# Response to “high-flow nasal cannula and intubation risk in severe PjP: methodological and clinical perspectives”

Florian Reizine, Vicky Stiegler, Benoit Tessoulin, Nahema Issa, Benjamin

Gaborit

► To cite this version:

Florian Reizine, Vicky Stiegler, Benoit Tessoulin, Nahema Issa, Benjamin Gaborit. Response to “high-flow nasal cannula and intubation risk in severe PjP: methodological and clinical perspectives”. Annals of Intensive Care, 2025, 15 (1), pp.182. 10.1186/s13613-025-01573-6. hal-05454246

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## LETTER TO THE EDITOR

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# Response to "high-flow nasal cannula and intubation risk in severe PjP: methodological and clinical perspectives"

Florian Reizine¹* ID, Vicky Stiegler², Benoit Tessoulin³, Nahema Issa⁴ and Benjamin Gaborit²,⁵* on behalf of the PRONOCYSTIS study group

**keywords** Pneumocystis jirovecii pneumonia, acute hypoxemic failure, HFNC, NIV

To the Editor,

We thank Wang and Cheng for their thoughtful comments [1] on our study of respiratory management in critically ill patients with *Pneumocystis jirovecii* pneumonia (PjP) [2]. We welcome the opportunity to clarify several methodological points.

### Competing-risk analysis with center and epoch adjustment

We agree that censoring patients who died without intubation may overestimate the "intubation-free" probability. In response, we performed an additional Fine-Gray competing-risk analysis, treating death prior to intubation as a competing event. We also adjusted for variability

across centers and temporal changes in practice (2011–2014, 2015–2018, 2019–2021). In this model, high-flow nasal cannula (HFNC) remained independently associated with a reduced subdistribution hazard of intubation compared with standard oxygen (sHR = 0.46; 95% CI 0.28–0.78; p = 0.004), while non-invasive ventilation (NIV) showed no significant effect (sHR = 0.84; 95% CI 0.51–1.36; p = 0.47). These findings confirm the robustness of our primary results after accounting for temporal and inter-center heterogeneity.

### Classification of alternating HFNC/NIV patients

Patients who alternated between HFNC and NIV primarily received repeated NIV sessions, with HFNC used for comfort between sessions. We therefore classified them under "NIV", which reflects bedside practice more accurately than a multi-state model that would overemphasize short HFNC intervals. Only a randomized trial could definitively disentangle the respective contributions of HFNC and NIV.

### Residual confounding and scope of additional analyses

We acknowledge that residual confounding remains possible despite inverse probability weighting and adjustment for center and epoch. A fully multivariable Fine-Gray model including all baseline covariates would require a dedicated analysis and exceeds the scope of this

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<footnote>*Correspondence:
Florian Reizine
florian.reizine@gmail.com
Benjamin Gaborit
benjamin.gaborit@chu-nantes.fr

¹Service de réanimation polyvalente, Centre Hospitalier de Vannes,
56000 Vannes, France

²Department of Infectious Diseases, University Hospital of Nantes and
Centre d'Investigation Clinique 1413, INSERM, 1 Place Alexis-Ricordeau,
44000 Nantes, France

³INSERM, U1232, Hematology Department, Nantes University Hospital,
CRCI2NA, Nantes University, Nantes, France

⁴Internal medicine and Infectious Disease Unit, Groupe Saint-André,
University Hospital, Bordeaux, France

⁵EA 3826, Laboratory of clinical and experimental therapeutics of
infections, IRS2-Nantes Biotech, Nantes, France</footnote>
letter. Our goal was to verify that the association between HFNC and lower intubation risk persisted under competing-risk modeling and key sources of heterogeneity, an objective that these additional analyses achieves.

**Subgroups, prophylaxis, and standardized protocols**

As noted, poor prognosis in patients with long-term corticosteroid use, solid tumors, or high SOFA scores is an important issue. Exploratory subgroup analyses did not reveal significant interactions with HFNC, but our sample size was insufficient for firm conclusions. Reinforcing pneumocystis prophylaxis and implementing standardized HFNC escalation strategies (e.g., ROX index thresholds, early awake prone positioning, predefined intubation criteria) are promising avenues for improving patient outcomes and should be evaluated prospectively.

**Conclusion**

Our study provides real-world evidence that HFNC is associated with a lower risk of intubation in severe PjP, although no survival benefit at day 90 was observed. The additional competing-risk analysis supports the robustness of this finding, while underlining the inherent limitations of retrospective data. Ultimately, only a prospective randomized controlled trial will definitively establish the role of HFNC versus alternative oxygenation strategies in critically ill PjP patients.

