Abstract
Background
COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a serious complication of severe SARS-CoV-2 pneumonia in critically ill patients requiring invasive mechanical ventilation (IMV). Several host- and treatment-related risk factors have been identified, but the role of environmental factors—particularly ICU room air pressure—remains underexplored.
Methods
We conducted an ancillary analysis of the COVID-ICU study, a prospective multicenter cohort of COVID-19 patients admitted to ICUs in France, Belgium and Switzerland during the first wave of the pandemic. Our analysis included 1233 mechanically ventilated patients. We compared the cumulative incidence of probable invasive pulmonary aspergillosis (IPA), defined according to the 2024 Invasive-Fungal-Diseases-in-Adult-Patients-in-ICU (FUNDICU) consensus criteria, between patients isolated in negative-pressure rooms and those housed in neutral-pressure rooms. Secondary outcomes included the incidence of putative IPA, the incidence of putative IPA or Aspergillus colonization (both defined according to the AspICU algorithm), and the association between probable IPA occurrence and clinical outcomes.
Results
Probable IPA occurred significantly less frequently in patients isolated in negative-pressure rooms, compared to those in neutral-pressure rooms (2.0% vs. 4.8%; adjusted cause-specific hazard ratio [cHR] 0.44, 95%CI 0.21–0.90, p = 0.024). No significant between-group difference was observed in the incidence of putative IPA alone or in combination with Aspergillus colonization (1.3% vs. 2.1%, adjusted cHR 0.65, 95% CI 0.23–1.77, p = 0.4 and 3.3% vs. 5.8%, adjusted cHR 0.66, 95% CI 0.30–1.42, p = 0.29, respectively). The occurrence of probable IPA was associated with longer IMV duration and ICU length-of-stay (adjusted HR 0.45, 95% CI 0.27–0.76, p = 0.002 and 0.59, 95% CI 0.38–0.91, p = 0.017, respectively).
Conclusion
In this large multicenter cohort of mechanically ventilated COVID-19 patients, isolation in negative-pressure ICU rooms was associated with a lower incidence of probable IPA, but the small event rate and potential confounders indicate this finding needs to be replicated and validated by other studies.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13054-026-06085-8.
Keywords: COVID-19, SARS-CoV-2, Aspergillus, Invasive pulmonary aspergillosis, Negative-pressure rooms, Intensive care
Introduction
Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) has emerged as a serious complication in mechanically ventilated patients with acute respiratory distress syndrome (ARDS) related to severe SARS-CoV-2 pneumonia [1, 2]. While its reported incidence has been highly variable (ranging from 2 to 47% [3]), CAPA has been associated with high morbidity and mortality rates [4]. Several patient-related risk factors for CAPA have been identified, including chronic liver disease, chronic obstructive pulmonary disease (COPD), immunosuppression, use of corticosteroids and interleukin-6 inhibitors [3], but the impact of environmental factors, including the air pressure applied in ICU rooms, remains underexplored.
During the pandemic, negative-pressure rooms were recommended—when possible—for critically ill patients with suspected or confirmed COVID-19 in order to mitigate the risk of airborne transmission of SARS-CoV-2 [5]. Negative-pressure rooms are designed to reduce the risk of viral dissemination by maintaining a lower pressure relative to surrounding areas, thereby directing airflow inward and filtering exhaust air. However, the impact of negative-pressure isolation room on the development of opportunistic infections, such as invasive pulmonary aspergillosis (IPA), remains uncertain. Indeed, a monocentric study published during the first wave of the COVID-19 pandemic suggested that negative pressure may inadvertently influence fungal spore circulation, humidity levels, and air quality in ways that could predispose critically ill patients to IPA [6].
In this study, we aimed to compare the incidence of CAPA in critically ill patients isolated in negative-pressure rooms with those housed in neutral-pressure rooms. To this end, we conducted an ancillary analysis of COVID-ICU, a large cohort of 4643 patients admitted to ICUs in Europe during the first wave of the COVID-19 pandemic [7].
Methods
Study design and patients
COVID-ICU is a multicenter, prospective cohort study conducted in 149 ICUs from 138 centers in France, Switzerland, and Belgium [7]. It included all consecutive patients over 16 years of age admitted to the participating ICUs between February 25th, 2020, and May 4th, 2020, with confirmed SARS-CoV-2 infection, defined as a positive result of a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay from nasal or pharyngeal swabs, or lower respiratory tract secretions.
For this ancillary analysis, we selected the subset of patients who (1) required invasive mechanical ventilation (IMV) during ICU stay, (2) had information on ICU room air pressure available in the study database, and (3) were admitted to centers that agreed to retrospectively provide additional data allowing to classify IPA cases according to predefined definitions.
COVID-ICU received approval from the ethical committees of the French Intensive Care Society (CE-SRLF 20–23), Switzerland (BASEC #2020–00704) and Belgium (2020–294). The study was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice, and in compliance with applicable local regulations. All patients or close relatives were informed that their data were included in the COVID-ICU cohort.
Data collection
The data collected as part of the original COVID-ICU study have been reported previously [7], and included demographics, comorbidities (including immunodeficiency, if present), ICU severity scores at admission, organ support received during ICU stay, adjuvant therapies for ARDS, and specific treatment received (including corticosteroids) until day 90. Air pressure in ICU rooms, categorized as negative or neutral, was recorded daily in each center. Identification of API cases followed a two-step process. First, patients in whom the diagnosis of IPA had been suspected and/or confirmed by the clinical team were selected. Second, detailed clinical signs at the time of diagnosis, imaging and bronchoscopy findings, results of serum and respiratory mycological investigations (culture, galactomannan, β-D-glucan), histopathological evidence if available, and antifungal treatment strategies were retrospectively retrieved among these patients.
Definitions
Exposure to negative-pressure rooms was defined as spending at least one day in a negative-pressure room during ICU stay. The decision to assign patients to negative- versus neutral-pressure rooms was left to the treating clinical team and based on room availability and local practices. The 2024 Invasive-Fungal-Diseases-in-Adult-Patients-in-ICU (FUNDICU) consensus definition was used to define probable IPA [8]. Of note, for patients in whom chest computed tomography (CT) was not performed, abnormal chest X-ray findings consistent with the diagnosis were considered to fulfil the FUNDICU imaging criterion. The AspICU algorithm was applied to identify putative IPA, considered a secondary outcome [9]. Cases with a positive culture for Aspergillus from a lower respiratory tract specimen but not meeting all criteria for putative IPA were classified as Aspergillus colonization [9]. Details on definitions used in the study are provided in Supplementary Tables 1 and 2.
Outcomes
The primary outcome was the 60-day cumulative incidence of probable IPA occurring under IMV. Secondary outcomes included the cumulative incidence of putative IPA alone or in combination with Aspergillus colonization, as well as clinical outcomes associated with the occurrence of probable IPA, including IMV duration, ICU length-of-stay and ICU mortality.
Statistical analysis
Continuous variables were reported as mean and standard deviation in case of normal distribution, or as median and interquartile range (IQR, i.e., 25th and 75th percentiles) otherwise. Categorical variables were expressed as numbers and percentages.
The cumulative incidence of probable IPA, putative IPA, and the combination of putative IPA and Aspergillus colonization was estimated using the Kalbfleisch and Prentice method [10], considering death or successful weaning of IMV (i.e., extubation alive) before day 60 post-intubation as competing events.
