Relationship between ventilator-associated pneumonia and mortality in COVID-19 patients: a planned ancillary analysis of the coVAPid cohort

Saad Nseir, Ignacio Martin-Loeches, Pedro Povoa, Matthieu Metzelard, Damien Du Cheyron, Fabien Lambiotte, Fabienne Tamion, Marie Labruyere, Demosthenes Makris, Claire Boulle Geronimi, Marc Pinetonde Chambrun, Martine Nyunga, Olivier Pouly, Bruno Mégarbane, Anastasia Saade, Gemma Gomà, Eleni Magira, Jean-François Llitjos, Antoni Torres, Iliana Ioannidou, Alexandre Pierre, Luis Coelho, Jean Reignier, Denis Garot, Louis Kreitmann, Jean-Luc Baudel, Guillaume Voiriot, Damien Contou, Alexandra Beurton, Pierre Asfar, Alexandre Boyer, Arnaud W Thille, Armand Mekontso-Dessap, Vassiliki Tsolaki, Christophe Vinsonneau, Pierre-Edouard Floch, Loïc Le Guennec, Adrian Ceccato, Antonio Artigas, Mathilde Bouchereau, Julien Labreuche, Alain Duhamel, Anahita Rouzé, coVAPid study group, Raphaël Favory, Sébastien Préau, Mercé Jourdain, Julien Poissy, Piehr Saint Leger, Thierry Van der Linden, Anne Veinstein, Elie Azoulay, Frédéric Pene, Maelle Martin, Keyvan Razazi, Gaëtan Plantefeve, Muriel Fartoukh, Didier Thevenin, Bertrand Guidet, Nicolas Weiss, Achille Kouatchet, Charlotte Salmon, Guillaume Brunin, Safaa Nemlaghi, David Meguerditchian, Laurent Argaud, Sebastian Voicu, Charles-Edouard Luyt, Benjamin Kowalski, Edgar Moglia, Luis Morales, Antonia Koutsoukou, Spyros D Mentzelopoulos, David Nora, Sean Boyd, Julien Maizel, Pierre Cuchet, Quentin Delforge, Jean-Pierre Quenot, Déborah Boyer, Catia Cilloniz, Saad Nseir, Ignacio Martin-Loeches, Pedro Povoa, Matthieu Metzelard, Damien Du Cheyron, Fabien Lambiotte, Fabienne Tamion, Marie Labruyere, Demosthenes Makris, Claire Boulle Geronimi, Marc Pinetonde Chambrun, Martine Nyunga, Olivier Pouly, Bruno Mégarbane, Anastasia Saade, Gemma Gomà, Eleni Magira, Jean-François Llitjos, Antoni Torres, Iliana Ioannidou, Alexandre Pierre, Luis Coelho, Jean Reignier, Denis Garot, Louis Kreitmann, Jean-Luc Baudel, Guillaume Voiriot, Damien Contou, Alexandra Beurton, Pierre Asfar, Alexandre Boyer, Arnaud W Thille, Armand Mekontso-Dessap, Vassiliki Tsolaki, Christophe Vinsonneau, Pierre-Edouard Floch, Loïc Le Guennec, Adrian Ceccato, Antonio Artigas, Mathilde Bouchereau, Julien Labreuche, Alain Duhamel, Anahita Rouzé, coVAPid study group, Raphaël Favory, Sébastien Préau, Mercé Jourdain, Julien Poissy, Piehr Saint Leger, Thierry Van der Linden, Anne Veinstein, Elie Azoulay, Frédéric Pene, Maelle Martin, Keyvan Razazi, Gaëtan Plantefeve, Muriel Fartoukh, Didier Thevenin, Bertrand Guidet, Nicolas Weiss, Achille Kouatchet, Charlotte Salmon, Guillaume Brunin, Safaa Nemlaghi, David Meguerditchian, Laurent Argaud, Sebastian Voicu, Charles-Edouard Luyt, Benjamin Kowalski, Edgar Moglia, Luis Morales, Antonia Koutsoukou, Spyros D Mentzelopoulos, David Nora, Sean Boyd, Julien Maizel, Pierre Cuchet, Quentin Delforge, Jean-Pierre Quenot, Déborah Boyer, Catia Cilloniz

Abstract

Background: Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients.

Methods: Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event.

Findings: Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16-2.47), p = 0.006), and influenza groups (1.75 (1.03-3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64-1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups.

Interpretation: VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality.

Clinical trial registration: The study was registered at ClinicalTrials.gov, number NCT04359693.

Keywords: COVID-19; Mortality; Ventilator-associated pneumonia.