**Acknowledgements**

*PRONOCYSTIS Study Group Collaborators: Francois Raffi, MD, PhD, David Boutoille, MD, PhD, Charlotte Biron, MD, Maeva Lefebvre, MD, Benjamin Jean Gaborit, MD, PhD, Paul Le Turnier, MD, Colin Deschanvres, MD, Raphael Lecomte, MD, Marie Chauveau, MD, Romain Lécuyer, MD, and Antoine Asquier-Khati, MD (Department of Infectious Diseases, Nantes University Hospital); Patrice Le Pape, MD, PhD, Florent Morio, PharmD, PhD, Rose-Anne Lavergne, PharmD, PhD, and Fakhri Jeddi, PharmD (Department of Parasitology-Mycology, Nantes University Hospital); Stéphane Corvec, PharmD, PhD Pascale Bemer, PharmD, PhD, Jocelyne Caillon, PharmD, PhD, Aurélie Guillouzouic, PharmD, and Anne-Gaëlle Leroy, PharmD, PhD (Department of Bacteriology, Nantes University Hospital); Karim Lakhal, MD, Raphaël Cinotti, MD, PhD and Antoine Roquilly, MD, PhD (Department of Anesthesiology and Intensive Care Medicine, Nantes University Hospital); Jean Reignier, MD, PhD, and Emmanuel Canet, MD, PhD (Medical Intensive Care, Nantes University Hospital); François Xavier Blanc, MD, PhD, Cédric Bretonniere, MD, PhD, and Jean Morin, MD (Service de Pneumologie, Nantes University Hospital); Fabrice Camou, MD, Nahéma Issa, MD, Olivier Guisset, MD, and Gaelle Mourissoux, MD (Intensive Care and Infectious Disease, Groupe Saint André, Bordeaux University Hospital); Isabelle Accoceberry, PharmD, Frederic Gabriel, MD, PhD, Noémie Coron, PharmD, Laurence Delhaes, PharmD, Sébastien Imbert, PharmD, Maxime Lefranc, PharmD, Florian Lussac-Sorton, PharmD, and Amandine Rougeron, PharmD (Laboratoire de Mycologie, Groupe Pellegrin, Bordeaux University Hospital); Marie Gousseff, MD, Yoann Crabol, MD, Grégory Corvaisier, MD, Florent Lautredoux, MD, and Romain Lécuyer, MD (Department of Internal Medicine and Infectious Diseases, Centre Hospitalier Bretagne-Atlantique, Vannes); and Anne Cady, PharmD, Myriam Auger, PharmD, and Pascal Pouedras, PharmD (Department of Microbiology, Centre Hospitalier Bretagne-Atlantique, Vannes). Other contributions: We thank the physicians, microbiologists, nurses and PRONOCYSTIS Study Group who contributed to the management of the study patients and for their commitment to providing optimal patient care.

Consortium name

Francois Raffi⁶, David Boutoille⁶, Charlotte Biron⁶, Maeva Lefebvre⁶, Benjamin Jean Gaborit⁶, Paul Le Turnier⁶, Colin Deschanvres⁶, Raphael Lecomte⁶, Marie Chauveau⁶, Romain Lécuyer⁶, Antoine Asquier-Khati⁶, Valentin Pineau⁶, Marie Prime⁶, Clarisse Delaunay⁶, Hakim Essid⁶, Vicky Steigler⁶, Patrice Le Pape⁷, Florent Morio⁷, Rose-Anne Lavergne⁷, Fakhri Jeddi⁷, Stéphane Corvec⁸, Pascale Bemer⁸, Jocelyne Caillon⁸, Aurélie Guillouzouic⁸, Anne-Gaëlle Leroy⁸, Karim Lakhal⁹, Raphaël Cinotti⁹, Antoine Roquilly⁹, Mickael Vourc'h⁹, Jean Reignier¹⁰, Emmanuel Canet¹⁰, Soraya Benguerfi¹⁰, François Xavier Blanc¹¹, Cédric Bretonniere¹¹, Jean Morin¹¹, Camille Le Blanc¹¹, Hakim Alami¹¹, Fabrice Camou¹², Nahéma Issa¹², Olivier Guisset¹², Gaelle Mourissoux¹², Isabelle Accoceberry¹³, Frederic Gabriel¹³, Isabelle Accoceberry¹³, Noémie Coron¹³, Laurence Delhaes¹³, Sébastien Imbert¹³, Maxime Lefranc¹³, Florian Lussac-Sorton¹³, Amandine Rougeron¹³, Marie Gousseff¹⁴, Yoann Crabol¹⁴, Grégory Corvaisier¹⁴, Florent Lautredoux¹⁴, Romain Lécuyer¹⁴, Anne Cady¹⁵, Myriam Auger¹⁵, Pascal Pouedras¹⁵

⁶Department of Infectious Diseases, Nantes University Hospital

⁷Department of Parasitology-Mycology, Nantes University Hospital

⁸Department of Bacteriology, Nantes University Hospital

⁹Department of Anesthesiology and Intensive Care Medicine, Nantes University Hospital

¹⁰Medical Intensive Care, Nantes University Hospital

¹¹Service de Pneumologie, Nantes University Hospital

¹²Intensive Care and infectious disease, Groupe Saint André, Bordeaux University Hospital

¹³Laboratoire de Mycologie, Groupe Pellegrin, Bordeaux University Hospital

¹⁴Department of Internal Medicine and Infectious Diseases, Centre Hospitalier Bretagne-Atlantique, Vannes

¹⁵Department of Microbiology, Centre Hospitalier Bretagne-Atlantique, Vannes

**Author contributions**

F.R, wrote the draft of the manuscript. V. S., N. I., B. T., and B. G. read and approved the final manuscript.

**Funding**

No funding was received for this work.

**Data availability**

Not applicable.

**Declarations**

**Ethics approval and consent to participate**

Not applicable.

**Consent for publication**

Not applicable.

**Competing interests**

B. G. reports receipt of nonfinancial support from Gilead Sciences, MSD, and Pfizer, outside the submitted work.

Received: 9 September 2025 / Accepted: 16 September 2025

Published online: 17 November 2025

**References**

1. Wang L, Cheng J. High-flow nasal cannula and intubation risk in severe PjP: methodological and clinical perspectives. Ann Intensive Care. 2025;2025:1 (in press).

2. Reizine F, et al. Respiratory management of critically ill pneumocystis pneumonia patients: a multicenter retrospective study. Ann Intensive Care. 2025;15:114.

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