The association between housing in negative- vs. neutral-pressure ICU rooms and the incidence of probable IPA (primary endpoint) was analyzed using cause-specific Cox’s proportional hazard models, considering death or successful weaning of IMV before day 60 post-intubation as competing events [11] and with sandwich covariance estimation to account for center clustering effect. The association was adjusted for pre-specified confounding factors, including the Simplified Acute Physiology Score II (SAPS II) and immunosuppression at ICU admission. Cause-specific hazard ratios (cHR) and their 95% confidence intervals (CIs) associated with probable IPA were derived from Cox’s models as effect sizes. The same method was applied to assess the association between negative- vs. neutral-pressure and putative IPA, and the combination of putative IPA and Aspergillus colonization. A sensitivity analysis was carried out by excluding patients who had experienced at least one change in room air-pressure status during their ICU stay.
The associations between probable IPA and clinical outcomes censored at day 60 from intubation (ICU mortality, successful weaning of IMV, and ICU discharge alive) were assessed using Cox’s regression model (with sandwich covariance estimation to account for center clustering effect), and adjusted for the same previously quoted confounding factors. Cause-specific hazard was estimated as effect size for IMV duration (considering successful weaning of IMV as event of interest, and death under IMV as competing event) and ICU length-of-stay (considering ICU discharge alive as event of interest, and death during ICU as competing event). IPA was treated as a time-varying variable to account for immortal time bias. The same model was used to estimate the cHR in subgroups of ICU room pressure by introducing an interaction term between probable IPA and pressure groups.
Statistical testing was performed at the two-tailed α level of 0.05. Data were analyzed using the SAS software package, release 9.4 (SAS Institute, Cary, NC).
Results
Patient characteristics at ICU admission
A total of 1233 patients (mean age 62.0 ± 11.8 years, 74% of men) from 75 participating ICUs were included (Fig. 1). There were 847 patients hospitalized for at least one day in negative-pressure ICU rooms, and 386 patients hospitalized in neutral-pressure ICU rooms. Among the 847 patients exposed to negative-pressure rooms, 88 (10,4%) experienced at least one change in room air pressure status during their ICU stay, and spent a median of 57% of their time under IMV in negative-pressure rooms. The distribution of the number of patients hospitalized in negative-pressure vs. neutral-pressure ICU rooms in each of the 75 participating centers is presented in Supplementary Fig. 1. There was no difference in the distribution of comorbidities and risk factors of IPA (including immunosuppression, steroids, ARDS, COPD, and lymphopenia) according to pressure levels in ICU rooms (Table 1). However, lower disease severity was observed among patients admitted to negative-pressure rooms than among those in neutral-pressure rooms, as reflected by lower rates of extracorporeal membrane oxygenation (ECMO) use (2.4% vs. 13.1%), bacterial co-infection (6.6% vs. 11.0%) and renal replacement therapy (RRT) at ICU admission (2.0% vs. 6.0%). The distribution of baseline characteristics in patients with and without probable IPA is presented in Supplementary Table 3.
Fig. 1.
Flow chart. ICU: intensive care unit; IMV: invasive mechanical ventilation
Table 1.
Patient characteristics at ICU admission according to ICU room pressure conditions
| Characteristics | N | Overall population | Negative-pressure rooms | Neutral-pressure rooms | Absolute standardized difference (negative- vs. neutral pressure rooms) |
|---|---|---|---|---|---|
| N = 1233 | N = 847 | N = 386 | |||
| Age, years, mean ± SD | 1233 | 62.0 ± 11.8 | 62.0 ± 11.7 | 61.9 ± 11.9 | < 0.01 |
| Men | 1222 | 901 (73.7) | 610 (72.5) | 291 (76.6) | 0.09 |
| Body mass index, kg/m2, median [25th – 75th percentile] | 1185 | 28.7 [25.8–33.0] | 28.7 [25.8–32.8] | 29.1 [26.0–33.2] | 0.02 |
| Severity scores | |||||
| SAPS II, median [25th – 75th percentile] | 1165 | 40 [31–53] | 40 [31–52] | 42 [31–54] | < 0.01 |
| SOFA score, median [25th – 75th percentile] | 1056 | 7 [4–10] | 7 [4–10] | 7 [4–10] | 0.04 |
| Chronic diseases | |||||
| Immunodeficiency | 1215 | 133 (11.0) | 93 (11.1) | 40 (10.6) | 0.01 |
| Solid cancer | 1213 | 21 (1.7) | 13 (1.6) | 8 (2.1) | 0.04 |
| Hematological malignancy | 1214 | 30 (2.5) | 18 (2.2) | 12 (3.2) | 0.06 |
| Bone marrow transplantation | 1213 | 6 (2.2) | 3 (0.4) | 3 (0.8) | 0.06 |
| Solid organ transplantation | 1213 | 29 (2.4) | 20 (2.4) | 9 (2.4) | < 0.01 |
| HIV | 1211 | 16 (1.3) | 13 (1.6) | 3 (0.8) | 0.07 |
| Immunosuppressive treatment | 662 | 53 (8.0) | 37 (8.1) | 16 (7.8) | < 0.01 |
| Long-term corticosteroid therapy | 662 | 51 (7.7) | 36 (7.9) | 15 (7.4) | 0.02 |
| COPD | 482 | 75 (15.6) | 51 (15.3) | 24 (16.1) | 0.02 |
| Suspected COPD | 479 | 30 (6.3) | 22 (6.7) | 8 (5.4) | 0.05 |
| Documented COPD | 482 | 45 (9.3) | 29 (8.7) | 16 (10.7) | 0.07 |
| Diabetes mellitus | 972 | 342 (35.2) | 241 (36.0) | 101 (33.4) | 0.05 |
| Chronic kidney disease | 1213 | 115 (9.5) | 80 (9.6) | 35 (9.3) | < 0.01 |
| Cardiovascular history | 1220 | 759 (62.2) | 525 (62.3) | 234 (62.1) | < 0.01 |
| Respiratory history | 1217 | 270 (22.2) | 187 (22.2) | 83 (22.1) | < 0.01 |
| Clinical frailty scale, median [25th – 75th percentile] | 1139 | 2 (2–3) | 2 (2–3) | 2 (2–3) | 0.13 |
| During the first 24 h in ICU | |||||
| Invasive mechanical ventilation | 1230 | 974 (79.2) | 664 (78.6) | 310 (80.5) | 0.05 |
| ARDS | 1110 | 990 (89.2) | 677 (89.0) | 313 (89.7) | 0.02 |
| Mild ARDS (PaO2/FiO2 = 201–300) | 839 | 214 (25.5) | 144 (25.4) | 70 (25.6) | - |
| Moderate ARDS (PaO2/FiO2 = 101–200) | 431 (51.4) | 295 (52.1) | 136 (49.8) | - | |
| Severe ARDS (PaO2/FiO2 < 100) | 194 (23.1) | 127 (22.4) | 67 (24.5) | - | |
| Prone positioning | 960 | 219 (22.8) | 147 (22.4) | 72 (23.6) | 0.03 |
| ECMO | 1221 | 70 (5.7) | 20 (2.4) | 50 (13.1) | 0.41 |
| Corticosteroids | 1221 | 114 (9.3) | 82 (9.8) | 32 (8.4) | 0.05 |
| Bacterial co-infection | 1190 | 95 (8.0) | 54 (6.6) | 41 (11.0) | 0.16 |
| Renal replacement therapy | 1224 | 40 (3.3) | 17 (2.0) | 23 (6.0) | 0.21 |
| Leukocytes, G/L | 1139 | 8.7 [6.4–11.9] | 8.4 [6.1–11.4] | 9.3 [6.8–12.7] | < 0.01 |
| Lymphocytes, G/L | 873 | 0.8 [0.6–1.1] | 0.8 [0.6–1.1] | 0.8 [0.6–1.3] | 0.06 |
| Platelets, G/L | 1137 | 225 [170–293] | 223 [171–289] | 237 [169–307] | 0.08 |
| CRP, mg/L | 582 | 167 [109–245] | 168 [110–250] | 164 [101–232] | 0.09 |
| Serum creatinine, µmol/L | 1151 | 78 [61–115] | 78 [61–113] | 78 [61–121] | < 0.01 |
| Total bilirubin, µmol/L | 890 | 9 [6–14] | 9 [6–13] | 10 [7–15] | 0.01 |
ARDS: acute respiratory distress syndrome; CRP: C-reactive protein; COPD: chronic obstructive pulmonary disease; ECMO: extracorporeal membrane oxygenation; HIV: human immunodeficiency virus; SAPS II: simplified acute physiology score II; SD: standard deviation; SOFA: sequential organ failure assessment
Patient characteristics during ICU stay
Patient characteristics during the ICU stay are presented in Table 2. Overall, these characteristics were broadly comparable between ICU room air pressure groups. However, patients isolated in negative-pressure rooms remained less severely ill during ICU stay, as reflected by a lower incidence of ECMO (8.8% vs. 18.3%) and RRT (21.3% vs. 27.9%). Among ICU survivors, the duration of IMV and ICU length-of-stay were marginally shorter in the negative-pressure group (15 [8–27] vs. 16 [10–25] median [IQR] days and 19 [11–33] vs. 21 [12–34] days, respectively), whereas ICU mortality was similar between pressure groups (30.1% vs. 30.8%). Corticosteroid use during ICU stay did not differ between groups (33.4% vs. 32%). In the overall cohort, 135 (11%) bronchoalveolar lavage (BAL) procedures with at least one mycological test were recorded, including 49 (5.8%) in the negative-pressure group, and 86 (22.3%) in the neutral-pressure group; and 220 (18%) serum galactomannan tests were performed, including 119 (14%) in the negative-pressure group and 101 (26%) in the neutral-pressure group.