Conflict of interest statement

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

Figures

Fig. 1
Fig. 1
Unadjusted and Adjusted hazard ratios for 28-day mortality, extubation alive and ICU discharge alive, associated with SARS-CoV-2 pneumonia, versus influenza pneumonia and no viral infection groups. HRs were calculated using cause-specific proportional hazard models, by considering mortality as competing event for MV duration, and length of ICU stay. Adjusted HRs were calculated, including age, gender, simplified acute physiology score II, Charlson score, MacCabe classification, shock, and acute respiratory distress syndrome as pre-specified covariates in Cox’s models (after handling missing values by multiple imputation). A HR > 1 indicates a decrease in survival duration (i.e. an increased risk for mortality), MV duration (i.e. an increased risk for extubation alive) and ICU length of stay (i.e. an increased risk for discharge alive) and a HR  1 for overall survival but was associated with a HR 

Fig. 2

Association between ventilator-associated lower respiratory…

Fig. 2

Association between ventilator-associated lower respiratory tract infections and outcomes. a 28-Day mortality. b…

Fig. 2
Association between ventilator-associated lower respiratory tract infections and outcomes. a 28-Day mortality. b Duration of mechanical ventilation. c Length of ICU stay. HRs were calculated using cause-specific proportional hazard models, considering the first VA-LRTI as a time dependent 3-levels categorical variable (No VA-LRTI vs. VAT vs. VAP). Adjusted HRs were calculated including age, gender, simplified acute physiology score II, Charlson score, MacCabe classification, shock, and acute respiratory distress syndrome as pre-specified covariables in Cox’s model. Since the event of interest for 28-Day mortality is a pejorative event (death), whereas for MV duration and ICU length of stay, the event of interest is a positive event (extubation or discharge alive), the detrimental effect of SARS-CoV-2 pneumonia (vs influenza pneumonia and no viral infection groups) was associated with a HR > 1 for 28-Day mortality, with a HR < 1 for MV duration and ICU length of stay. HR, hazard ratio; ICU, intensive care unit; MV, mechanical ventilation; VA-LRTI, ventilator-associated respiratory tract infection; VAP, ventilator-associated pneumonia; VAT, ventilator-associated tracheobronchitis
Fig. 2
Fig. 2
Association between ventilator-associated lower respiratory tract infections and outcomes. a 28-Day mortality. b Duration of mechanical ventilation. c Length of ICU stay. HRs were calculated using cause-specific proportional hazard models, considering the first VA-LRTI as a time dependent 3-levels categorical variable (No VA-LRTI vs. VAT vs. VAP). Adjusted HRs were calculated including age, gender, simplified acute physiology score II, Charlson score, MacCabe classification, shock, and acute respiratory distress syndrome as pre-specified covariables in Cox’s model. Since the event of interest for 28-Day mortality is a pejorative event (death), whereas for MV duration and ICU length of stay, the event of interest is a positive event (extubation or discharge alive), the detrimental effect of SARS-CoV-2 pneumonia (vs influenza pneumonia and no viral infection groups) was associated with a HR > 1 for 28-Day mortality, with a HR < 1 for MV duration and ICU length of stay. HR, hazard ratio; ICU, intensive care unit; MV, mechanical ventilation; VA-LRTI, ventilator-associated respiratory tract infection; VAP, ventilator-associated pneumonia; VAT, ventilator-associated tracheobronchitis

References

    1. COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. Intensive Care Med. 2021;47:60–73. doi: 10.1007/s00134-020-06294-x.
    1. Rouzé A, Martin-Loeches I, Povoa P, Makris D, Artigas A, Bouchereau M, Lambiotte F, Metzelard M, Cuchet P, Boulle Geronimi C, Labruyere M, Tamion F, Nyunga M, Luyt C-E, Labreuche J, Pouly O, Bardin J, Saade A, Asfar P, Baudel J-L, Beurton A, Garot D, Ioannidou I, Kreitmann L, Llitjos J-F, Magira E, Mégarbane B, Meguerditchian D, Moglia E, Mekontso-Dessap A, et al. Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study. Intensive Care Med. 2021;47:188–98.
    1. Maes M, Higginson E, Pereira-Dias J, Curran MD, Parmar S, Khokhar F, Cuchet-Lourenço D, Lux J, Sharma-Hajela S, Ravenhill B, Hamed I, Heales L, Mahroof R, Solderholm A, Forrest S, Sridhar S, Brown NM, Baker S, Navapurkar V, Dougan G, Bartholdson Scott J, Conway Morris A. Ventilator-associated pneumonia in critically ill patients with COVID-19. Crit Care. 2021;25:25. doi: 10.1186/s13054-021-03460-5.
    1. Pickens CO, Gao CA, Cuttica M, Smith SB, Pesce L, Grant R, Kang M, Morales-Nebreda L, Bavishi AA, Arnold J, Pawlowski A, Qi C, Budinger GS, Singer BD, Wunderink RG, Investigators for the NC. Bacterial superinfection pneumonia in SARS-CoV-2 respiratory failure. medRxiv 2021:2021.01.12.20248588.
    1. Razazi K, Arrestier R, Haudebourg AF, Benelli B, Carteaux G, Decousser J, Fourati S, Woerther PL, Schlemmer F, Charles-Nelson A, Botterel F, de Prost N, Mekontso Dessap A. Risks of ventilator-associated pneumonia and invasive pulmonary aspergillosis in patients with viral acute respiratory distress syndrome related or not to Coronavirus 19 disease. Crit Care. 2020;24:699. doi: 10.1186/s13054-020-03417-0.
    1. Luyt C-E, Sahnoun T, