# Characteristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease

Romain Lécuyer, Nahéma Issa, Fabrice Camou, Rose-Anne Lavergne, Frederic Gabriel, Florent Morio, Emmanuel Canet, François Raffi, David Boutoille, Anne Cady, et al.

<figure><img src="image_1.png" /></figure>

► To cite this version:

Romain Lécuyer, Nahéma Issa, Fabrice Camou, Rose-Anne Lavergne, Frederic Gabriel, et al. Charac-teristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease. Chest, 2024, pp.S0012-3692(24)00022-9. 10.1016/j.chest.2024.01.015. inserm-04446239

HAL Id: inserm-04446239

https://inserm.hal.science/inserm-04446239

Submitted on 8 Feb 2024

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Distributed under a Creative Commons Attribution 4.0 International License
# Characteristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease

Romain Lécuyer, Nahéma Issa, Fabrice Camou, Rose-anne Lavergne, Frederic Gabriel, Florent Morio, Emmanuel Canet, François Raffi, David Boutoille, Anne Cady, et al.

► To cite this version:

Romain Lécuyer, Nahéma Issa, Fabrice Camou, Rose-anne Lavergne, Frederic Gabriel, et al. Characteristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease. Chest, 2024, pp.S0012-3692(24)00022-9. 10.1016/j.chest.2024.01.015. inserm-04446239

HAL Id: inserm-04446239

https://inserm.hal.science/inserm-04446239v1

Submitted on 8 Feb 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Characteristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease

## A Retrospective Multicenter Study

Romain Lécuyer, MD, PharmD; Nahéma Issa, MD; Fabrice Camou, MD; Rose-anne Lavergne, PharmD, PhD; Frederic Gabriel, MD, PhD; Florent Morio, PharmD, PhD; Emmanuel Canet, MD, PhD; François Raffi, MD, PhD; David Boutoille, MD, PhD; Anne Cady, PharmD; Marie Gousseff, MD; Yoann Crabol, MD; Antoine Néel, MD, PhD; Benoît Tessoulin, MD, PhD; and Benjamin Gaborit, MD, PhD; and the PRONOCYSTIS Study Group*

**BACKGROUND:** Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical presentation, severity, and mortality of PcP has not been adequately evaluated.

**RESEARCH QUESTION:** Does the underlying disease and immunosuppression causing PcP impact the outcome and clinical presentation of the disease?

**STUDY DESIGN AND METHODS:** In this multicenter retrospective observational study, conducted from January 2011 to December 2021, all consecutive patients admitted with a proven or probable diagnosis of PcP according to The European Organisation for Research and Treatment of Cancer consensus definitions were included to assess the epidemiology and impact of underlying immunosuppressive diseases on overall and 90-day mortality.

**RESULTS:** Overall, 481 patients were included in the study; 180 (37.4%) were defined as proven PcP and 301 (62.6%) were defined as probable PcP. Patients with immune-mediated inflammatory diseases (IMIDs) or solid tumors had a statistically poorer prognosis than other patients with PcP at day 90. In multivariate analysis, among the HIV-negative population, solid tumor underlying disease (OR, 5.47; 95% CI, 2.16-14.1; *P* < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; *P* = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; *P* = .045), cysts in sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; *P* = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; *P* < .001) were independently associated with 90-day mortality. Prior corticotherapy was the only immunosuppressant associated with 90-day mortality (OR, 1.67; 95% CI, 1.03-2.71; *P* = .035), especially for a prednisone daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; *P* = .010).

**INTERPRETATION:** Among patients who were HIV-negative, long-term corticosteroid prior to PcP diagnosis was independently associated with increased 90-day mortality, specifically in patients with IMIDs. These results highlight both the needs for PcP prophylaxis in patients with IMIDs and to early consider PcP curative treatment in severe pneumonia among patients with IMIDs.

**KEY WORDS:** corticosteroids; immune-mediated inflammatory diseases; Pneumocystis jirovecii pneumonia; outcome; solid tumors
# Characteristics and Prognosis Factors of Pneumocystis jirovecii Pneumonia According to Underlying Disease

## A Retrospective Multicenter Study

Romain Lécuyer, MD, PharmD; Nahéma Issa, MD; Fabrice Camou, MD; Rose-anne Lavergne, PharmD, PhD; Frederic Gabriel, MD, PhD; Florent Morio, PharmD, PhD; Emmanuel Canet, MD, PhD; François Raffi, MD, PhD; David Boutoille, MD, PhD; Anne Cady, PharmD; Marie Gousseff, MD; Yoann Crabol, MD; Antoine Néel, MD, PhD; Benoît Tessoulin, MD, PhD; and Benjamin Gaborit, MD, PhD; and the PRONOCYSTIS Study Group*

**BACKGROUND:** Pneumocystis jirovecii pneumonia (PcP) remains associated with high rates of mortality, and the impact of immunocompromising underlying disease on the clinical presentation, severity, and mortality of PcP has not been adequately evaluated.

**RESEARCH QUESTION:** Does the underlying disease and immunosuppression causing PcP impact the outcome and clinical presentation of the disease?

**STUDY DESIGN AND METHODS:** In this multicenter retrospective observational study, conducted from January 2011 to December 2021, all consecutive patients admitted with a proven or probable diagnosis of PcP according to The European Organisation for Research and Treatment of Cancer consensus definitions were included to assess the epidemiology and impact of underlying immunosuppressive diseases on overall and 90-day mortality.

**RESULTS:** Overall, 481 patients were included in the study; 180 (37.4%) were defined as proven PcP and 301 (62.6%) were defined as probable PcP. Patients with immune-mediated inflammatory diseases (IMIDs) or solid tumors had a statistically poorer prognosis than other patients with PcP at day 90. In multivariate analysis, among the HIV-negative population, solid tumor underlying disease (OR, 5.47; 95% CI, 2.16-14.1; *P* < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; *P* = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; *P* = .045), cysts in sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; *P* = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; *P* < .001) were independently associated with 90-day mortality. Prior corticotherapy was the only immunosuppressant associated with 90-day mortality (OR, 1.67; 95% CI, 1.03-2.71; *P* = .035), especially for a prednisone daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; *P* = .010).

**INTERPRETATION:** Among patients who were HIV-negative, long-term corticosteroid prior to PcP diagnosis was independently associated with increased 90-day mortality, specifically in patients with IMIDs. These results highlight both the needs for PcP prophylaxis in patients with IMIDs and to early consider PcP curative treatment in severe pneumonia among patients with IMIDs.

**KEY WORDS:** corticosteroids; immune-mediated inflammatory diseases; Pneumocystis jirovecii pneumonia; outcome; solid tumors
Take-home Points

**Study Question:** Does the underlying disease and immunosuppression causing *Pneumocystis jirovecii* pneumonia (PcP) impact the outcome and clinical presentation of the disease?

**Results:** We present the findings of a cohort study involving 481 patients diagnosed with probable or proven PcP to assess the impact of various immunocompromising underlying conditions on the clinical presentation and mortality associated with PcP. This large multicenter study is the first to identify patients with immune-mediated inflammatory diseases (IMIDs), solid tumors, and prolonged corticosteroid therapy as independent factors contributing to 90-day mortality. Notably, patients with IMIDs, particularly those exposed to long-term corticosteroid therapy, exhibit the most unfavorable prognosis compared with other immunocompromised conditions.

**Interpretation:** These results highlight that, across all patient categories, patients with IMID and solid tumors experience the most severe forms of PcP and the highest mortality rates. Additionally, a history of prior long-term corticosteroid therapy was associated with a poor prognosis, especially among patients with IMIDs. These findings emphasize the necessity of considering PcP prophylaxis for patients with IMIDs and promptly initiating PcP treatment in cases of severe pneumonia in this specific population.

The growing number of patients undergoing immunosuppressive treatments and the development of new biotherapies for hematologic malignancies, solid organ transplantations, or immune-mediated inflammatory diseases (IMIDs) has led to the emergence of new conditions for opportunistic

pulmonary fungal infections. Currently, around three-quarters of *Pneumocystis jirovecii* pneumonia (PcP) cases are diagnosed in patients who are HIV-negative in high-income countries.¹,² HIV-negative PcP is associated with a higher morbidity and mortality rate, and may be more challenging to diagnose than in patients who are HIV-positive; therefore, it is necessary to further improve risk reduction, diagnosis,¹⁸ and treatment procedures. In the HIV-negative population, the prognosis of PcP is highly variable, suggesting that the underlying disease and immunosuppressive therapies both have an impact on the severity and outcome of this infection.³ Prior corticosteroid therapy has been identified as a risk factor for PcP⁴⁻⁶ and has been associated with mortality.⁷ The advent of new immunosuppressive treatments raise the question of the appropriate criteria to introduce primary prophylaxis.⁸ We previously reported that the pattern of immune responses,⁹ and respiratory coinfection by cytomegalovirus (CMV)¹⁰ as a probable marker of profound immunosuppression, were associated with a worse prognosis. However, the impact of underlying disease and of specific immunologic disorders on the clinical presentation, severity, and mortality of PcP is poorly studied in the contemporary cohorts of patients. Investigating the features and the prognosis of PcP subpopulations according to the underlying disease and immunosuppressive therapies may allow an earlier diagnosis of PcP and a faster initiation of anti-*Pneumocystis* treatment.¹⁹

In this study, we took a large multicenter cohort of patients with probable or proven PcP from three French hospitals over 10 years of follow-up and studied the impact of the immunocompromising underlying disease and of the type of immunosuppressive treatment on the clinical presentation and mortality of PcP.

**ABBREVIATIONS:** CMV = cytomegalovirus; IMID = immune-mediated inflammatory disease; PcP = *Pneumocystis jirovecii* pneumonia; SOFA = Sequential Organ Failure Assessment

**AFFILIATIONS:** From Internal Medicine and Infectious Diseases (R. L., M. G., and Y. C.), Centre Hospitalier Bretagne-Atlantique, Vannes; Nantes Université (R. L., R.-a. L., and F. M.), CHU Nantes, Cibles et médicaments des infections et de l'immunité, IICiMed, UR1155, Nantes; the Intensive Care and Infectious Disease Unit (N. I. and F. C.), Groupe Saint-André, University Hospital, Bordeaux; the Centre Hospitalier Universitaire de Bordeaux (F. G.), Service de Parasitologie Mycologie, Bordeaux; the Laboratoire de Parasitologie-Mycologie (F. M.), Institut de Biologie, University Hospital, Nantes; the Medical Intensive Care (E. C.), University Hospital, Nantes; the Department of Infectious Diseases (F. R., D. B., and B. G.), University Hospital of Nantes and Centre d'Investigation Clinique 1413, INSERM, Nantes; the Nantes Université (D. B. and B. G.), CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR

1064, Nantes; the Department of Microbiology (A. C.), Centre Hospitalier Bretagne-Atlantique, Vannes; the CRTI UMR 1064 (A. N.), INSERM, Université de Nantes, Nantes; the Department of Internal Medicine (A. N.), University Hospital, Nantes; and the INSERM (B. T.), U1232, Hematology Department, Nantes University Hospital, CRCI²NA, Nantes University, Nantes, France.

*Collaborators from the PRONOCYSTIS Study Group are listed in the Acknowledgments.

Drs Lécuyer and Issa contributed equally to this manuscript.

**CORRESPONDENCE TO:** Benjamin Gaborit, MD, PhD; email: benjamin.gaborit@chu-nantes.fr

Copyright © 2024 The Author(s). Published by Elsevier Inc under license from the American College of Chest Physicians. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

**DOI:** https://doi.org/10.1016/j.chest.2024.01.015
Take-home Points

**Study Question:** Does the underlying disease and immunosuppression causing *Pneumocystis jirovecii* pneumonia (PcP) impact the outcome and clinical presentation of the disease?