Table 2.
Patient characteristics during ICU stay according to ICU room pressure conditions
| Characteristics | N | Overall population | Negative-pressure rooms | Neutral-pressure rooms |
|---|---|---|---|---|
| Invasive mechanical ventilation | 1233 | 1233 (100) | 847 (100) | 386 (100) |
| Prone positioning | 1225 | 828 (67.6) | 565 (66.9) | 263 (69.0) |
| Inhaled nitric oxide | 1221 | 176 (14.4) | 111 (13.2) | 65 (17.2) |
| Progression of ARDS severity | 839 | |||
| Mild ARDS (PaO2/FiO2 = 201–300) | 214 (25.5) | 144 (25.4) | 70 (25.6) | |
| Moderate ARDS (PaO2/FiO2 = 101–200) | 431 (51.4) | 295 (52.1) | 136 (49.8) | |
| Severe ARDS (PaO2/FiO2 < 100) | 194 (23.1) | 127 (22.4) | 67 (24.5) | |
| ECMO | 1226 | 144 (11.8) | 74 (8.8) | 70 (18.3) |
| Corticosteroids | 1229 | 405 (33.0) | 282 (33.4) | 123 (32.0) |
| Renal replacement therapy | 1231 | 287 (23.3) | 180 (21.3) | 107 (27.9) |
| Duration of invasive ventilation, days | ||||
| Discharged alive from ICU | 745 | 15 (9–26) | 15 (8–27) | 16 (10–25) |
| Dead in ICU | 358 | 12 (6–23) | 12 (6–21) | 13 (7–28) |
| ICU length-of-stay | ||||
| Discharged alive from ICU | 855 | 19 (11–33) | 19 (11–33) | 21 (12–34) |
| Dead in ICU | 372 | 13 (7–23) | 13 (6–22) | 14 (8–28) |
| ICU mortality | 1227 | 372 (30.3) | 254 (30.1) | 118 (30.8) |
| Day-28 mortality | 1228 | 397 (32.3) | 276 (32.6) | 121 (31.7) |
| Day-60 mortality | 1181 | 408 (34.6) | 282 (34.1) | 126 (35.6) |
ARDS: acute respiratory distress syndrome; CRP: C-reactive protein; ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; PaO2/FiO2: ratio of the arterial partial pressure in O2 over the fraction of inspired O2
Incidence of IPA
Probable IPA was diagnosed in 35 patients (60-day cumulative incidence 2.9%, 95% CI 2.0–3.9%), with a median delay of 7 days (IQR 4–19) following intubation. Among these, 21/35 patients (60%) had a positive Aspergillus BAL culture (mostly Aspergillus fumigatus [n = 19], including 9 in the negative-pressure group and 10 in the neutral-pressure group), 16/30 (53.3%) a positive serum galactomannan (> 0.5 optical density index; ODI), and 8/15 (53.3%) a positive BAL galactomannan (≥ 1.0 ODI). All patients had abnormal findings on chest imaging deemed compatible with the diagnosis of IPA, including 21 by chest CT and 14 by chest X-ray. The 60-day cumulative incidence of probable IPA was significantly lower in patients hospitalized in negative-pressure than in patients in neutral-pressure rooms (2.0% vs. 4.8%, adjusted cHR 0.44, 95% CI 0.21–0.90, p = 0.024; Fig. 2A and Table 3). The cumulative incidences of putative IPA, as well as the combination of putative IPA and Aspergillus colonization—while directionally consistent with the findings for probable IPA—did not differ significantly between the study groups (1.3% vs. 2.1%, adjusted cHR 0.65, 95% CI 0.23–1.77, p = 0.4 and 3.3% vs. 5.8%, adjusted cHR 0.66, 95% CI 0.30–1.42, p = 0.29, respectively; Fig. 2B-C and Table 3). Similar findings were obtained in a sensitivity analysis excluding the 88 patients who had experienced at least one change in room air pressure status during their ICU stay (Supplementary Table 4).
Fig. 2.
Cumulative incidence of probable IPA (A), putative IPA (B) and the combination of putative IPA and Aspergillus colonization (C) in negative-pressure (dotted line) vs. neutral-pressure rooms (full line). Time starting on the day of intubation
Table 3.
Incidence of IPA according to ICU room pressure conditions
| Negative- pressure rooms N = 847 |
Neutral-pressure rooms N = 386 |
Unadjusted cHR (95% CI) | Adjusted cHR* (95%CI) | p value* | |
|---|---|---|---|---|---|
| Probable IPA | 17/847 (2.0) | 18/386 (4.8) | 0.45 (0.22 to 0.90) | 0.44 (0.21 to 0.90) | 0.024 |
| Putative IPA | 11/847 (1.3) | 8/386 (2.1) | 0.67 (0.24 to 1.82) | 0.65 (0.23 to 1.77) | 0.40 |
| Putative IPA or Aspergillus colonization | 28/847 (3.3) | 22/386 (5.8) | 0.61 (0.27 to 1.36) | 0.66 (0.30 to 1.42) | 0.29 |
Values are number of events; 60-day cumulative incidence is expressed as %, considering extubation alive and death as competing events
cHR calculated using cause-specific Cox’s proportional hazard model with sandwich covariance estimation to account for center clustering effect
*Adjusted for prespecified confounders (SAPS II and immunosuppression)
cHR: cause-specific hazard ratio; CI: confidence interval; IPA: invasive pulmonary aspergillosis
Association of probable IPA with clinical outcomes
In the overall cohort, there was no significant association between the occurrence of probable IPA and mortality (adjusted HR 1.43, 95% CI 0.83–2.46, p = 0.19; Supplementary Table 5). In subgroup analyses, mortality was significantly higher among patients with probable IPA housed in neutral-pressure rooms (adjusted HR 1.92, 95% CI 1.10–3.37, p = 0.021), whereas no significant association was observed in negative-pressure rooms (after adjustment on immunosuppression and SAPS-II). However, no statistically significant interaction between probable IPA and ICU room air pressure was observed, suggesting no evidence of effect modification by room pressure. Patients with probable IPA had a longer duration of IMV and a longer ICU length-of-stay (adjusted HR 0.45, 95% CI 0.27–0.76, p = 0.002 and 0.59, 95% CI 0.38–0.91, p = 0.017, respectively). Although these effects appeared more pronounced among patients housed in neutral-pressure rooms, no significant interaction with pressure group was detected.
Discussion
In this ancillary analysis of the COVID-ICU cohort including 1233 mechanically ventilated COVID-19 patients during the first wave of the pandemic, we found that patients isolated in negative-pressure ICU rooms had a significantly lower incidence of probable IPA than patients housed in neutral-pressure rooms. In contrast, no difference was observed between pressure groups for the incidence of putative IPA according to the AspICU algorithm, nor for the combined outcome of putative IPA and Aspergillus colonization.
These findings were initially unexpected. Negative-pressure ventilation has long been suspected to favor the intrusion of unfiltered air and environmental fungal spores into patient rooms, which is precisely why patients at high risk for invasive fungal infections—such as those with hematological malignancies or neutropenia—are traditionally cared for in positive-pressure environments. Accordingly, our results may appear counter-intuitive considering previous reports suggesting a protective effect of positive-pressure ventilation against IPA in patients with classical risk factors. However, as discussed in a review article [12], most studies addressing this issue provide low-quality evidence, and many have evaluated bundles of infection control measures rather than isolating the effect of room pressure alone, making causal inference difficult. Interestingly, a study conducted prior to the COVID-19 pandemic showed that mold concentrations in air samples were similar in rooms with neutral- and positive-pressure ventilation, but higher in non-ventilated areas [13]. This suggests that air treatment strategies—such as laminar airflow combined with high-efficiency particulate air (HEPA) filtration—may play a more important role in reducing exposure to airborne Aspergillus spores than the direction of air pressure per se. If confirmed, our findings may have implications extending beyond the specific epidemiological context of CAPA, and apply to other airborne pathogens and potential future pandemics.
During the COVID-19 pandemic, ICU environments were profoundly modified. Units were rapidly expanded or reorganized, storage areas were repurposed, and temporary facilities were sometimes created, occasionally under conditions resembling construction or renovation settings. Such circumstances are well known to increase the risk of environmental fungal dispersion, and therefore represent a context in which increased environmental exposure could plausibly occur. This may limit the generalizability of our findings beyond the first wave of the COVID-19 pandemic, as the specific conditions of care delivery during this period may have introduced unique and unmeasured risks not representative of current practice. However, to our knowledge, only two studies specifically investigated the impact of negative-pressure ICU rooms on the risk of IPA [6]. The first report included 26 patients and described clusters of IPA cases associated with environmental Aspergillus contamination that resolved after switching rooms from negative to neutral or slightly positive pressure. A second retrospective study on 31 CAPA cases described a drop in IPA incidence when an academic hospital in Boston (USA) changed its infection control policies by reducing negative-pressure utilization rates [14]. However, methodological limitations of both studies (small sample size, absence of adjustment for important confounders, and lack of a strict comparative design) limit the generalizability of those findings. Such observations nonetheless raised concerns that negative-pressure ventilation could increase the risk of both Aspergillus colonization and IPA.
In contrast, in the present study, we did not observe any increase in the incidence of IPA or Aspergillus colonization associated with negative-pressure rooms. On the contrary, the incidence of probable IPA was even lower in this group, even after adjustment for major confounders, including baseline disease severity and immunosuppression—one of the strongest risk factors for IPA [3]. Although the associations between negative-pressure rooms and the incidence of putative IPA, or the composite outcome of putative IPA and Aspergillus colonization, were not statistically significant, the crude and adjusted estimates were directionally consistent with those observed for probable IPA. Overall, these findings suggest that, in this specific epidemiological setting, isolation in negative-pressure ICU rooms was not associated with an increased risk of either Aspergillus colonization or IPA, regardless of the definition used.
The differential impact of ICU room pressure on probable versus putative IPA outcomes may be related to the diagnostic performance of the case definitions used. Indeed, the multiple IPA case definitions that have been proposed for critically ill patients differ markedly in diagnostic accuracy when compared with histologically confirmed IPA [15, 16]. Some definitions tend to misclassify Aspergillus colonization as invasive disease, whereas others, although highly specific, suffer from limited sensitivity. The AspICU algorithm, initially validated in a histologically proven cohort [9], is highly specific for diagnosing IPA in ICU patients but poorly sensitive, with reported sensitivities as low as 6% when compared with histology-proven IPA [15]. In contrast, the FUNDICU consensus definition [8] demonstrates improved diagnostic performance, with a sensitivity of 44% and a specificity of 75% against histologically confirmed IPA, the remaining lack of sensitivity being largely attributable to restrictive host-factor criteria [15]. This motivated the use of the FUNDICU definition of probable IPA as the primary endpoint for this study. Importantly, the FUNDICU definition incorporates non-culture-based mycological criteria, notably galactomannan detection in BAL fluid, a biomarker strongly associated with active fungal growth and considered the most reliable mycological test for the diagnosis of IPA in critically ill patients [17, 18]. As such, the FUNDICU definition provides a standardized research framework that enhances comparability and generalizability across studies in a field previously characterized by heterogeneous case definitions and study populations. Taken together, these differences indicate that probable IPA and putative IPA capture distinct entities, which may partly account for the heterogeneous associations observed across outcomes in our cohort.
The reported incidence of CAPA varies widely in the literature, ranging from 1% to more than 30% [19], reflecting substantial heterogeneity in study design, patient populations, diagnostic strategies and case definitions [1, 20]. In this context, the overall incidence observed in the present study was relatively low, and consistent with findings from large French multicenter cohorts (in which CAPA diagnosis was based on clinical suspicion) that reported incidences of probable IPA around 3% in critically ill COVID-19 patients [21, 22].
Despite its relatively low incidence, CAPA has consistently been associated with high morbidity and mortality. In line with prior studies, patients with probable IPA in our cohort experienced prolonged duration of IMV and ICU length-of-stay [3, 19, 22], and a trend toward higher mortality. Importantly, no interaction was observed between IPA and ICU room pressure for clinical outcomes, suggesting that the prognostic impact of IPA was independent of the ventilation pressure strategy.
Our study has important strengths. To our knowledge, it is the first multicenter analysis specifically designed to evaluate the impact of ICU room pressure on the risk of IPA. The large sample size, prospective data collection, and use of multiple IPA definitions—including Aspergillus colonization—allowed for a comprehensive assessment of potential environmental exposure.
Several limitations should be acknowledged. First, we were unable to precisely measure air pressure in negative-pressure rooms, nor the ventilation characteristics or air filtration performance in the ICU rooms of participating centers, which may have introduced unmeasured heterogeneity in environmental exposure. Second, environmental sampling of air or surfaces was not available, precluding direct correlations between fungal burden and clinical outcomes. Given that all inclusions occurred in a relatively narrow period, we were not able to analyze if spore exposure and IPA incidence were directly related to seasonality. Third, this study was conducted during the first wave of the COVID-19 pandemic, at a time when awareness of CAPA was still limited and corticosteroid therapy was not yet routinely used, which may have contributed to underdiagnosis due to lower diagnostic suspicion. In addition, indications for diagnostic testing for IPA were not standardized and were left to the discretion of duty physicians and to test availability. Due to the retrospective nature of the study, we observed that the proportions of patients who underwent bronchoscopy with BAL, as well as BAL and serum galactomannan testing, were lower in the negative- than in the neutral-pressure group. Because CAPA lacks specific clinical or radiological manifestations, and because BAL galactomannan and culture are central to case identification, this variability in diagnostic practices may have led to underdiagnosis of cases and differential detection across patient groups, thereby introducing an important risk of classification bias. Therefore, the observed association between negative-pressure rooms and lower probable IPA incidence should be interpreted cautiously and should not be considered evidence of a protective effect of negative-pressure rooms. Besides, our study does not provide a longitudinal assessment of Aspergillus colonisation during ICU stay, including baseline colonisation at ICU admission. As a result, we were unable to distinguish between pre-existing colonisation and ICU-acquired colonisation, or to analyse the dynamics of progression from colonisation to invasive infection. Fourth, the relatively low number of IPA events limited the ability to adjust for all potential confounders, including COPD, ECMO, RRT or steroid exposure during ICU stay [3]. Analyses were only adjusted for baseline immunosuppression and disease severity at ICU admission, and residual confounding cannot be excluded (especially given imbalances in baseline characteristics between patients housed in negative- vs. neutral-pressure rooms). Importantly, this applies to the association between ICU room pressure and the occurrence of probable IPA, but also to the association between probable IPA and outcomes. Although the associations observed were consistent across outcomes, our findings should be interpreted with caution and require confirmation in larger, independent cohorts. Finally, ICU room pressure was largely center driven, although center effects were accounted for in the analyses. Approximately 10% of patients initially exposed to negative-pressure rooms experienced at least one pressure change; however, they remained under negative pressure for most of their exposure to IMV, limiting the risk of exposure misclassification.
Conclusion
In an ancillary analysis of a large multicenter prospective cohort including 1233 mechanically ventilated COVID-19 patients during the first wave of the pandemic, isolation in negative-pressure rooms was associated with a lower incidence of probable IPA, in comparison to neutral-pressure rooms. These findings do not support the hypothesis that negative-pressure environments constitute a major environmental risk factor for IPA in this setting. However, because mycological investigations were performed less frequently in patients housed in negative-pressure rooms, differential diagnostic intensity may have contributed to the observed lower incidence of probable IPA. Confirmation in prospective cohorts with standardized fungal surveillance or systematic diagnostic protocols is warranted.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Acknowledgements
In addition to the authors, the COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators includes the following participating sites and collaborators: Matthieu Schmidt, David Hajage, Alexandre Demoule, Tài Pham, Alain Combes, Martin Dres, Said Lebbah, Antoine Kimmoun, Alain Mercat, Gaëtan Beduneau, Jessica Palmyre, Margot Prevost, Pierre Asfar, François Beloncle, Julien Demiselle, Arthur Pavot, Xavier Monnet, Christian Richard, Julien Mayaux, Alexandra Beurton, Richard Descamps, Aurélie Joret, Damien Du Cheyron, Frédéric Pene, Jean-Daniel Chiche, Mathieu Jozwiak, Paul Jaubert, Jean-Pierre Bedos, Guillaume Voiriot, Muriel Fartoukh, Marion Teulier, Clarisse Blayau, Erwen L’Her, Cécile Aubron, Laetitia Bodenes, Nicolas Ferriere, Johann Auchabie, Anthony Le Meur, Sylvain Pignal, Thierry Mazzoni, Jean-Pierre Quenot, Pascal Andreu, Jean-Baptiste Roudau, Marie Labruyère, Saad Nseir, Sébastien Preau, Julien Poissy, Daniel Mathieu, Sarah Benhamida, Rémi Paulet, Nicolas Roucaud, Martial Thyrault, Florence Daviet, Sami Hraiech, Gabriel Parzy, Aude Sylvestre, Sébastien Jochmans, Anne-Laure Bouilland, Mehran Monchi, Marc Danguy des Déserts, Quentin Mathais, Gwendoline Rager, Pierre Pasquier, Reignier Jean, Seguin Amélie, Garret Charlotte, Canet Emmanuel, Jean Dellamonica, Clément Saccheri, Romain Lombardi, Yanis Kouchit, Sophie Jacquier, Armelle Mathonnet, Mai-Ahn Nay, Isabelle Runge, Frédéric Martino, Laure Flurin, Amélie Rolle, Michel Carles, Rémi Coudroy, Arnaud W. Thille, Jean-Pierre Frat, Maeva Rodriguez, Pascal Beuret, Audrey Tientcheu, Arthur Vincent, Florian Michelin, Marie Anne Melone, Maxime Gauzi, Arnaud Guilbert, Geoffrey Kouadri, Valérie Gissot, Stéphan Ehrmann, Charlotte Salmon-Gandonnière, Djlali Elaroussi, Agathe Delbove, Yannick Fedun, Julien Huntzinger, Eddy Lebas, Grâce Kisoka, Céline Grégoire, Stella Marchetta, Bernard Lambermont, Laurent Argaud, Thomas Baudry, Pierre-Jean Bertrand, Auguste Dargent, Christophe Guitton, Nicolas Chudeau, Mickaël Landais, Cédric Darreau, Alexis Ferre, Antoine Gros, Guillaume Lacave, Fabrice Bruneel, Mathilde Neuville, Jérôme Devaquet, Guillaume Tachon, Richard Gallot, Riad Chelha, Arnaud Galbois, Anne Jallot, Ludivine Chalumeau Lemoine, Khaldoun Kuteifan, Valentin Pointurier, Louise-Marie Jandeaux, Joy Mootien, Charles Damoisel, Benjamin Sztrymf, Juliette Chommeloux, Charles Edouard Luyt, Frédérique Schortgen, Leon Rusel, Camille Jung, Florent Gobert, Damien Vimpere, Lionel Lamhaut, Bertrand Sauneuf, Liliane Charrier, Julien Calus, Isabelle Desmeules, Benoît Painvin, Jean-Marc Tadie, Vincent Castelain, Baptiste Michard, Jean-Etienne Herbrecht, Mathieu Baldacini, Nicolas Weiss, Sophie Demeret, Clémence Marois, Benjamin Rohaut, Pierre-Henri Moury, Anne-Charlotte Savida, Emmanuel Couadau, Mathieu Série, Nica Alexandru, Cédric Bruel, Candice Fontaine, Sonia Garrigou, Juliette Courtiade Mahler, Maxime Leclerc, Michel Ramakers, Pierre Garçon, Nicole Massou, Ly Phacs Van Vong, Juliane Sen, Nolwenn Lucas, Franck Chemouni, Annabelle Stoclin, Alexandre Avenel, Henri Faure, Angélie Gentilhomme, Sylvie Ricome, Paul Abraham, Céline Monard, Julien Textoris, Thomas Rimmele, Florent