyvan Razazi, Romain Arrestier, Vassiliki Tsolaki, Mehdi Marzouk, Guillaume Brunin, Nicolas Weiss, Luis Morales

Abstract

Background: Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients.

Objectives: To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients.

Methods: This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event.

Results: A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53-7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88-5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization.

Conclusions: Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 .

Keywords: COVID-19; Intensive care unit; Invasive pulmonary aspergillosis; Mechanical ventilation; Severe influenza.

Conflict of interest statement

AR received personal fees from Maat Pharma, IML received personal fees from MSD, and Gilead. AA received personal fees from Lilly Foundation, and grants from Grifols and Fisher & Paykel. CEL received personal fees from Bayer, Merck, Aerogen, Biomérieux, ThermoFisher Brahms, and Carmat. SN received personal fees from MSD, Bio-Rad, BioMérieux, Gilead, Fisher and Paykel, and Pfizer. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart. Suspected IPA refers to clinical suspicion associated with any positive serum or respiratory sample for Aspergillus. Putative IPA and Aspergillus colonization are defined according to Blot definition. IPA, invasive pulmonary aspergillosis
Fig. 2
Fig. 2
Cumulative incidence of putative or probable invasive pulmonary aspergillosis according to Blot (A) and Verweij (B) definitions. Cumulative incidence was estimated using Kalbfleisch and Prentice method, considering extubation (alive or due to death) within 28 days as competing event. Time axis starts at the day of intubation. IPA, invasive pulmonary aspergillosis, MV, mechanical ventilation
Fig. 3
Fig. 3
Cumulative incidence of putative invasive pulmonary aspergillosis or Aspergillus colonization according to Blot definition. Cumulative incidence was estimated using Kalbfleisch and Prentice method, considering extubation (alive or due to death) within 28 days as competing event. Time axis starts at the day of intubation. IPA, invasive pulmonary aspergillosis, MV, mechanical ventilation
Fig. 4
Fig. 4
Association of putative invasive pulmonary aspergillosis, and Aspergillus colonization, according to Blot definition, with 28-day outcomes in overall population and according to study groups (SARS-CoV-2 pneumonia and influenza pneumonia). HRs were calculated using cause-specific proportional hazard models, considering death as competing event for mechanical ventilation and length of ICU stay. Adjusted HRs were calculated by including simplified acute physiology score II, chronic obstructive pulmonary disease, immunosuppression, recent antibiotic treatment before ICU admission, acute respiratory distress syndrome on admission, and corticosteroid treatment during ICU stay, as pre-specified covariates in Cox’s models (after handling missing values by multiple imputation). A HR > 1 indicates a decrease in survival (i.e., an increased risk for mortality), MV duration (i.e., an increased risk for extubation alive) and ICU length of stay (i.e., an increased risk for discharge alive) and a HR p value for heterogeneity in association of invasive pulmonary aspergillosis and 28-day outcomes across study groups (SARS-CoV-2 pneumonia vs. influenza pneumonia). * Not estimable, as no patient was discharged alive within 28 days. CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; IPA, invasive pulmonary aspergillosis; MV, mechanical ventilation

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