**Results:** We present the findings of a cohort study involving 481 patients diagnosed with probable or proven PcP to assess the impact of various immunocompromising underlying conditions on the clinical presentation and mortality associated with PcP. This large multicenter study is the first to identify patients with immune-mediated inflammatory diseases (IMIDs), solid tumors, and prolonged corticosteroid therapy as independent factors contributing to 90-day mortality. Notably, patients with IMIDs, particularly those exposed to long-term corticosteroid therapy, exhibit the most unfavorable prognosis compared with other immunocompromised conditions.

**Interpretation:** These results highlight that, across all patient categories, patients with IMID and solid tumors experience the most severe forms of PcP and the highest mortality rates. Additionally, a history of prior long-term corticosteroid therapy was associated with a poor prognosis, especially among patients with IMIDs. These findings emphasize the necessity of considering PcP prophylaxis for patients with IMIDs and promptly initiating PcP treatment in cases of severe pneumonia in this specific population.

The growing number of patients undergoing immunosuppressive treatments and the development of new biotherapies for hematologic malignancies, solid organ transplantations, or immune-mediated inflammatory diseases (IMIDs) has led to the emergence of new conditions for opportunistic

pulmonary fungal infections. Currently, around three-quarters of *Pneumocystis jirovecii* pneumonia (PcP) cases are diagnosed in patients who are HIV-negative in high-income countries.¹,² HIV-negative PcP is associated with a higher morbidity and mortality rate, and may be more challenging to diagnose than in patients who are HIV-positive; therefore, it is necessary to further improve risk reduction, diagnosis,⁹ and treatment procedures. In the HIV-negative population, the prognosis of PcP is highly variable, suggesting that the underlying disease and immunosuppressive therapies both have an impact on the severity and outcome of this infection.³ Prior corticosteroid therapy has been identified as a risk factor for PcP⁴⁻⁶ and has been associated with mortality.⁷ The advent of new immunosuppressive treatments raise the question of the appropriate criteria to introduce primary prophylaxis.⁸ We previously reported that the pattern of immune responses,⁹ and respiratory coinfection by cytomegalovirus (CMV)¹⁰ as a probable marker of profound immunosuppression, were associated with a worse prognosis. However, the impact of underlying disease and of specific immunologic disorders on the clinical presentation, severity, and mortality of PcP is poorly studied in the contemporary cohorts of patients. Investigating the features and the prognosis of PcP subpopulations according to the underlying disease and immunosuppressive therapies may allow an earlier diagnosis of PcP and a faster initiation of anti-*Pneumocystis* treatment.⁹

In this study, we took a large multicenter cohort of patients with probable or proven PcP from three French hospitals over 10 years of follow-up and studied the impact of the immunocompromising underlying disease and of the type of immunosuppressive treatment on the clinical presentation and mortality of PcP.

**ABBREVIATIONS:** CMV = cytomegalovirus; IMID = immune-mediated inflammatory disease; PcP = *Pneumocystis jirovecii* pneumonia; SOFA = Sequential Organ Failure Assessment

**AFFILIATIONS:** From Internal Medicine and Infectious Diseases (R. L., M. G., and Y. C.), Centre Hospitalier Bretagne-Atlantique, Vannes; Nantes Université (R. L., R.-a. L., and F. M.), CHU Nantes, Cibles et médicaments des infections et de l'immunité, IICiMed, UR1155, Nantes; the Intensive Care and Infectious Disease Unit (N. I. and F. C.), Groupe Saint-André, University Hospital, Bordeaux; the Centre Hospitalier Universitaire de Bordeaux (F. G.), Service de Parasitologie Mycologie, Bordeaux; the Laboratoire de Parasitologie-Mycologie (F. M.), Institut de Biologie, University Hospital, Nantes; the Medical Intensive Care (E. C.), University Hospital, Nantes; the Department of Infectious Diseases (F. R., D. B., and B. G.), University Hospital of Nantes and Centre d'Investigation Clinique 1413, INSERM, Nantes; the Nantes Université (D. B. and B. G.), CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR

1064, Nantes; the Department of Microbiology (A. C.), Centre Hospitalier Bretagne-Atlantique, Vannes; the CRTI UMR 1064 (A. N.), INSERM, Université de Nantes, Nantes; the Department of Internal Medicine (A. N.), University Hospital, Nantes; and the INSERM (B. T.), U1232, Hematology Department, Nantes University Hospital, CRCI²NA, Nantes University, Nantes, France.

*Collaborators from the PRONOCYSTIS Study Group are listed in the Acknowledgments.

Drs Lécuyer and Issa contributed equally to this manuscript.

**CORRESPONDENCE TO:** Benjamin Gaborit, MD, PhD; email: benjamin.gaborit@chu-nantes.fr

Copyright © 2024 The Author(s). Published by Elsevier Inc under license from the American College of Chest Physicians. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

**DOI:** https://doi.org/10.1016/j.chest.2024.01.015
# Study Design and Methods

## Study Design and Population

This study is a substudy from the PRONOCYSTIS cohort,¹⁰ a retrospective multicenter network involving three French hospitals. All consecutive patients admitted with a proven or probable diagnosis of PcP according to The European Organisation for Research and Treatment of Cancer and the Mycoses Study Group¹¹ consensus definitions of invasive fungal diseases from January 2011 to December 2021 were retrospectively included. Patients were followed-up for at least a year.

The study was designed in accordance with the Declaration of Helsinki and conducted in accordance with French legislation with approval obtained from the local ethics committee (groupe nantais d'éthique dans le domaine de la santé [GNEDS] No. 23-34-03-091).

## Data Collection

For each case, data were collected for patient demographic characteristics, underlying disease, immunosuppressive treatment exposition during the year prior to PcP onset, use of PcP prophylaxis, nature of symptoms and time from symptoms onset to PcP diagnosis and hospital admission, laboratory findings, presence of other pathogenic microorganisms (bacteria, virus, or fungi) on diagnostic respiratory samples, use of corticosteroid therapy and its duration, oxygen requirement, and ventilatory support at admission. The Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score II were retrospectively determined for each patient at the time of PcP diagnosis based on the medical records. If any parameters required were missing, the score values were treated as missing data. The retrospective assessments of $F_{102}$ in non-ICU patients were approximated using a concordance table (with estimated $F_{102}$ values for nasal oxygen = 0.3, mask oxygen = 0.4, and reservoir mask = 0.6).¹² Finally, final outcome with 90-day mortality was registered in the study database.

## Definitions

Criteria for PcP diagnosis involved compatible clinical presentation (fever, respiratory symptoms, cough, dyspnea, and hypoxemia) and an interstitial syndrome on chest radiograph or CT scan, along with mycologic evidence for *P. jirovecii* in respiratory samples, induced sputum, bronchial aspiration fluid, or BAL. PcP was proven when *P. jirovecii* asci (cysts) were found at direct microscopic examination. Probable PcP was determined by a negative direct mycologic examination but a positive *P. jirovecii* qPCR (laboratory-defined threshold) in respiratory sample,¹¹ associated with a compatible clinico-radiologic presentation. Colonization was defined as the presence of a positive real-time polymerase chain reaction without meeting the clinical and/or radiologic criteria for a proven or

# Results

## Patient Characteristics

Over the 10-year study period, a total of 8,508 respiratory samples were tested for *P. jirovecii* across the three hospitals, with 1,238 patients having a positive *P. jirovecii* qPCR. After assessment of clinical and radiologic data, 508 patients were categorized as probable or proven PcP (730 colonized patients were excluded). Of these, nine patients < 18 years of age and 18 patients with missing data during follow-up

probable diagnosis of PcP. PcP cases involving patients < 18 years of age or with mortality missing data were excluded from the study. Date of PcP diagnosis was the day of confirmation by mycologic investigation (direct examination or qPCR).

Several predisposing clinical conditions were considered, including HIV infection, hematologic malignancies, progressive cancer, solid organ transplantation, and IMIDs. Ongoing immunosuppressive or immunomodulatory treatment did not constitute an independent subgroup of predisposing condition but was an analysis parameter. Patients undergoing corticosteroid treatment were considered to be immunosuppressed if they had been receiving > 7 days at a dose ≥ 1 mg/kg/d (prednisone equivalent) or for > 3 months at a lower dose. When a patient had several predisposing conditions (n = 30), the underlying disease chronologically associated with the onset of PcP was considered (eg, an immuno-virologically controlled patient who was HIV-positive receiving secondary chemotherapy for lung cancer would be classified in the solid oncology group).

Adjuvant corticosteroid therapy was defined as any current or initiated high-dose steroid treatment justified by a PcP severe form, with a regimen similar to that used for patients with HIV with severe PcP.¹³

## Statistical Analysis

Patient characteristics were described using mean ± SD for continuous variables (or 95% CI when appropriate) and proportions for qualitative variables. Overall survival estimates were assessed using the Kaplan-Meier method. To remove potential biases associated with underlying condition impact on overall outcome in the long term, 90-day all-cause mortality was used (as previously described¹⁰). Preanalysis of the dataset did not show discrepancies across centers (n = 3) for the results, and we decided to carry on with a fixed-effect logistic regression model. All regression tests (OR estimates and CIs) for 90-day mortality were performed on variables involving > 10 events. The multivariate analysis was primarily performed to assess the respective weights of each variable, taking into account the other variables as fixed. Factors associated with 90-day mortality were identified by logistic regression analysis. Only factors reaching statistical significance (P < .05), with no more than 10% missing data, were included in the multivariate model. For subcategory comparisons with a low number of occurrences, numbers and percentages are given. When colinearity between covariates was detected, only the variable with the highest OR was kept in the multivariate regression model. Results were reported as log-transformed coefficients with their 95% CIs. Missing data were not interpolated. Analyses were performed on the overall population and then on the HIV-negative and IMIDs subgroups, taking into account respective missing data percentages. All analyses were conducted in R (4.3.1), using the finalfit and survminer packages.

were excluded (Fig 1). A total of 481 patients were therefore included, of which 180 (37.4%) were defined as having proven PcP and 301 (62.6%) as having probable PcP. The baseline characteristics of the included patients are shown in Table 1 (comparison according to HIV status in e-Table 1 or to other underlying diseases in e-Table 2). All patients from this cohort were immunocompromised with hematologic malignancy ranking first (n = 118, 24.5%), followed by HIV infection (n = 114, 23.7%), solid organ transplantation (n = 103, 21.4%), IMIDs
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# Study Design and Methods

## Study Design and Population

This study is a substudy from the PRONOCYSTIS cohort,¹⁰ a retrospective multicenter network involving three French hospitals. All consecutive patients admitted with a proven or probable diagnosis of PcP according to The European Organisation for Research and Treatment of Cancer and the Mycoses Study Group¹¹ consensus definitions of invasive fungal diseases from January 2011 to December 2021 were retrospectively included. Patients were followed-up for at least a year.

The study was designed in accordance with the Declaration of Helsinki and conducted in accordance with French legislation with approval obtained from the local ethics committee (groupe nantais d'éthique dans le domaine de la santé [GNEDS] No. 23-34-03-091).

## Data Collection

For each case, data were collected for patient demographic characteristics, underlying disease, immunosuppressive treatment exposition during the year prior to PcP onset, use of PcP prophylaxis, nature of symptoms and time from symptoms onset to PcP diagnosis and hospital admission, laboratory findings, presence of other pathogenic microorganisms (bacteria, virus, or fungi) on diagnostic respiratory samples, use of corticosteroid therapy and its duration, oxygen requirement, and ventilatory support at admission. The Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score II were retrospectively determined for each patient at the time of PcP diagnosis based on the medical records. If any parameters required were missing, the score values were treated as missing data. The retrospective assessments of $F_{102}$ in non-ICU patients were approximated using a concordance table (with estimated $F_{102}$ values for nasal oxygen = 0.3, mask oxygen = 0.4, and reservoir mask = 0.6).¹² Finally, final outcome with 90-day mortality was registered in the study database.

## Definitions

Criteria for PcP diagnosis involved compatible clinical presentation (fever, respiratory symptoms, cough, dyspnea, and hypoxemia) and an interstitial syndrome on chest radiograph or CT scan, along with mycologic evidence for *P. jirovecii* in respiratory samples, induced sputum, bronchial aspiration fluid, or BAL. PcP was proven when *P. jirovecii* asci (cysts) were found at direct microscopic examination. Probable PcP was determined by a negative direct mycologic examination but a positive *P. jirovecii* qPCR (laboratory-defined threshold) in respiratory sample,¹¹ associated with a compatible clinico-radiologic presentation. Colonization was defined as the presence of a positive real-time polymerase chain reaction without meeting the clinical and/or radiologic criteria for a proven or

# Results

## Patient Characteristics

Over the 10-year study period, a total of 8,508 respiratory samples were tested for *P. jirovecii* across the three hospitals, with 1,238 patients having a positive *P. jirovecii* qPCR. After assessment of clinical and radiologic data, 508 patients were categorized as probable or proven PcP (730 colonized patients were excluded). Of these, nine patients < 18 years of age and 18 patients with missing data during follow-up

probable diagnosis of PcP. PcP cases involving patients < 18 years of age or with mortality missing data were excluded from the study. Date of PcP diagnosis was the day of confirmation by mycologic investigation (direct examination or qPCR).

Several predisposing clinical conditions were considered, including HIV infection, hematologic malignancies, progressive cancer, solid organ transplantation, and IMIDs. Ongoing immunosuppressive or immunomodulatory treatment did not constitute an independent subgroup of predisposing condition but was an analysis parameter. Patients undergoing corticosteroid treatment were considered to be immunosuppressed if they had been receiving > 7 days at a dose ≥ 1 mg/kg/d (prednisone equivalent) or for > 3 months at a lower dose. When a patient had several predisposing conditions (n = 30), the underlying disease chronologically associated with the onset of PcP was considered (eg, an immuno-virologically controlled patient who was HIV-positive receiving secondary chemotherapy for lung cancer would be classified in the solid oncology group).

Adjuvant corticosteroid therapy was defined as any current or initiated high-dose steroid treatment justified by a PcP severe form, with a regimen similar to that used for patients with HIV with severe PcP.¹³

## Statistical Analysis

Patient characteristics were described using mean ± SD for continuous variables (or 95% CI when appropriate) and proportions for qualitative variables. Overall survival estimates were assessed using the Kaplan-Meier method. To remove potential biases associated with underlying condition impact on overall outcome in the long term, 90-day all-cause mortality was used (as previously described¹⁰). Preanalysis of the dataset did not show discrepancies across centers (n = 3) for the results, and we decided to carry on with a fixed-effect logistic regression model. All regression tests (OR estimates and CIs) for 90-day mortality were performed on variables involving > 10 events. The multivariate analysis was primarily performed to assess the respective weights of each variable, taking into account the other variables as fixed. Factors associated with 90-day mortality were identified by logistic regression analysis. Only factors reaching statistical significance (P < .05), with no more than 10% missing data, were included in the multivariate model. For subcategory comparisons with a low number of occurrences, numbers and percentages are given. When colinearity between covariates was detected, only the variable with the highest OR was kept in the multivariate regression model. Results were reported as log-transformed coefficients with their 95% CIs. Missing data were not interpolated. Analyses were performed on the overall population and then on the HIV-negative and IMIDs subgroups, taking into account respective missing data percentages. All analyses were conducted in R (4.3.1), using the finalfit and survminer packages.

were excluded (Fig 1). A total of 481 patients were therefore included, of which 180 (37.4%) were defined as having proven PcP and 301 (62.6%) as having probable PcP. The baseline characteristics of the included patients are shown in Table 1 (comparison according to HIV status in e-Table 1 or to other underlying diseases in e-Table 2). All patients from this cohort were immunocompromised with hematologic malignancy ranking first (n = 118, 24.5%), followed by HIV infection (n = 114, 23.7%), solid organ transplantation (n = 103, 21.4%), IMIDs

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330
<figure><img src="image_3.png" /><figcaption>Figure 1 – Flowchart of the study. PcP = Pneumocystis jirovecii pneumonia.</figcaption></figure>

(n = 87, 18.1%), solid tumor (n = 56, 11.6%), and other immunodeficiency (n = 3, 0.6%). The mean CD4 T lymphocyte count at the time of PcP diagnosis was significantly higher in the HIV-negative group than in the HIV-positive group (292 ± 360 vs 64 ± 129/mm³, respectively; *P* < .001). Only 50 of 481 patients (10.4%) were given PcP prophylaxis prior to their PcP episode. Trimethoprim-sulfamethoxazole was used as first-line therapy for 443 patients (92.1%), and adjuvant corticosteroid therapy was administered to 226 patients (47.0%). The average SOFA score was 3.3 ± 3.0. The 90-day mortality rate was 25.6% (n = 123). BAL was conducted at PcP diagnosis in 342 patients (71.1%). The detailed characteristics of BAL according to patient groups are presented in e-Table 3.

Previous Immunosuppressive Treatments

Among the overall population, 330 patients (89.9%) who were HIV-negative had received immunosuppressive treatment prior to PcP diagnosis (e-Table 4). The most common immunosuppressants were corticosteroids (n = 232, 63.2%), with an average dose of 29.2 mg/ d prednisone equivalent. Prior corticosteroid therapy was more frequent in patients with IMIDs (79 of 87 [90.8%] vs 152 of 280 [54.3%]; OR, 8.25; 95% CI, 3.84- 17.7; *P* < .001) and given at higher doses (31.0 vs 19.5 mg/d; *P* = .008) (e-Table 4).

Outcomes and Predictors of 90-Day Mortality

Patients with IMIDs and solid tumors had a statistically significant worse outcome at 90 days (e-Figs 1, 2; Fig 2), whereas patients who were HIV-positive had the best survival rate at 90 days (Fig 2, Table 2). Of the 56 patients with solid tumors, 36 (64.3%) had metastatic

disease, which was associated with 90-day mortality in the univariate analysis (OR, 4.71; 95% CI, 1.40-15.9; *P* = .010). Subtype of hematologic disease was not associated with 90-day mortality, as indicated in e-Table 5.

Among the overall population in multivariate analysis, solid tumor underlying disease (OR, 5.73; 95% CI, 2.25- 14.84; *P* < .01), long-term corticosteroid use (OR, 2.25; 95% CI, 1.12-4.71; *P* = .026), and SOFA score at admission (OR, 1.63; 95% CI, 1.44-1.87; *P* < .001) were independently associated with 90-day mortality.

Among patients who were HIV-negative, solid tumor (OR, 5.47; 95% CI, 2.16-14.1; *P* < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; *P* = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; *P* = .045), positive direct examination of sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; *P* = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; *P* < .001) were independently associated with higher 90-day mortality in multivariate analysis (Fig 3, Table 3). Prior corticotherapy was no longer associated with 1-year mortality (Fig 3). Finally, prior corticotherapy was the only immunosuppressive drug associated with 90-day mortality (OR, 1.67; 95% CI, 1.03- 2.71; *P* = .035), especially for a daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; *P* = .010) (Table 3).

In patients who were HIV-positive, 69.3% presented positive direct examination of sputum/BAL smears without significant association with 90-day mortality (n = 74; OR, 0.47; 95% CI, 0.08-2.72; *P* = .394) nor with a neutrophilic BAL profile (n = 57; OR, 0.41; 95% CI, 0.07-2.45; *P* = .317). Conversely, only 27.5% of patients who were HIV-negative presented positive direct examination of sputum/BAL smears (e-Table 1), which was associated with high 90-day mortality
<figure><img src="image_2.png" /><figcaption>Figure 1 – Flowchart of the study. PcP = Pneumocystis jirovecii pneumonia.</figcaption></figure>

(n = 87, 18.1%), solid tumor (n = 56, 11.6%), and other immunodeficiency (n = 3, 0.6%). The mean CD4 T lymphocyte count at the time of PcP diagnosis was significantly higher in the HIV-negative group than in the HIV-positive group (292 ± 360 vs 64 ± 129/mm³, respectively; *P* < .001). Only 50 of 481 patients (10.4%) were given PcP prophylaxis prior to their PcP episode. Trimethoprim-sulfamethoxazole was used as first-line therapy for 443 patients (92.1%), and adjuvant corticosteroid therapy was administered to 226 patients (47.0%). The average SOFA score was 3.3 ± 3.0. The 90-day mortality rate was 25.6% (n = 123). BAL was conducted at PcP diagnosis in 342 patients (71.1%). The detailed characteristics of BAL according to patient groups are presented in e-Table 3.

Previous Immunosuppressive Treatments

Among the overall population, 330 patients (89.9%) who were HIV-negative had received immunosuppressive treatment prior to PcP diagnosis (e-Table 4). The most common immunosuppressants were corticosteroids (n = 232, 63.2%), with an average dose of 29.2 mg/ d prednisone equivalent. Prior corticosteroid therapy was more frequent in patients with IMIDs (79 of 87 [90.8%] vs 152 of 280 [54.3%]; OR, 8.25; 95% CI, 3.84- 17.7; *P* < .001) and given at higher doses (31.0 vs 19.5 mg/d; *P* = .008) (e-Table 4).

Outcomes and Predictors of 90-Day Mortality

Patients with IMIDs and solid tumors had a statistically significant worse outcome at 90 days (e-Figs 1, 2; Fig 2), whereas patients who were HIV-positive had the best survival rate at 90 days (Fig 2, Table 2). Of the 56 patients with solid tumors, 36 (64.3%) had metastatic

disease, which was associated with 90-day mortality in the univariate analysis (OR, 4.71; 95% CI, 1.40-15.9; *P* = .010). Subtype of hematologic disease was not associated with 90-day mortality, as indicated in e-Table 5.

Among the overall population in multivariate analysis, solid tumor underlying disease (OR, 5.73; 95% CI, 2.25- 14.84; *P* < .01), long-term corticosteroid use (OR, 2.25; 95% CI, 1.12-4.71; *P* = .026), and SOFA score at admission (OR, 1.63; 95% CI, 1.44-1.87; *P* < .001) were independently associated with 90-day mortality.

Among patients who were HIV-negative, solid tumor (OR, 5.47; 95% CI, 2.16-14.1; *P* < .001), IMIDs (OR, 2.19; 95% CI, 1.05-4.60; *P* = .037), long-term corticosteroid exposure (OR, 2.07; 95% CI, 1.03-4.31; *P* = .045), positive direct examination of sputum/BAL smears (OR, 1.92; 95% CI, 1.02-3.62; *P* = .043), and SOFA score at admission (OR, 1.58; 95% CI, 1.39-1.82; *P* < .001) were independently associated with higher 90-day mortality in multivariate analysis (Fig 3, Table 3). Prior corticotherapy was no longer associated with 1-year mortality (Fig 3). Finally, prior corticotherapy was the only immunosuppressive drug associated with 90-day mortality (OR, 1.67; 95% CI, 1.03- 2.71; *P* = .035), especially for a daily dose ≥ 10 mg (OR, 1.80; 95% CI, 1.14-2.85; *P* = .010) (Table 3).

In patients who were HIV-positive, 69.3% presented positive direct examination of sputum/BAL smears without significant association with 90-day mortality (n = 74; OR, 0.47; 95% CI, 0.08-2.72; *P* = .394) nor with a neutrophilic BAL profile (n = 57; OR, 0.41; 95% CI, 0.07-2.45; *P* = .317). Conversely, only 27.5% of patients who were HIV-negative presented positive direct examination of sputum/BAL smears (e-Table 1), which was associated with high 90-day mortality
<table><caption>**TABLE 1**] Characteristics of Patients at the Time of Diagnosis of PcP and Follow-up (N = 481)</caption><thead><tr><th>Characteristic</th><th>Value</th></tr></thead><tbody><tr><td>Age, y</td><td>58.2 ± 14.7</td></tr><tr><td>Male</td><td>306 (63.6)</td></tr><tr><td>BMI, kg/m²</td><td>22.94 ± 9.7</td></tr><tr><td>Albumin, g/L</td><td>27.7 ± 13.9</td></tr><tr><td>Chronic underlying disease</td><td></td></tr><tr><td>Chronic kidney disease</td><td>166 (34.5)</td></tr><tr><td>Chronic pulmonary disease</td><td>101 (21.0)</td></tr><tr><td>Underlying cause of immunodeficiency</td><td></td></tr><tr><td>Hemotologic malignancy</td><td>118 (24.5)</td></tr><tr><td>Acute leukemia</td><td>34 (7.1)</td></tr><tr><td>Lymphoma</td><td>32 (6.7)</td></tr><tr><td>Chronic lymphoid leukemia</td><td>25 (5.2)</td></tr><tr><td>Multiple myeloma</td><td>15 (3.1)</td></tr><tr><td>Myelodysplastic syndrome</td><td>10 (2.1)</td></tr><tr><td>Chronic myelomonocytic leukemia</td><td>2 (0.4)</td></tr><tr><td>Allogeneic HSCT</td><td>32 (6.7)</td></tr><tr><td>Autologous HSCT</td><td>9 (1.9)</td></tr><tr><td>HIV infection</td><td>114 (23.7)</td></tr><tr><td>Therapeutic rupture</td><td>68 (14.1)</td></tr><tr><td>Discovery of HIV-positive status</td><td>46 (9.6)</td></tr><tr><td>Solid organ transplantation</td><td>103 (21.4)</td></tr><tr><td>Immune-mediated inflammatory disease</td><td>87 (18.1)</td></tr><tr><td>Solid tumor</td><td>56 (11.6)</td></tr><tr><td>Others<sup>a</sup></td><td>3 (0.6)</td></tr><tr><td>Ongoing immunosuppressive therapy</td><td>334 (69.4)</td></tr><tr><td>Symptoms</td><td></td></tr><tr><td>Dyspnea<sup>b</sup></td><td>396 (82.3)</td></tr><tr><td>Hyperthermia</td><td>355 (73.8)</td></tr><tr><td>Cough</td><td>309 (64.2)</td></tr><tr><td>Alteration of general condition</td><td>290 (60.3)</td></tr><tr><td>Positive sputum/BAL direct examination (cysts in smears)</td><td>180 (37.4)</td></tr><tr><td>Prophylaxis prescribed</td><td>50 (10.4)</td></tr><tr><td>Aerosolized pentamidine</td><td>15 (3.1)</td></tr><tr><td>TMP-SMX</td><td>25 (5.2)</td></tr><tr><td>Atovaquone</td><td>9 (1.9)</td></tr><tr><td>Prophylaxis observance during the last 2 mo</td><td>26 (5.4)</td></tr><tr><td>Aerosolized pentamidine</td><td>11 (2.3)</td></tr><tr><td>TMP-SMX</td><td>8 (1.7)</td></tr><tr><td>Atovaquone</td><td>6 (1.2)</td></tr><tr><td>Time from symptom onset to, d</td><td></td></tr><tr><td>Hospitalization</td><td>14.3 ± 27.6</td></tr></tbody></table>

(Continued)

<table><caption>**TABLE 1**] (Continued)</caption><thead><tr><th>Characteristic</th><th>Value</th></tr></thead><tbody><tr><td>Diagnostic</td><td>20.1 ± 27.1</td></tr><tr><td>Anti-Pneumocystis treatment</td><td>19.9 ± 26.9</td></tr><tr><td>SAPS II score</td><td>34.4 ± 16.2</td></tr><tr><td>SOFA score</td><td>3.3 ± 3.0</td></tr><tr><td>ICU admission</td><td>237 (49.3)</td></tr><tr><td>ICU length of stay, d</td><td>13.2 ± 11.8</td></tr><tr><td>Laboratory findings</td><td></td></tr><tr><td>WBCs/mm³</td><td>7,579 ± 5,000</td></tr><tr><td>Neutrophils/mm³</td><td>6,093 ± 4,581</td></tr><tr><td>Lymphocytes/mm³, c</td><td>828 ± 800</td></tr><tr><td>CD4/mm³, d</td><td>182 ± 227</td></tr><tr><td>CRP, mg/L<sup>e</sup></td><td>109 ± 100</td></tr><tr><td>LDH, International Units/L<sup>f</sup></td><td>460 ± 250</td></tr><tr><td>Time from diagnosis to PcP treatment</td><td>-0.2 ± 2.4</td></tr><tr><td>Anti-Pneumocystis treatment</td><td></td></tr><tr><td>TMP-SMX</td><td>443 (92.1)</td></tr><tr><td>Atovaquone</td><td>95 (19.8)</td></tr><tr><td>IV pentamidine</td><td>12 (2.5)</td></tr><tr><td>Respiratory support</td><td>396 (82.3)</td></tr><tr><td>Mechanical ventilation</td><td>109 (22.7)</td></tr><tr><td>Exclusive noninvasive ventilation</td><td>15 (3.1)</td></tr><tr><td>Exclusive high-flow nasal oxygen therapy</td><td>44 (9.2)</td></tr><tr><td>Exclusive simple nasal oxygen therapy</td><td>190 (39.5)</td></tr><tr><td>Adjunctive corticotherapy</td><td>226 (47.0)</td></tr><tr><td>In-hospital mortality</td><td>102 (21.2)</td></tr><tr><td>90-d mortality</td><td>123 (25.6)</td></tr></tbody></table>

Values are mean ± SD or No. (%). CRP = C-reactive protein; HSCT = hematopoietic stem cell transplantation; LDH = lactate dehydrogenase; PcP = *Pneumocystis jirovecii* pneumonia; SAPS II = Simplified Acute Physiology Score II; SOFA = Sequential Organ Failure Assessment; TMP-SMX = trimethoprim-sulfamethoxazole.

<sup>a</sup>Of these three patients, two had Cushing syndrome and one had cirrhosis and lymphopenia without any immunosuppressants.

<sup>b</sup>Decreased FEV₁ included.

<sup>c</sup>Twenty-four missing values and 10 censored data from patients with leukemia.

<sup>d</sup>One hundred and seventy-four missing values.

<sup>e</sup>Thirty-nine missing values.

<sup>f</sup>Two hundred and thirty-two missing values.

<sup>g</sup>Eleven missing values.

(n = 257; OR, 1.94; 95% CI, 1.13-3.32; P = .016) and a neutrophilic BAL profile (n = 184; OR, 1.83; 95% CI, 0.97-3.42; P = .059) (Table 3).

### Characteristics of Patients With IMIDs and Their Prognosis

An overview of the diseases of the IMIDs group (n = 87) is given in e-Table 6. The most prevalent
<figure><img src="image_4.png" /><figcaption>Figure 2 – Survival analysis according to the underlying cause of immunodeficiency. HEM = hematologic malignancies; IMID = immunemediated inflammatory diseases; SOT = solid organ transplantation; ST = solid tumor.</figcaption></figure>

disease was rheumatoid arthritis (n = 14, 16.1%), followed by antineutrophil cytoplasmic antibody-associated vasculitis (n = 9, 10.3%) and sarcoidosis (n = 8, 9.2%). Seventy-nine patients with IMIDs (90.8%) received long-term corticosteroid therapy, 37 (42.5%) received antimetabolite drugs, and 17 (19.5%) received anti-CD20 monoclonal antibody therapy

<figure><img src="image_5.png" /><figcaption>Figure 3 – Survival analysis according to long-term steroid exposure prior to Pneumocystis jirovecii pneumonia diagnosis in patients who are HIV-negative. D90 = day 90.</figcaption></figure>

(e-Table 4) prior to PcP diagnosis. For 68 patients (78%), immunosuppressive treatment had been introduced or modified in the year prior to PcP diagnosis. The mean time between introduction or change of immunosuppressive therapy and the onset of PcP was 78 days.

Among patients who were HIV-negative, patients with IMIDs were the oldest (P < .001) and presented

<table><caption>TABLE 2 Underlying Conditions Associated With 90-Day Mortality in the Overall Population (N = 481)</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="3">Univariate Analysis</th></tr><tr><th>OR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td><strong>Characteristic</strong></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>1.04</td><td>1.02-1.05</td><td><strong>&lt;.001</strong></td></tr><tr><td>Male</td><td>0.90</td><td>0.52-1.54</td><td>.625</td></tr><tr><td>Albuminemia ≤ 30 g/L<sup>a</sup></td><td>3.40</td><td>1.89-6.10</td><td><strong>&lt;.001</strong></td></tr><tr><td><strong>Immunodeficiency</strong></td><td></td><td></td><td></td></tr><tr><td>HIV infection</td><td>0.24</td><td>0.13-0.47</td><td><strong>&lt;.001</strong></td></tr><tr><td>Hematologic malignancy</td><td>0.88</td><td>0.54-1.43</td><td>.597</td></tr><tr><td>Solid tumor</td><td>3.19</td><td>1.80-5.65</td><td><strong>&lt;.001</strong></td></tr><tr><td>Solid organ transplantation</td><td>0.86</td><td>0.51-1.43</td><td>.551</td></tr><tr><td>Immune-mediated inflammatory disease</td><td>1.94</td><td>1.18-3.18</td><td><strong>.008</strong></td></tr><tr><td><strong>Immunosuppressive drug exposure</strong></td><td></td><td></td><td></td></tr><tr><td>Long-term corticosteroid therapy</td><td>2.58</td><td>1.68-3.96</td><td><strong>&lt;.001</strong></td></tr></tbody></table>

<footnote>ªItem with > 30% missing values.</footnote>
<figure><img src="image_3.png" /><figcaption>Figure 2 – Survival analysis according to the underlying cause of immunodeficiency. HEM = hematologic malignancies; IMID = immunemediated inflammatory diseases; SOT = solid organ transplantation; ST = solid tumor.</figcaption></figure>

disease was rheumatoid arthritis (n = 14, 16.1%), followed by antineutrophil cytoplasmic antibody-associated vasculitis (n = 9, 10.3%) and sarcoidosis (n = 8, 9.2%). Seventy-nine patients with IMIDs (90.8%) received long-term corticosteroid therapy, 37 (42.5%) received antimetabolite drugs, and 17 (19.5%) received anti-CD20 monoclonal antibody therapy

<figure><img src="image_4.png" /><figcaption>Figure 3 – Survival analysis according to long-term steroid exposure prior to Pneumocystis jirovecii pneumonia diagnosis in patients who are HIV-negative. D90 = day 90.</figcaption></figure>

(e-Table 4) prior to PcP diagnosis. For 68 patients (78%), immunosuppressive treatment had been introduced or modified in the year prior to PcP diagnosis. The mean time between introduction or change of immunosuppressive therapy and the onset of PcP was 78 days.

Among patients who were HIV-negative, patients with IMIDs were the oldest (P < .001) and presented

<table><caption>TABLE 2 Underlying Conditions Associated With 90-Day Mortality in the Overall Population (N = 481)</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="3">Univariate Analysis</th></tr><tr><th>OR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td><strong>Characteristic</strong></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>1.04</td><td>1.02-1.05</td><td><strong>&lt; .001</strong></td></tr><tr><td>Male</td><td>0.90</td><td>0.52-1.54</td><td>.625</td></tr><tr><td>Albuminemia ≤ 30 g/L<sup>a</sup></td><td>3.40</td><td>1.89-6.10</td><td><strong>&lt; .001</strong></td></tr><tr><td><strong>Immunodeficiency</strong></td><td></td><td></td><td></td></tr><tr><td>HIV infection</td><td>0.24</td><td>0.13-0.47</td><td><strong>&lt; .001</strong></td></tr><tr><td>Hematologic malignancy</td><td>0.88</td><td>0.54-1.43</td><td>.597</td></tr><tr><td>Solid tumor</td><td>3.19</td><td>1.80-5.65</td><td><strong>&lt; .001</strong></td></tr><tr><td>Solid organ transplantation</td><td>0.86</td><td>0.51-1.43</td><td>.551</td></tr><tr><td>Immune-mediated inflammatory disease</td><td>1.94</td><td>1.18-3.18</td><td><strong>.008</strong></td></tr><tr><td><strong>Immunosuppressive drug exposure</strong></td><td></td><td></td><td></td></tr><tr><td>Long-term corticosteroid therapy</td><td>2.58</td><td>1.68-3.96</td><td><strong>&lt; .001</strong></td></tr></tbody></table>

<footnote>ªItem with > 30% missing values.</footnote>
<table><caption>TABLE 3 ] Factors Associated With 90-Day Mortality in the HIV-Negative Population</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="3">Univariate Analysis (n = 367)</th><th colspan="3">Multivariate Analysis (n = 315)</th></tr><tr><th>OR</th><th>95% CI</th><th>P Value</th><th>OR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td><strong>Characteristic</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>1.02</td><td>1.00-1.04</td><td><strong>.023</strong></td><td>1.01</td><td>0.99-1.03</td><td>.401</td></tr><tr><td>Male</td><td>0.90</td><td>0.52-1.54</td><td>.874</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Albuminemia &lt; 30 g/L<sup>a</sup></td><td>4.36</td><td>2.33-8.18</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Chronic kidney disease</td><td>0.88</td><td>0.56-1.39</td><td>.594</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Chronic pulmonary disease</td><td>1.10</td><td>0.66-1.82</td><td>.713</td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Immunodeficiency</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Hematologic malignancy</td><td>0.61</td><td>0.37-1.00</td><td>.052</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Solid tumor</td><td>2.48</td><td>1.39-4.42</td><td><strong>.002</strong></td><td>5.47</td><td>2.16-14.1</td><td><strong>&lt; .001</strong></td></tr><tr><td>Solid organ transplantation</td><td>0.61</td><td>0.36-1.03</td><td>.061</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Immune-mediated inflammatory disease</td><td>1.46</td><td>0.88-2.42</td><td>.146</td><td>2.19</td><td>1.05-4.60</td><td><strong>.037</strong></td></tr><tr><td>Connective tissue diseases</td><td>1.57</td><td>0.68-3.61</td><td>.286</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Immunosuppressive drug exposure</td><td>1.59</td><td>0.70-3.60</td><td>0.265</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Long-term corticosteroid</td><td>1.67</td><td>1.03-2.71</td><td><strong>.035</strong></td><td>2.07</td><td>1.03-4.31</td><td><strong>.045</strong></td></tr><tr><td>Steroid daily dose ≥ 10 mg</td><td>1.80</td><td>1.14-2.85</td><td><strong>.010</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Anticalcineurin</td><td>0.68</td><td>0.41-1.13</td><td>.132</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Mycophenolic acid</td><td>0.71</td><td>0.41-1.23</td><td>.219</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Antimetabolites</td><td>1.10</td><td>0.64-1.91</td><td>.724</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Alkylating drug</td><td>1.31</td><td>0.70-2.45</td><td>.395</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Monoclonal antibodies</td><td>1.25</td><td>0.73-2.16</td><td>.416</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Anti-CD20</td><td>1.22</td><td>0.65-2.29</td><td>.543</td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Symptomatology</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Dyspnea</td><td>2.51</td><td>1.22-5.16</td><td><strong>.010</strong></td><td>1.08</td><td>0.44-2.86</td><td>.870</td></tr><tr><td>Hyperthermia</td><td>0.86</td><td>0.53-1.41</td><td>.556</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Cough</td><td>0.79</td><td>0.50-1.24</td><td>.296</td><td>...</td><td>...</td><td>...</td></tr><tr><td>AGC</td><td>1.89</td><td>1.20-2.98</td><td><strong>.006</strong></td><td>1.31</td><td>0.72-2.38</td><td>.373</td></tr><tr><td><strong>Sputum/BAL examination<sup>b</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Positive direct examinations<br>(cysts in smears)<sup>c</sup></td><td>1.99</td><td>1.22-3.24</td><td><strong>.005</strong></td><td>1.92</td><td>1.02-3.62</td><td><strong>.043</strong></td></tr><tr><td>Neutrophilic BAL profile<sup>a</sup></td><td>3.23</td><td>1.65-6.34</td><td><strong>.001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Macrophagic BAL profile<sup>a</sup></td><td>1.19</td><td>0.63-2.22</td><td>.598</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Lymphocytic BAL profile<sup>a</sup></td><td>0.25</td><td>0.11-0.52</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>CMV respiratory coinfection<sup>a, d</sup></td><td>5.23</td><td>2.63-10.4</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Laboratory findings</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Neutrophils ≥ 7,500/mm<sup>3</sup></td><td>1.52</td><td>0.93-24.48</td><td>.092</td><td>...</td><td>...</td><td>...</td></tr><tr><td>CD4 ≥ 200/mm<sup>3a</sup></td><td>1.04</td><td>0.46-2.33</td><td>.930</td><td>...</td><td>...</td><td>...</td></tr><tr><td>CRP ≥ 100 mg/L<sup>e</sup></td><td>1.79</td><td>1.11-2.90</td><td><strong>.017</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>LDH ≥ 400<sup>a</sup></td><td>2.76</td><td>1.13-6.76</td><td><strong>.024</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Care</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Time hospitalization/treatment</td><td>1.04</td><td>1.02-1.06</td><td><strong>.001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Adjunctive corticosteroids</td><td>1.61</td><td>1.02-2.53</td><td><strong>.039</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Exclusive nasal oxygen therapy</td><td>0.51</td><td>0.32-0.82</td><td><strong>.005</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>High-flow oxygen therapy</td><td>2.47</td><td>1.42-4.31</td><td>.932</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Noninvasive ventilation</td><td>2.46</td><td>1.48-4.07</td><td><strong>.001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Mechanical ventilation</td><td>6.94</td><td>4.10-11.8</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 3] Factors Associated With 90-Day Mortality in the HIV-Negative Population</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="3">Univariate Analysis (n = 367)</th><th colspan="3">Multivariate Analysis (n = 315)</th></tr><tr><th>OR</th><th>95% CI</th><th>P Value</th><th>OR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td><strong>Characteristic</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>1.02</td><td>1.00-1.04</td><td><strong>.023</strong></td><td>1.01</td><td>0.99-1.03</td><td>.401</td></tr><tr><td>Male</td><td>0.90</td><td>0.52-1.54</td><td>.874</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Albuminemia &lt; 30 g/L<sup>a</sup></td><td>4.36</td><td>2.33-8.18</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Chronic kidney disease</td><td>0.88</td><td>0.56-1.39</td><td>.594</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Chronic pulmonary disease</td><td>1.10</td><td>0.66-1.82</td><td>.713</td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Immunodeficiency</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Hematologic malignancy</td><td>0.61</td><td>0.37-1.00</td><td>.052</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Solid tumor</td><td>2.48</td><td>1.39-4.42</td><td><strong>.002</strong></td><td>5.47</td><td>2.16-14.1</td><td><strong>&lt; .001</strong></td></tr><tr><td>Solid organ transplantation</td><td>0.61</td><td>0.36-1.03</td><td>.061</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Immune-mediated inflammatory disease</td><td>1.46</td><td>0.88-2.42</td><td>.146</td><td>2.19</td><td>1.05-4.60</td><td><strong>.037</strong></td></tr><tr><td>Connective tissue diseases</td><td>1.57</td><td>0.68-3.61</td><td>.286</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Immunosuppressive drug exposure</td><td>1.59</td><td>0.70-3.60</td><td>0.265</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Long-term corticosteroid</td><td>1.67</td><td>1.03-2.71</td><td><strong>.035</strong></td><td>2.07</td><td>1.03-4.31</td><td><strong>.045</strong></td></tr><tr><td>Steroid daily dose ≥ 10 mg</td><td>1.80</td><td>1.14-2.85</td><td><strong>.010</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Anticalcineurin</td><td>0.68</td><td>0.41-1.13</td><td>.132</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Mycophenolic acid</td><td>0.71</td><td>0.41-1.23</td><td>.219</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Antimetabolites</td><td>1.10</td><td>0.64-1.91</td><td>.724</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Alkylating drug</td><td>1.31</td><td>0.70-2.45</td><td>.395</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Monoclonal antibodies</td><td>1.25</td><td>0.73-2.16</td><td>.416</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Anti-CD20</td><td>1.22</td><td>0.65-2.29</td><td>.543</td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Symptomatology</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Dyspnea</td><td>2.51</td><td>1.22-5.16</td><td><strong>.010</strong></td><td>1.08</td><td>0.44-2.86</td><td>.870</td></tr><tr><td>Hyperthermia</td><td>0.86</td><td>0.53-1.41</td><td>.556</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Cough</td><td>0.79</td><td>0.50-1.24</td><td>.296</td><td>...</td><td>...</td><td>...</td></tr><tr><td>AGC</td><td>1.89</td><td>1.20-2.98</td><td><strong>.006</strong></td><td>1.31</td><td>0.72-2.38</td><td>.373</td></tr><tr><td><strong>Sputum/BAL examination<sup>b</sup></strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Positive direct examinations<br>(cysts in smears)<sup>c</sup></td><td>1.99</td><td>1.22-3.24</td><td><strong>.005</strong></td><td>1.92</td><td>1.02-3.62</td><td><strong>.043</strong></td></tr><tr><td>Neutrophilic BAL profile<sup>a</sup></td><td>3.23</td><td>1.65-6.34</td><td><strong>.001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Macrophagic BAL profile<sup>a</sup></td><td>1.19</td><td>0.63-2.22</td><td>.598</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Lymphocytic BAL profile<sup>a</sup></td><td>0.25</td><td>0.11-0.52</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>CMV respiratory coinfection<sup>a, d</sup></td><td>5.23</td><td>2.63-10.4</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Laboratory findings</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Neutrophils ≥ 7,500/mm<sup>3</sup></td><td>1.52</td><td>0.93-24.48</td><td>.092</td><td>...</td><td>...</td><td>...</td></tr><tr><td>CD4 ≥ 200/mm<sup>3a</sup></td><td>1.04</td><td>0.46-2.33</td><td>.930</td><td>...</td><td>...</td><td>...</td></tr><tr><td>CRP ≥ 100 mg/L<sup>e</sup></td><td>1.79</td><td>1.11-2.90</td><td><strong>.017</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>LDH ≥ 400<sup>a</sup></td><td>2.76</td><td>1.13-6.76</td><td><strong>.024</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td><strong>Care</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Time hospitalization/treatment</td><td>1.04</td><td>1.02-1.06</td><td><strong>.001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Adjunctive corticosteroids</td><td>1.61</td><td>1.02-2.53</td><td><strong>.039</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Exclusive nasal oxygen therapy</td><td>0.51</td><td>0.32-0.82</td><td><strong>.005</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>High-flow oxygen therapy</td><td>2.47</td><td>1.42-4.31</td><td>.932</td><td>...</td><td>...</td><td>...</td></tr><tr><td>Noninvasive ventilation</td><td>2.46</td><td>1.48-4.07</td><td><strong>.001</strong></td><td>...</td><td>...</td><td>...</td></tr><tr><td>Mechanical ventilation</td><td>6.94</td><td>4.10-11.8</td><td><strong>&lt; .001</strong></td><td>...</td><td>...</td><td>...</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 3] (Continued)</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="3">Univariate Analysis (n = 367)</th><th colspan="3">Multivariate Analysis (n = 315)</th></tr><tr><th>OR</th><th>95% CI</th><th>P Value</th><th>OR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td>Severity</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>SOFA</td><td>1.50</td><td>1.35-1.70</td><td>&lt; .001</td><td>1.58</td><td>1.39-1.82</td><td>&lt; .001</td></tr><tr><td>ICU admission</td><td>3.42</td><td>2.17-5.51</td><td>&lt; .001</td><td>...</td><td>...</td><td>...</td></tr></tbody></table>