Montini, Gabriel Lejour, Thierry Lazard, Isabelle Etienney, Younes Kerroumi, Dupuis Claire, Bereiziat Marine Coupez, Thouy François, Clémet Hoffmann, Nicolas Donat, Violaine Muller, Thibault Martinez, Audrey Jacquot, Matthieu Mattei, Bruno Levy, Ramin Ravan, Loïc Dopeux, Jean-Mathias Liteaudon, Delphine Roux, Brice Rey, Radu Anghel, Deborah Schenesse, Vincent Gevrey, Jermy Castanera, Philippe Petua, Benjamin Madeux, Otto Hartman, Michael Piagnerelli, Anne Joosten, Cinderella Noel, Patrick Biston, Thibaut Noel, Gurvan L. E. Bouar, Messabi Boukhanza, Elsa Demarest, Marie-France Bajolet, Nathanaël Charrier, Audrey Quenet, Cécile Zylberfajn, Nicolas Dufour, Buno Mégarbane, Sqébastian Voicu, Nicolas Deye, Isabelle Malissin, François Legay, Matthieu Debarre, Nicolas Barbarot, Pierre Fillatre, Bertrand Delord, Thomas Laterrade, Tahar Saghi, Wilfried Pujol, Pierre Julien Cungi, Pierre Esnault, Mickael Cardinale, Vivien Hong Tuan Ha, Grégory Fleury, Marie-Ange Brou, Daniel Zafimahazo, David Tran-Van, Patrick Avargues, Lisa Carenco, Nicolas Robin, Alexandre Ouali, Lucie Houdou, Christophe Le Terrier, Noémie Suh, Steve Primmaz, Jérome Pugin, Emmanuel Weiss, Tobias Gauss, Jean-Denis Moyer, Catherine Paugam-Burtz, Béatrice La Combe, Rolland Smonig, Jade Violleau, Pauline Cailliez, Jonathan Chelly, Antoine Marchalot, Cécile Saladin, Christelle Bigot, Pierre-Marie Fayolle, Jules Fatséas, Amr Ibrahim, Dabor Resiere, Rabih Hage, Clémentine Cholet, Marie Cantier, Pierre Trouiller, Philippe Montravers, Brice Lortat-Jacob, Sebastien Tanaka, Alexy Tran-Dinh, Jacques Duranteau, Anatole Harrois, Guillaume Dubreuil, Marie Werner, Anne Godier, Sophie Hamada, Diane Zlotnik, Hélène Nougue, Armand Mekontso-Dessap, Guillaume Carteaux, Keyvan Razazi, Nicolas De Prost, Nicolas Mongardon, Olivier Langeron, Eric Levesque, Arié Attias, Charles de Roquetaillade, Benjamin G. Chousterman, Alexandre Mebazaa, Etienne Gayat, Marc Garnier, Emmanuel Pardo, Lea Satre-Buisson, Christophe Gutton, Elise Yvin, Clémence Marcault, Elie Azoulay, Michael Darmon, Nicolas Bonnet, Nathan Ebstein, Stéphane Gaudry, Yves Cohen, Hafid Ait-Oufella, Geoffroy Hariri, Tomas Urbina, Sandie Mazerand, Nicholas Heming, Francesca Santi, Pierre Moine, Djillali Annane, Adrien Bouglé, Edris Omar, Aymeric Lancelot, Emmanuelle Begot, Gaétan Plantefeve, Damien Contou, Hervé Mentec, Olivier Pajot, Stanislas Faguer, Olivier Cointault, Laurence Lavayssiere, Marie-Béatrice Nogier, Matthieu Jamme, Claire Pichereau, Jan Hayon, Hervé Outin, François Dépret, Maxime Coutrot, Maité Chaussard, Lucie Guillemet, Pierre Goffin, Romain Thouny, Julien Guntz, Laurent Jadot, Romain Persichini, Vanessa Jean-Michel, Hugues Georges, Thomas Caulier, Gaël Pradel, Marie-Hélène Hausermann, ThiMy Hue Nguyen-Valat, Michel Boudinaud, Emmanuel Vivier, Sylvène Rosseli, Gaël Bourdin, Christian Pommier, Marc Vinclair, Simon Poignant, Sandrine Mons, Wulfran Bougouin, Franklin Bruna, Quentin Maestraggi, Christian Roth, Laurent Bitker, François Dhelft, Justine Bonnet-Chateau, Mathilde Filippelli, Tristan Morichau-Beauchant, Stéphane Thierry, Charlotte Le Roy, Mélanie Saint Jouan, Bruno Goncalves, Aurélien Mazeraud, Matthieu Daniel, Tarek Sharshar, Cyril Cadoz, Rostane Gaci, Sébastien Gette, Guillaune Louis, Sophe-Caroline Sacleux, Marie-Amélie Ordan, Aurélie Cravoisy, Marie Conrad, Guilhem Courte, Sébastien Gibot, Younès Benzidi, Claudia Casella, Laurent Serpin, Jean-Lou Setti, Marie-Catherine Besse, Anna Bourreau, Jérôme Pillot, Caroline Rivera, Camille Vinclair, Marie-Aline Robaux, Chloé Achino, Marie-Charlotte Delignette, Tessa Mazard, Frédéric Aubrun, Bruno Bouchet, Aurélien Frérou, Laura Muller, Charlotte Quentin, Samuel Degoul, Xavier Stihle, Claude Sumian, Nicoletta Bergero, Bernard Lanaspre, Hervé Quintard, Eve Marie Maiziere, Pierre-Yves Egreteau, Guillaume Leloup, Florin Berteau, Marjolaine Cottrel, Marie Bouteloup, Matthieu Jeannot, Quentin Blanc, Julien Saison, Isabelle Geneau, Romaric Grenot, Abdel Ouchike, Pascal Hazera, Anne-Lyse Masse, Suela Demiri, Corinne Vezinet, Elodie Baron, Déborah Benchetrit, Antoine Monsel, Grégoire Trebbia, Emmanuelle Schaack, Raphaël Lepecq, Mathieu Bobet, Christophe Vinsonneau, Thibault Dekeyser, Quentin Delforge, Imen Rahmani, Bérengère Vivet, Jonathan Paillot, Lucie Hierle, Claire Chaignat, Sarah Valette, Benoït Her, Jennifier Brunet, Mathieu Page, Fabienne Boiste, Anthony Collin, Florent Bavozet, Aude Garin, Mohamed Dlala, Kais Mhamdi, Bassem Beilouny, Alexandra Lavalard, Severine Perez, Benoit Veber, Pierre-Gildas Guitard, Philippe Gouin, Anna Lamacz, Fabienne Plouvier, Bertrand P. Delaborde, Aïssa Kherchache, Amina Chaalal, Jean-Damien Ricard, Marc Amouretti, Santiago Freita-Ramos, Damien Roux, Jean-Michel Constantin, Mona Assefi, Marine Lecore, Agathe Selves, Florian Prevost, Christian Lamer, Ruiying Shi, Lyes Knani, Sébastien Pili-Floury, Lucie Vettoretti, Michael Levy, Lucile Marsac, Stéphane Dauger, Sophie Guilmin-Crépon, Jean-Baptiste Putegnat, Frédérique Bayle, Maya Perrou, Ghyslaine Thao, Guillaume Géri, Cyril Charron, Xavier Repessé, Antoine Vieillard-Baron, Mathieu Guilbart, Pierre-Alexandre Roger, Sébastien Hinard, Pierre-Yves Macq, Kevin Chaulier, Sylvie Goutte, Patrick Chillet, Anaïs Pitta, Barbara Darjent, Amandine Bruneau, Sigismond Lasocki, Maxime Leger, Soizic Gergaud, Pierre Lemarie, Nicolas Terzi, Carole Schwebel, Anaïs Dartevel, Louis-Marie Galerneau, Jean-Luc Diehl, Caroline Hauw-Berlemont, Nicolas Péron, Emmanuel Guérot, Abolfazl Mohebbi Amoli, Michel Benhamou, Jean-Pierre Deyme, Olivier Andremont, Diane Lena, Julien Cady, Arnaud Causeret, Arnaud De La Chapelle, Christophe Cracco, Stéphane Rouleau, David Schnell, Cécile Lory, Thibault Chapelle, Vincent Bruckert, Julie Garcia, Abdlazize Sahraoui, Nathalie Abbosh, Caroline Bornstain, Pierre Pernet, Florent Poirson, Ahmed Pasem, Philippe Karoubi, Virginie Poupinel, Caroline Gauthier, François Bouniol, Philippe Feuchere, Florent Bavozet, Anne Heron, Serge Carreira, Malo Emery, Anne Le Floch, Luana Giovannangeli, Nicolas Herzog, Christophe Giacardi, Thibaut Baudic, Chloé Thill, Florence Tubach, Olivier Lesieur & Julie Noublanche
Abbreviations
- ARDS
Acute respiratory distress syndrome
- BAL
Bronchoalveolar lavage
- CAPA
COVID-19-associated pulmonary aspergillosis
- CI
Confidence interval
- COVID-19
Coronavirus disease 2019
- cHR
Cause-specific hazard ratio
- COPD
Chronic obstructive pulmonary disease
- CRP
C-reactive protein
- ECMO
Extracorporeal membrane oxygenation
- EORTC
European Organization for Research and Treatment of Cancer
- HEPA
High-efficiency particulate air
- ICU
Intensive care unit
- IPA
Invasive pulmonary aspergillosis
- IAPA
Influenza-associated pulmonary aspergillosis
- IMV
Invasive mechanical ventilation
- IQR
Interquartile range
- MSGERC
Mycosis Study Group Education and Research Consortium
- ODI
Optical density index
- RRT
Renal replacement therapy
- RT-PCR
Reverse transcription polymerase chain reaction
- SAPS-II
Simplified Acute Physiology Score II
- SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2
- SOFA
Sequential organ failure assessment
Author contributions
LK: manuscript drafting. AR: conceptualisation, data collection, manuscript drafting. HB: statistical analysis, visualisation. SN: conceptualisation, supervision, final revision of the manuscript. All other authors: data collection, final revision of the manuscript.
Funding
No specific funding was obtained for this study.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval
COVID-ICU received approval from the ethical committees of the French Intensive Care Society (CE-SRLF 20–23), Switzerland (BASEC #2020–00704) and Belgium (2020–294). The study was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice, and in compliance with applicable local regulations. All patients or close relatives were informed that their data were included in the COVID-ICU cohort.
Consent for publication
Not applicable.
Competing interests
No competing interests related to this manuscript.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Louis Kreitmann and Anahita Rouzé contributed equally.
Contributor Information
Saad Nseir, Email: s-nseir@chru-lille.fr.
COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators:
Matthieu Schmidt, David Hajage, Alexandre Demoule, Tài Pham, Alain Combes, Martin Dres, Said Lebbah, Antoine Kimmoun, Alain Mercat, Gaëtan Beduneau, Jessica Palmyre, Margot Prevost, Pierre Asfar, François Beloncle, Julien Demiselle, Arthur Pavot, Xavier Monnet, Christian Richard, Julien Mayaux, Alexandra Beurton, Richard Descamps, Aurélie Joret, Damien-Du Cheyron, Frédéric Pene, Jean-Daniel Chiche, Mathieu Jozwiak, Paul Jaubert, Jean-Pierre Bedos, Guillaume Voiriot, Marion Teulier, Clarisse Blayau, Erwen L’Her, Cécile Aubron, Laetitia Bodenes, Nicolas Ferriere, Johann Auchabie, Anthony-Le Meur, Sylvain Pignal, Thierry Mazzoni, Jean-Pierre Quenot, Pascal Andreu, Jean-Baptiste Roudau, Marie Labruyère, Sébastien Preau, Julien Poissy, Daniel Mathieu, Sarah Benhamida, Rémi Paulet, Nicolas Roucaud, Martial Thyrault, Florence Daviet, Sami Hraiech, Gabriel Parzy, Aude Sylvestre, Sébastien Jochmans, Anne-Laure Bouilland, Mehran Monchi, Marc Danguy des Déserts, Quentin Mathais, Gwendoline Rager, Pierre Pasquier, Reignier Jean, Seguin Amélie, Garret Charlotte, Canet Emmanuel, Jean Dellamonica, Clément Saccheri, Romain Lombardi, Yanis Kouchit, Sophie Jacquier, Armelle Mathonnet, Mai-Ahn Nay, Isabelle Runge, Frédéric Martino, Laure Flurin, Amélie Rolle, Michel Carles, Rémi Coudroy, Arnaud W. Thille, Jean-Pierre Frat, Maeva Rodriguez, Pascal Beuret, Audrey Tientcheu, Arthur Vincent, Florian Michelin, Marie-Anne Melone, Maxime Gauzi, Arnaud Guilbert, Geoffrey Kouadri, Valérie Gissot, Stéphan Ehrmann, Charlotte Salmon Gandonnière, Djlali Elaroussi, Agathe Delbove, Yannick Fedun, Julien Huntzinger, Eddy Lebas, Grâce Kisoka, Céline Grégoire, Stella Marchetta, Bernard Lambermont, Laurent Argaud, Thomas Baudry, Pierre-Jean Bertrand, Auguste Dargent, Christophe Guitton, Nicolas Chudeau, Mickaël Landais, Cédric Darreau, Alexis Ferre, Antoine Gros, Guillaume Lacave, Mathilde Neuville, Jérôme Devaquet, Guillaume Tachon, Richard Gallot, Riad Chelha, Arnaud Galbois, Anne Jallot, Ludivine Chalumeau Lemoine, Khaldoun Kuteifan, Valentin Pointurier, Louise-Marie Jandeaux, Joy Mootien, Charles Damoisel, Benjamin Sztrymf, Juliette Chommeloux, Charles Edouard Luyt, Frédérique Schortgen, Leon Rusel, Camille Jung, Florent Gobert, Damien Vimpere, Lionel Lamhaut, Bertrand Sauneuf, Liliane Charrier, Julien Calus, Isabelle Desmeules, Benoît Painvin, Jean-Marc Tadie, Vincent Castelain, Baptiste Michard, Jean-Etienne Herbrecht, Mathieu Baldacini, Nicolas Weiss, Sophie Demeret, Clémence Marois, Benjamin Rohaut, Pierre-Henri Moury, Anne-Charlotte Savida, Emmanuel Couadau, Mathieu Série, Nica Alexandru, Cédric Bruel, Candice Fontaine, Sonia Garrigou, Juliette Courtiade Mahler, Maxime Leclerc, Michel Ramakers, Pierre Garçon, Nicole Massou, Ly Phacs Van Vong, Juliane Sen, Nolwenn Lucas, Franck Chemouni, Annabelle Stoclin, Alexandre Avenel, Henri Faure, Angélie Gentilhomme, Sylvie Ricome, Paul Abraham, Céline Monard, Julien Textoris, Thomas Rimmele, Florent Montini, Gabriel Lejour, Thierry Lazard, Isabelle Etienney, Younes Kerroumi, Dupuis Claire, Marine Bereiziat Coupez, Thouy François, Clémet Hoffmann, Nicolas Donat, Violaine Muller, Thibault Martinez, Audrey Jacquot, Matthieu Mattei, Bruno Levy, Ramin Ravan, Loïc Dopeux, Jean-Mathias Liteaudon, Delphine Roux, Brice Rey, Radu Anghel, Deborah Schenesse, Vincent Gevrey, Jermy Castanera, Philippe Petua, Benjamin Madeux, Otto Hartman, Michael Piagnerelli, Anne Joosten, Cinderella Noel, Patrick Biston, Thibaut Noel, Gurvan Le Bouar, Messabi Boukhanza, Elsa Demarest, Marie-France Bajolet, Nathanaël Charrier, Audrey Quenet, Cécile Zylberfajn, Nicolas Dufour, Buno Mégarbane, Sqébastian Voicu, Nicolas Deye, Isabelle Malissin, François Legay, Matthieu Debarre, Nicolas Barbarot, Pierre Fillatre, Bertrand Delord, Thomas Laterrade, Tahar Saghi, Wilfried Pujol, Pierre-Julien Cungi, Pierre Esnault, Mickael Cardinale, Vivien Hong Tuan Ha, Grégory Fleury, Marie-Ange Brou, Daniel Zafimahazo, David Tran-Van, Patrick Avargues, Lisa Carenco, Nicolas Robin, Alexandre Ouali, Lucie Houdou, Christophe Le Terrier, Noémie Suh, Steve Primmaz, Jérome Pugin, Emmanuel Weiss, Tobias Gauss, Jean-Denis