AGC = alteration of general condition; CMV = cytomegalovirus; CRP = C-reactive protein; LDH = lactate dehydrogenase; SOFA = Sequential Organ Failure Assessment.

aItem with > 30% missing values.

bOne hundred and seventy-two sputum examinations and 269 BAL examinations; 74 patients had both sputum and BAL examinations.

cPositive direct examination in BAL only (OR, 1.94; 95% CI, 1.13-3.32; P = .016).

dCMV polymerase chain reaction was only performed on BAL samples.

eItem with > 10% missing values.

significantly more severe inaugural dyspnea forms of PcP (OR, 4.05; 95% CI, 1.57-10.5; P = .002), increased neutrophilia (P = .002), and more CMV respiratory coinfection (OR, 2.69; 95% CI, 1.65-6.34; P = .007) (e-Table 7). Patients with IMIDs reported the worst SOFA score on admission compared with the other HIV-negative subgroups (e-Table 7). These patients had less adjuvant corticosteroid therapy (OR, 0.49; 95% CI, 0.30-0.81; P = .005) and a higher rate of mechanical ventilation (OR, 2.01; 95% CI, 1.18-3.40; P = .009) to treat PcP (e-Table 7).

Patients with IMIDs with a poor outcome reported a lower albumin level (P < .001), were admitted to hospital earlier from their onset of symptoms (2.8 vs 15.8 days, P = .037) with the worst SOFA score on admission (6.9 vs 2.8, P < .001), but a had longer time to initiation of anti-Pneumocystis therapy from the time of hospitalization (7.6 vs 3.9 days, P = .027), a higher rate of positive direct examination of respiratory samples (P = .018), and a higher rate of respiratory CMV coinfection (P = .002) (e-Tables 8, 9). Prior prescription of anti-Pneumocystis prophylaxis was rarer among patients with IMIDs (five of 87, 5.7%) and solid tumors (one of 56, 1.8%) (e-Table 2). Among patients with IMIDs, only SOFA score was independently associated with 90-day mortality (OR, 1.50; 95% CI, 1.17-2.10; P = .007) (e-Table 9).

## Discussion

To our knowledge, our work is the largest study to use a comprehensive approach of the characteristics and outcome of PcP as a function of the underlying disease and the type of immunosuppressive therapies in a large cohort of patients. We reported that PcP in patients with IMIDs presented the most severe forms of PcP at

admission, with higher SOFA score and the highest mortality rate attributable to PcP among patients who were HIV-negative. On the other hand, patients with PcP with solid tumors displayed a higher 90-day mortality rate and a poorer long-term outcome, despite a lower SOFA score at PcP diagnosis. These results suggest that these patients (most of whom had metastatic disease) may not have developed the most severe forms of PcP, but that the onset of this opportunistic infection could be a marker of their frailty.

Burghi et al¹⁴ reported in an analysis of patients who were HIV-negative (n = 321) that 30-day mortality and presentation of PcP were associated with the underlying disease. However, this study did not include patients who were HIV-positive, and did not provide details of patients with IMIDs as a specific subgroup. In our study, prior long-term corticosteroid therapy appeared to be a major risk factor and was associated with a poorer prognosis, especially in patients with IMIDs. This higher mortality rate among patients with long-term corticosteroid exposure fades at 1 year, which may be explained by the mortality related to each underlying condition among the HIV-negative group. The longer time to diagnosis and the higher severity of PcP in patients with IMIDs at admission suggest that the delayed diagnosis may be in part responsible for their poor prognosis.

Almost 90% of the patients had not been prescribed PcP prophylaxis, confirming previous findings¹⁵ which identified the lack of trimethoprim-sulfamethoxazole prophylaxis as a major risk factor for PcP in high-risk patients.¹⁶ To reduce PcP mortality in patients with IMIDs, the first step would be to improve prophylactic coverage against this preventable opportunistic infection; however, determining criteria for
<table><caption>TABLE 3] (Continued)</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="3">Univariate Analysis (n = 367)</th><th colspan="3">Multivariate Analysis (n = 315)</th></tr><tr><th>OR</th><th>95% CI</th><th>P Value</th><th>OR</th><th>95% CI</th><th>P Value</th></tr></thead><tbody><tr><td>Severity</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>SOFA</td><td>1.50</td><td>1.35-1.70</td><td>&lt; .001</td><td>1.58</td><td>1.39-1.82</td><td>&lt; .001</td></tr><tr><td>ICU admission</td><td>3.42</td><td>2.17-5.51</td><td>&lt; .001</td><td>...</td><td>...</td><td>...</td></tr></tbody></table>

AGC = alteration of general condition; CMV = cytomegalovirus; CRP = C-reactive protein; LDH = lactate dehydrogenase; SOFA = Sequential Organ Failure Assessment.

aItem with > 30% missing values.

bOne hundred and seventy-two sputum examinations and 269 BAL examinations; 74 patients had both sputum and BAL examinations.

cPositive direct examination in BAL only (OR, 1.94; 95% CI, 1.13-3.32; P = .016).

dCMV polymerase chain reaction was only performed on BAL samples.

eItem with > 10% missing values.

significantly more severe inaugural dyspnea forms of PcP (OR, 4.05; 95% CI, 1.57-10.5; P = .002), increased neutrophilia (P = .002), and more CMV respiratory coinfection (OR, 2.69; 95% CI, 1.65-6.34; P = .007) (e-Table 7). Patients with IMIDs reported the worst SOFA score on admission compared with the other HIV-negative subgroups (e-Table 7). These patients had less adjuvant corticosteroid therapy (OR, 0.49; 95% CI, 0.30-0.81; P = .005) and a higher rate of mechanical ventilation (OR, 2.01; 95% CI, 1.18-3.40; P = .009) to treat PcP (e-Table 7).

Patients with IMIDs with a poor outcome reported a lower albumin level (P < .001), were admitted to hospital earlier from their onset of symptoms (2.8 vs 15.8 days, P = .037) with the worst SOFA score on admission (6.9 vs 2.8, P < .001), but a had longer time to initiation of anti-Pneumocystis therapy from the time of hospitalization (7.6 vs 3.9 days, P = .027), a higher rate of positive direct examination of respiratory samples (P = .018), and a higher rate of respiratory CMV coinfection (P = .002) (e-Tables 8, 9). Prior prescription of anti-Pneumocystis prophylaxis was rarer among patients with IMIDs (five of 87, 5.7%) and solid tumors (one of 56, 1.8%) (e-Table 2). Among patients with IMIDs, only SOFA score was independently associated with 90-day mortality (OR, 1.50; 95% CI, 1.17-2.10; P = .007) (e-Table 9).

Discussion

To our knowledge, our work is the largest study to use a comprehensive approach of the characteristics and outcome of PcP as a function of the underlying disease and the type of immunosuppressive therapies in a large cohort of patients. We reported that PcP in patients with IMIDs presented the most severe forms of PcP at

admission, with higher SOFA score and the highest mortality rate attributable to PcP among patients who were HIV-negative. On the other hand, patients with PcP with solid tumors displayed a higher 90-day mortality rate and a poorer long-term outcome, despite a lower SOFA score at PcP diagnosis. These results suggest that these patients (most of whom had metastatic disease) may not have developed the most severe forms of PcP, but that the onset of this opportunistic infection could be a marker of their frailty.

Burghi et al¹⁴ reported in an analysis of patients who were HIV-negative (n = 321) that 30-day mortality and presentation of PcP were associated with the underlying disease. However, this study did not include patients who were HIV-positive, and did not provide details of patients with IMIDs as a specific subgroup. In our study, prior long-term corticosteroid therapy appeared to be a major risk factor and was associated with a poorer prognosis, especially in patients with IMIDs. This higher mortality rate among patients with long-term corticosteroid exposure fades at 1 year, which may be explained by the mortality related to each underlying condition among the HIV-negative group. The longer time to diagnosis and the higher severity of PcP in patients with IMIDs at admission suggest that the delayed diagnosis may be in part responsible for their poor prognosis.

Almost 90% of the patients had not been prescribed PcP prophylaxis, confirming previous findings¹⁵ which identified the lack of trimethoprim-sulfamethoxazole prophylaxis as a major risk factor for PcP in high-risk patients.¹⁶ To reduce PcP mortality in patients with IMIDs, the first step would be to improve prophylactic coverage against this preventable opportunistic infection; however, determining criteria for
Pneumocystis prophylaxis in patients with IMIDs is challenging, given the wide range of diseases involved.17-19 Specific prophylaxis guidelines have been developed for antineutrophil cytoplasmic antibody-associated vasculitis, scleroderma, and autoimmune inflammatory myopathies,20 and for patients receiving prolonged corticosteroid therapy,21,22 but there are currently insufficient data for rarer IMIDs to allow specific prophylaxis recommendations to be established.23 This study supports that high-dose corticosteroids are a major issue in patients who are HIV-negative because of the risk of PcP, and unlike patients who are HIV-positive, CD4 cell count cannot be used as an indication for prophylaxis in these patients. Rheumatoid arthritis was the most prevalent IMID in this cohort, which is consistent with a recent national study based on the French RESSIF Network.17 This highlights the difficulty in identifying the patients who would benefit from Pneumocystis prophylaxis and explains the lack of official recommendations/consensus guidelines for these patients. More than one-half of patients with rheumatoid arthritis in this cohort developed PcP < 6 months after initiation or intensifying their immunosuppressive therapy. Atovaquone prophylaxis during the year after the initiation of their immunosuppressive therapy could be an effective alternative24 with a favorable benefit to risk ratio, while avoiding the risk of cumulative myelotoxicity of methotrexate and trimethoprim-sulfamethoxazole. Sarcoidosis seems to be another emerging condition highly exposed to corticosteroids, for which there are yet no Pneumocystis prophylaxis recommendations.

Another important factor in improving the outcome of patients with IMIDs with PcP would be to treat them earlier. Identifying patients with IMIDs with features compatible with a severe PcP diagnosis as early as possible and ensuring prompt treatment is particularly relevant. Our work suggests that delayed treatment in patients with IMIDs has a potentially dramatic impact on their prognosis.

Analysis of 90-day risk factors among patients who were HIV-negative in the extended cohort confirms our previous results that BAL examination can provide several important markers of mortality, including direct cyst examination, neutrophilic alveolitis profile, and respiratory coinfection with CMV at the time of PcP diagnosis. Furthermore, prior corticosteroid therapy has been reported to impair the anti-pneumocystic immune response leading to an inefficient neutrophilic alveolitis

and subsequent alveolointerstitial inflammatory lesions in PcP.25-27 Indeed, positive direct examination of cysts in respiratory samples could indicate profound immunosuppression. In patients who are HIV-positive, highly active antiretroviral therapy may contribute to more rapid control of the infectious process through faster recovery of the immune system. In patients who are HIV-negative, patterns of immunosuppression, including long-term corticosteroid therapy, appear to be associated with an inappropriate inflammatory response in cases of high fungal load.