Moyer, Catherine Paugam-Burtz, Béatrice La Combe, Rolland Smonig, Jade Violleau, Pauline Cailliez, Jonathan Chelly, Antoine Marchalot, Cécile Saladin, Christelle Bigot, Pierre-Marie Fayolle, Jules Fatséas, Amr Ibrahim, Dabor Resiere, Rabih Hage, Clémentine Cholet, Marie Cantier, Pierre Trouiller, Philippe Montravers, Brice Lortat-Jacob, Sebastien Tanaka, Alexy Tran-Dinh, Jacques Duranteau, Anatole Harrois, Guillaume Dubreuil, Marie Werner, Anne Godier, Sophie Hamada, Diane Zlotnik, Hélène Nougue, Armand Mekontso-Dessap, Guillaume Carteaux, Nicolas De Prost, Nicolas Mongardon, Olivier Langeron, Eric Levesque, Arié Attias, Charles-de Roquetaillade, Benjamin-G. Chousterman, Alexandre Mebazaa, Etienne Gayat, Marc Garnier, Emmanuel Pardo, Lea Satre-Buisson, Christophe Gutton, Elise Yvin, Clémence Marcault, Elie Azoulay, Michael Darmon, Nicolas Bonnet, Nathan Ebstein, Stéphane Gaudry, Yves Cohen, Hafid Ait-Oufella, Geoffroy Hariri, Tomas Urbina, Sandie Mazerand, Nicholas Heming, Francesca Santi, Pierre Moine, Djillali Annane, Adrien Bouglé, Edris Omar, Aymeric Lancelot, Emmanuelle Begot, Gaétan Plantefeve, Damien Contou, Hervé Mentec, Olivier Pajot, Stanislas Faguer, Olivier Cointault, Laurence Lavayssiere, Marie-Béatrice Nogier, Matthieu Jamme, Claire Pichereau, Jan Hayon, Hervé Outin, François Dépret, Maxime Coutrot, Maité Chaussard, Lucie Guillemet, Pierre Goffin, Romain Thouny, Julien Guntz, Laurent Jadot, Romain Persichini, Vanessa Jean-Michel, Hugues Georges, Thomas Cvaulier, Gaël Pradel, Marie-Hélène Hausermann, Thi My Hue Nguyen Valat, Michel Boudinaud, Emmanuel Vivier, Sylvène Rosseli, Gaël Bourdin, Christian Pommier, Marc Vinclair, Simon Poignant, Sandrine Mons, Wulfran Bougouin, Franklin Bruna, Quentin Maestraggi, Christian Roth, Laurent Bitker, François Dhelft, Justine Bonnet-Chateau, Mathilde Filippelli, Tristan Morichau-Beauchant, Stéphane Thierry, Charlotte-Le Roy, Mélanie Saint Jouan, Bruno Goncalves, Aurélien Mazeraud, Matthieu Daniel, Tarek Sharshar, Cyril Cadoz, Rostane Gaci, Sébastien Gette, Guillaune Louis, Caroline Sophe Sacleux, Marie-Amélie Ordan, Aurélie Cravoisy, Marie Conrad, Guilhem Courte, Sébastien Gibot, Younès Benzidi, Claudia Casella, Laurent Serpin, Jean-Lou Setti, Marie-Catherine Besse, Anna Bourreau, Jérôme Pillot, Caroline Rivera, Camille Vinclair, Marie-Aline Robaux, Chloé Achino, Marie-Charlotte Delignette, Tessa Mazard, Frédéric Aubrun, Bruno Bouchet, Aurélien Frérou, Laura Muller, Charlotte Quentin, Samuel Degoul, Xavier Stihle, Claude Sumian, Nicoletta Bergero, Bernard Lanaspre, Hervé Quintard, Eve-Marie Maiziere, Pierre-Yves Egreteau, Guillaume Leloup, Florin Berteau, Marjolaine Cottrel, Marie Bouteloup, Matthieu Jeannot, Quentin Blanc, Julien Saison, Isabelle Geneau, Romaric Grenot, Abdel Ouchike, Pascal Hazera, Anne-Lyse Masse, Suela Demiri, Corinne Vezinet, Elodie Baron, Déborah Benchetrit, Antoine Monsel, Grégoire Trebbia, Emmanuelle Schaack, Raphaël Lepecq, Mathieu Bobet, Christophe Vinsonneau, Thibault Dekeyser, Quentin Delforge, Imen Rahmani, Bérengère Vivet, Jonathan Paillot, Lucie Hierle, Claire Chaignat, Sarah Valette, Benoït Her, Jennifier Brunet, Mathieu Page, Fabienne Boiste, Anthony Collin, Florent Bavozet, Aude Garin, Mohamed Dlala, Kais Mhamdi, Bassem Beilouny, Alexandra Lavalard, Severine Perez, Benoit Veber, Pierre-Gildas Guitard, Philippe Gouin, Anna Lamacz, Fabienne Plouvier, Bertrand P. Delaborde, Aïssa Kherchache, Amina Chaalal, Jean-Damien Ricard, Marc Amouretti, Santiago Freita-Ramos, Damien Roux, Jean-Michel Constantin, Mona Assefi, Marine Lecore, Agathe Selves, Florian Prevost, Christian Lamer, Ruiying Shi, Lyes Knani, Sébastien Pili-Floury, Lucie Vettoretti, Michael Levy, Lucile Marsac, Stéphane Dauger, Sophie Guilmin-Crépon, Jean-Baptiste Putegnat, Frédérique Bayle, Maya Perrou, Ghyslaine Thao, Guillaume Géri, Cyril Charron, Xavier Repessé, Antoine Vieillard-Baron, Mathieu Guilbart, Pierre-Alexandre Roger, Sébastien Hinard, Pierre-Yves Macq, Kevin Chaulier, Sylvie Goutte, Patrick Chillet, Anaïs Pitta, Barbara Darjent, Amandine Bruneau, Sigismond Lasocki, Maxime Leger, Soizic Gergaud, Pierre Lemarie, Nicolas Terzi, Carole Schwebel, Anaïs Dartevel, Louis-Marie Galerneau, Jean-Luc Diehl, Caroline Hauw-Berlemont, Nicolas Péron, Emmanuel Guérot, Abolfazl-Mohebbi Amoli, Michel Benhamou, Jean-Pierre Deyme, Olivier Andremont, Diane Lena, Julien Cady, Arnaud Causeret, Arnaud De La Chapelle, Christophe Cracco, Stéphane Rouleau, David Schnell, Cécile Lory, Thibault Chapelle, Vincent Bruckert, Julie Garcia, Abdlazize Sahraoui, Nathalie Abbosh, Caroline Bornstain, Pierre Pernet, Florent Poirson, Ahmed Pasem, Philippe Karoubi, Virginie Poupinel, Caroline Gauthier, François Bouniol, Philippe Feuchere, Florent Bavozet, Anne Heron, Serge Carreira, Malo Emery, Anne-Le Floch, Luana Giovannangeli, Nicolas Herzog, Christophe Giacardi, Thibaut Baudic, Chloé Thill, Florence Tubach, Olivier Lesieur, and Julie Noublanche
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.