Because patients with IMIDs more frequently present, at PcP diagnosis, a BAL pattern that associates immunosuppression and inflammation markers, we can hypothesize that their greater exposure to long-term corticosteroid therapy may induce dysregulation of the anti-Pneumocystis response, which in turn may be responsible for a more severe disease. Such prior exposure to immunosuppressive drugs in patients with IMIDs has also been shown to be associated with poor outcome of SARS-CoV-2 pneumonia.28 Our study indicates that patients with the most severe IMIDs did not receive more adjuvant corticosteroids. Indeed, no evidence is available to support adjuvant corticosteroid therapy in patients who are HIV-negative presenting with severe PcP. The low use of adjuvant corticosteroid therapy to treat PcP in patients with IMIDs may be related both to the lack of guidelines for adjuvant corticosteroid therapy in patients who are HIV-negative and the high rate of prior corticosteroid exposure in these patients, which probably contributed to the development of PcP. In a previous study, we reported that adjuvant corticosteroid therapy was associated with the highest mortality rates in patients with respiratory CMV coinfection among patients who are HIV-negative, and that such CMV coinfection was more common in patients with IMIDs.10 Patients already exposed to prior long-term corticosteroid therapy may therefore not benefit from higher doses of steroids adjunctive therapy in cases of severe PcP. Therefore, to improve the management of PcP in IMIDs, there is a need to assess the benefit of immunomodulatory therapies, other than corticosteroids, to reduce the damaging pulmonary immune response.

This study presents several limitations because of the retrospective nature of the cohort. Indeed, this study was not designed to assess the incidence of PcP among underlying conditions, but rather to identify emerging diseases over this 10-year period. The higher rate of PcP in patients with rheumatoid arthritis could reflect a
Pneumocystis prophylaxis in patients with IMIDs is challenging, given the wide range of diseases involved.¹⁷⁻¹⁹ Specific prophylaxis guidelines have been developed for antineutrophil cytoplasmic antibody-associated vasculitis, scleroderma, and autoimmune inflammatory myopathies,²⁰ and for patients receiving prolonged corticosteroid therapy,²¹,²² but there are currently insufficient data for rarer IMIDs to allow specific prophylaxis recommendations to be established.²³ This study supports that high-dose corticosteroids are a major issue in patients who are HIV-negative because of the risk of PcP, and unlike patients who are HIV-positive, CD4 cell count cannot be used as an indication for prophylaxis in these patients. Rheumatoid arthritis was the most prevalent IMID in this cohort, which is consistent with a recent national study based on the French RESSIF Network.¹⁷ This highlights the difficulty in identifying the patients who would benefit from Pneumocystis prophylaxis and explains the lack of official recommendations/consensus guidelines for these patients. More than one-half of patients with rheumatoid arthritis in this cohort developed PcP < 6 months after initiation or intensifying their immunosuppressive therapy. Atovaquone prophylaxis during the year after the initiation of their immunosuppressive therapy could be an effective alternative²⁴ with a favorable benefit to risk ratio, while avoiding the risk of cumulative myelotoxicity of methotrexate and trimethoprim-sulfamethoxazole. Sarcoidosis seems to be another emerging condition highly exposed to corticosteroids, for which there are yet no Pneumocystis prophylaxis recommendations.

Another important factor in improving the outcome of patients with IMIDs with PcP would be to treat them earlier. Identifying patients with IMIDs with features compatible with a severe PcP diagnosis as early as possible and ensuring prompt treatment is particularly relevant. Our work suggests that delayed treatment in patients with IMIDs has a potentially dramatic impact on their prognosis.

Analysis of 90-day risk factors among patients who were HIV-negative in the extended cohort confirms our previous results that BAL examination can provide several important markers of mortality, including direct cyst examination, neutrophilic alveolitis profile, and respiratory coinfection with CMV at the time of PcP diagnosis. Furthermore, prior corticosteroid therapy has been reported to impair the anti-pneumocystic immune response leading to an inefficient neutrophilic alveolitis

and subsequent alveolointerstitial inflammatory lesions in PcP.²⁵⁻²⁷ Indeed, positive direct examination of cysts in respiratory samples could indicate profound immunosuppression. In patients who are HIV-positive, highly active antiretroviral therapy may contribute to more rapid control of the infectious process through faster recovery of the immune system. In patients who are HIV-negative, patterns of immunosuppression, including long-term corticosteroid therapy, appear to be associated with an inappropriate inflammatory response in cases of high fungal load.

Because patients with IMIDs more frequently present, at PcP diagnosis, a BAL pattern that associates immunosuppression and inflammation markers, we can hypothesize that their greater exposure to long-term corticosteroid therapy may induce dysregulation of the anti-Pneumocystis response, which in turn may be responsible for a more severe disease. Such prior exposure to immunosuppressive drugs in patients with IMIDs has also been shown to be associated with poor outcome of SARS-CoV-2 pneumonia.²⁸ Our study indicates that patients with the most severe IMIDs did not receive more adjuvant corticosteroids. Indeed, no evidence is available to support adjuvant corticosteroid therapy in patients who are HIV-negative presenting with severe PcP. The low use of adjuvant corticosteroid therapy to treat PcP in patients with IMIDs may be related both to the lack of guidelines for adjuvant corticosteroid therapy in patients who are HIV-negative and the high rate of prior corticosteroid exposure in these patients, which probably contributed to the development of PcP. In a previous study, we reported that adjuvant corticosteroid therapy was associated with the highest mortality rates in patients with respiratory CMV coinfection among patients who are HIV-negative, and that such CMV coinfection was more common in patients with IMIDs.¹⁰ Patients already exposed to prior long-term corticosteroid therapy may therefore not benefit from higher doses of steroids adjunctive therapy in cases of severe PcP. Therefore, to improve the management of PcP in IMIDs, there is a need to assess the benefit of immunomodulatory therapies, other than corticosteroids, to reduce the damaging pulmonary immune response.

This study presents several limitations because of the retrospective nature of the cohort. Indeed, this study was not designed to assess the incidence of PcP among underlying conditions, but rather to identify emerging diseases over this 10-year period. The higher rate of PcP in patients with rheumatoid arthritis could reflect a
higher prevalence of this disease among patients with IMIDs. In addition, the lack of standardization of adjuvant corticosteroid therapy does not allow any conclusions regarding its efficacy in patients who are HIV-negative. Finally, determining the exact cause of mortality after hospital discharge represents a significant challenge, especially in a retrospective cohort of patients with severe chronic diseases that involve potential limitations in intensive care, which may have overestimated PcP mortality in each of the subgroups.

1002

## Interpretation

This large multicenter PcP cohort is the first to identify IMIDs, solid tumors, and long-term corticosteroid therapy as independent mortality factors in patients who are HIV-negative. Patients with IMIDs are the most exposed to long-term corticosteroid therapy and have the worst prognosis because of PcP when compared with other immunocompromised conditions. The onset of PcP in patients with solid tumors is associated with the highest 90-day mortality and is probably related to very advanced tumor disease. Broadening indications for primary prophylaxis against *P. jirovecii* in patients with

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## Acknowledgments

**Author contributions:** R. L., N. I., F. C., B. T., and B. G. analyzed and interpreted the data.

R.-a. L., F. M., F. G., and A. C. performed microbial analysis of bronchoalveolar fluid samples.

B. T., E. C., M. G., Y. C., A. N., D. B., and F. R. contributed to interpretation of results and revision of the manuscript. R. L., N. I., and B. G. wrote the manuscript. All authors read and approved the final manuscript.

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**Role of sponsors:** The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

1032

## *PRONOCYSTIS Study Group

**Collaborators:** Francois Raffi, David Boutoille, Charlotte Biron, Maeva Lefebvre, Benjamin Jean Gaborit, Paul Le Turnier, Colin Deschanvres, Raphael Lecomte, Marie Chauveau, Romain Lécuyer, and Antoine Asquier-Khati (Department of Infectious Diseases, Nantes University Hospital); Patrice Le Pape, Florent Morio, Rose-Anne Lavergne, and Fakhri Jeddi (Department of Parasitology-Mycology, Nantes University Hospital); Stéphane Corvec, Pascale Bemer, Jocelyne Caillon, Aurélie Guillouzouic, and Anne-Gaëlle Leroy (Department of Bacteriology, Nantes University Hospital); Karim Lakhal, Raphaël Cinotti, and Antoine Roquilly (Department of

Anesthesiology and Intensive Care Medicine, Nantes University Hospital); Jean Reignier and Emmanuel Canet (Medical Intensive Care, Nantes University Hospital); François Xavier Blanc, Cédric Bretonniere, and Paul Morin (Service de Pneumologie, Nantes University Hospital); Fabrice Camou, Nahéma Issa, Olivier Guisset, and Gaelle Mourissoux (Intensive Care and Infectious Disease, Groupe Saint André, Bordeaux University Hospital); Isabelle Accoceberry, Frederic Gabriel, Isabelle Accoceberry, Noémie Coron, Laurence Delhaes, Sébastien Imbert, Maxime Lefranc, Florian Lussac-Sorton, and Amandine Rougeron (Laboratoire de Mycologie, Groupe Pellegrin, Bordeaux University Hospital); Marie Gousseff, Yoann Crabol, Grégory Corvaisier, Florent Lautredoux, and Romain Lécuyer (Department of Internal Medicine and Infectious Diseases, Centre Hospitalier Bretagne-Atlantique, Vannes); and Anne Cady, Myriam Auger, and Pascal Pouedras (Department of Microbiology, Centre Hospitalier Bretagne-Atlantique, Vannes).

**Other contributions:** We thank the physicians, microbiologists, and PRONOCYSTIS Study Group who contributed to the management of the study patients and for their commitment to providing optimal patient care.

**Additional information:** The e-Figures and e-Tables are available online under "Supplementary Data."

underlying immunocompromised conditions, earlier awareness, diagnosis and probabilistic treatment, and new therapeutic approaches for severe forms are the three key factors which could contribute to reducing *P. jirovecii* mortality in patients who are HIV-negative.

## Funding/Support

The authors have reported to CHEST that no funding was received for this study.

## Financial/Nonfinancial Disclosures

The authors have reported to CHEST the following: B. G. reports receipt of nonfinancial support from Gilead Sciences, MSD, and Pfizer, outside the submitted work. F. R. reports receipt of personal fees from Abbvie, Astra Zeneca, Gilead Sciences, Janssen, Merck, Roche, and ViiV Healthcare, outside the submitted work. E. C. reports personal fees from Gilead, Sanofi-Genzyme, and Baxter, outside the submitted work. None declared (R. L., N. I., F. C., R.-a. L., F. G., F. M., D. B., A. C., M. G., Y. C., A. N., B. T.).

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## References

1. Festic E, Gajic O, Limper AH, Aksamit TR. Acute respiratory failure due to pneumocystis pneumonia in patients without human immunodeficiency virus infection: outcome and associated features. Chest. 2005;128(2):573-579.

2. Bretagne S, Sitbon K, Desnos-Ollivier M, et al. Active surveillance program to increase awareness on invasive fungal diseases: the French RESSIF Network (2012 to 2018). mBio. 2022;13(3):e0092022.

3. Roux A, Canet E, Valade S, et al. Pneumocystis jirovecii pneumonia in patients with or without AIDS, France. Emerg Infect Dis. 2014;20(9):1490-1497.

4. Burke BA, Good RA. Pneumocystis carinii infection. Medicine (Baltimore). 1973;52(1):23-51.

5. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc. 1996;71(1):5-13.

6. Sepkowitz KA. Pneumocystis carinii pneumonia in patients without AIDS. Clin Infect Dis. 1993;17(suppl 2):S416-S422.

7. Boonsarngsuk V, Sirilak S, Kiatboonsri S. Acute respiratory failure due to Pneumocystis pneumonia: outcome and prognostic factors. Int J Infect Dis. 2009;13(1):59-66.

8. Tasaka S, Tokuda H. Pneumocystis jirovecii pneumonia in non-HIV-infected
higher prevalence of this disease among patients with IMIDs. In addition, the lack of standardization of adjuvant corticosteroid therapy does not allow any conclusions regarding its efficacy in patients who are HIV-negative. Finally, determining the exact cause of mortality after hospital discharge represents a significant challenge, especially in a retrospective cohort of patients with severe chronic diseases that involve potential limitations in intensive care, which may have overestimated PcP mortality in each of the subgroups.

### Interpretation

This large multicenter PcP cohort is the first to identify IMIDs, solid tumors, and long-term corticosteroid therapy as independent mortality factors in patients who are HIV-negative. Patients with IMIDs are the most exposed to long-term corticosteroid therapy and have the worst prognosis because of PcP when compared with other immunocompromised conditions. The onset of PcP in patients with solid tumors is associated with the highest 90-day mortality and is probably related to very advanced tumor disease. Broadening indications for primary prophylaxis against *P. jirovecii* in patients with

underlying immunocompromised conditions, earlier awareness, diagnosis and probabilistic treatment, and new therapeutic approaches for severe forms are the three key factors which could contribute to reducing *P. jirovecii* mortality in patients who are HIV-negative.

### Funding/Support

The authors have reported to CHEST that no funding was received for this study.

### Financial/Nonfinancial Disclosures

The authors have reported to CHEST the following: B. G. reports receipt of nonfinancial support from Gilead Sciences, MSD, and Pfizer, outside the submitted work. F. R. reports receipt of personal fees from Abbvie, Astra Zeneca, Gilead Sciences, Janssen, Merck, Roche, and ViiV Healthcare, outside the submitted work. E. C. reports personal fees from Gilead, Sanofi-Genzyme, and Baxter, outside the submitted work. None declared (R. L., N. I., F. C., R.-a. L., F. G., F. M., D. B., A. C., M. G., Y. C., A. N., B. T.).

### Acknowledgments

**Author contributions:** R. L., N. I., F. C., B. T., and B. G. analyzed and interpreted the data.

R.-a. L., F. M., F. G., and A. C. performed microbial analysis of bronchoalveolar fluid samples.

B. T., E. C., M. G., Y. C., A. N., D. B., and F. R. contributed to interpretation of results and revision of the manuscript. R. L., N. I., and B. G. wrote the manuscript. All authors read and approved the final manuscript.

**Role of sponsors:** The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

**\*PRONOCYSTIS Study Group**

**Collaborators:** François Raffi, David Boutoille, Charlotte Biron, Maeva Lefebvre, Benjamin Jean Gaborit, Paul Le Turnier, Colin Deschanvres, Raphael Lecomte, Marie Chauveau, Romain Lécuyer, and Antoine Asquier-Khati (Department of Infectious Diseases, Nantes University Hospital); Patrice Le Pape, Florent Morio, Rose-Anne Lavergne, and Fakhri Jeddi (Department of Parasitology-Mycology, Nantes University Hospital); Stéphane Corvec, Pascale Bemer, Jocelyne Caillon, Aurélie Guillouzouic, and Anne-Gaëlle Leroy (Department of Bacteriology, Nantes University Hospital); Karim Lakhal, Raphaël Cinotti, and Antoine Roquilly (Department of

Anesthesiology and Intensive Care Medicine, Nantes University Hospital); Jean Reignier and Emmanuel Canet (Medical Intensive Care, Nantes University Hospital); François Xavier Blanc, Cédric Bretonniere, and Paul Morin (Service de Pneumologie, Nantes University Hospital); Fabrice Camou, Nahéma Issa, Olivier Guisset, and Gaelle Mourissoux (Intensive Care and Infectious Disease, Groupe Saint André, Bordeaux University Hospital); Isabelle Accoceberry, Frederic Gabriel, Isabelle Accoceberry, Noémie Coron, Laurence Delhaes, Sébastien Imbert, Maxime Lefranc, Florian Lussac-Sorton, and Amandine Rougeron (Laboratoire de Mycologie, Groupe Pellegrin, Bordeaux University Hospital); Marie Gousseff, Yoann Crabol, Grégory Corvaisier, Florent Lautredoux, and Romain Lécuyer (Department of Internal Medicine and Infectious Diseases, Centre Hospitalier Bretagne-Atlantique, Vannes); and Anne Cady, Myriam Auger, and Pascal Pouedras (Department of Microbiology, Centre Hospitalier Bretagne-Atlantique, Vannes).

**Other contributions:** We thank the physicians, microbiologists, and PRONOCYSTIS Study Group who contributed to the management of the study patients and for their commitment to providing optimal patient care.

**Additional information:** The e-Figures and e-Tables are available online under "Supplementary Data."

### References

1. Festic E, Gajic O, Limper AH, Aksamit TR. Acute respiratory failure due to pneumocystis pneumonia in patients without human immunodeficiency virus infection: outcome and associated features. Chest. 2005;128(2):573-579.

2. Bretagne S, Sitbon K, Desnos-Ollivier M, et al. Active surveillance program to increase awareness on invasive fungal diseases: the French RESSIF Network (2012 to 2018). mBio. 2022;13(3):e0092022.

3. Roux A, Canet E, Valade S, et al. Pneumocystis jirovecii pneumonia in patients with or without AIDS, France. Emerg Infect Dis. 2014;20(9):1490-1497.

4. Burke BA, Good RA. Pneumocystis carinii infection. Medicine (Baltimore). 1973;52(1):23-51.

5. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc. 1996;71(1):5-13.

6. Sepkowitz KA. Pneumocystis carinii pneumonia in patients without AIDS. Clin Infect Dis. 1993;17(suppl 2):S416-S422.

7. Boonsarngsuk V, Sirilak S, Kiatboonsri S. Acute respiratory failure due to Pneumocystis pneumonia: outcome and prognostic factors. Int J Infect Dis. 2009;13(1):59-66.

8. Tasaka S, Tokuda H. Pneumocystis jirovecii pneumonia in non-HIV-infected

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1101 patients in the era of novel immunosuppressive therapies.
1102 Kansenshōgaku Zasshi J Jpn Assoc Infect Dis. 2014;88(6 suppl 11):26-39.
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1104 9. Gaborit B, Tessoulin B, Lavergne R, et al. Outcome and prognostic factors of Pneumocystis jirovecii pneumonia in immunocompromised adults: a prospective observational study. *Ann Intensive Care*. 2019;9:131.
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1109 10. Lécuyer R, Issa N, Tessoulin B, et al. Epidemiology and clinical impact of respiratory coinfections at diagnosis of Pneumocystis jirovecii pneumonia. *J Infect Dis*. 2022;225(5):868-880.
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1113 11. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. *Clin Infect Dis*. 2020;71(6):1367-1376.
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1119 12. Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of SpO2/FiO2 ratio to impute for PaO2/FiO2 ratio in the respiratory component of the Sequential Organ Failure Assessment (SOFA) Score. *Crit Care Med*. 2009;37(4):1317-1321.
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1128 14. Burghi G, Biard L, Roux A, et al. Characteristics and outcome according to underlying disease in non-AIDS patients with acute respiratory failure due to Pneumocystis pneumonia. *Eur J Clin Microbiol Infect*. 2021;40(6):1191-1198.
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1134 15. Zahar JR, Robin M, Azoulay E, Fieux F, Nitenberg G, Schlemmer B.

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Pneumocystis carinii pneumonia in critically ill patients with malignancy: a descriptive study. *Clin Infect Dis*. 2002;35(8):929-934.

16. Azoulay E, Roux A, Vincent F, et al. A multivariable prediction model for Pneumocystis jirovecii pneumonia in hematology patients with acute respiratory failure. *Am J Respir Crit Care Med*. 2018;198(12):1519-1526.

17. Galmiche S, Thoreau B, Bretagne S, et al. Invasive fungal diseases in patients with autoimmune diseases: a case series from the French RESSIF network. *RMD Open*. 2023;9(3):e003281.

18. Hänsel L, Schumacher J, Denis B, Hamane S, Cornely OA, Koehler P. How to diagnose and treat a patient without human immunodeficiency virus infection having Pneumocystis jirovecii pneumonia? *Clin Microbiol Infect*. 2023;29(8):1015-1023.

19. Giacobbe DR, Dettori S, Di Pilato V, et al. Pneumocystis jirovecii pneumonia in intensive care units: a multicenter study by ESGCIP and EFISG. *Crit Care Lond Engl*. 2023;27(1):323.

20. Wolfe RM, Peacock JE. Pneumocystis pneumonia and the rheumatologist: Which patients are at risk and how can PCP be prevented? *Curr Rheumatol Rep*. 2017;19(6):35.

21. Baden LR, Swaminathan S, Angarone M, et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN Clinical Practice Guidelines in Oncology. *J Natl Compr Cancer Netw*. 2016;14(7):882-913.

22. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA

Clinical Practice Guideline Update. *J Clin Oncol*. 2018;36(30):3043-3054.
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24. Jinno S, Akashi K, Onishi A, Nose Y, Yamashita M, Saegusa J. Comparative effectiveness of trimethoprim-sulfamethoxazole versus atovaquone for the prophylaxis of pneumocystis pneumonia in patients with connective tissue diseases receiving prolonged high-dose glucocorticoids. *Rheumatol Int*. 2022;42(8):1403-1409.
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26. Limper AH, Offord KP, Smith TF, Martin WJ. Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. *Am Rev Respir Dis*. 1989;140(5):1204-1209.
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27. Chastain DB, Spradlin M, Ahmad H, Henao-Martinez AF. Unintended consequences: risk of opportunistic infections associated with long-term glucocorticoid therapies in adults [published online ahead of print September 6, 2023]. *Clin Infect Dis*. https://doi.org/10.1093/cid/ciad474
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28. Yadaw AS, Sahner DK, Sidky H, et al. Preexisting autoimmunity is associated with increased severity of coronavirus disease 2019: a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C). *Clin Infect*. 2023;77(6):816-826.
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1101 patients in the era of novel immunosuppressive therapies.
1102 Kansenshōgaku Zasshi J Jpn Assoc Infect Dis. 2014;88(6 suppl 11):26-39.
1103

1104 9. Gaborit B, Tessoulin B, Lavergne R, et al. Outcome and prognostic factors of Pneumocystis jirovecii pneumonia in immunocompromised adults: a prospective observational study. *Ann Intensive Care*. 2019;9:131.
1105
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1109 10. Lécuyer R, Issa N, Tessoulin B, et al. Epidemiology and clinical impact of respiratory coinfections at diagnosis of Pneumocystis jirovecii pneumonia. *J Infect Dis*. 2022;225(5):868-880.
1110
1111
1112

1113 11. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. *Clin Infect Dis*. 2020;71(6):1367-1376.
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1119 12. Pandharipande PP, Shintani AK, Hagerman HE, et al. Derivation and validation of SpO2/FiO2 ratio to impute for PaO2/FiO2 ratio in the respiratory component of the Sequential Organ Failure Assessment (SOFA) Score. *Crit Care Med*. 2009;37(4):1317-1321.
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1124 13. Briel M, Bucher HC, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. *Cochrane Database Syst Rev*. 2006;3:CD006150.
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1128 14. Burghi G, Biard L, Roux A, et al. Characteristics and outcome according to underlying disease in non-AIDS patients with acute respiratory failure due to Pneumocystis pneumonia. *Eur J Clin Microbiol Infect*. 2021;40(6):1191-1198.
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1134 15. Zahar JR, Robin M, Azoulay E, Fieux F, Nitenberg G, Schlemmer B.

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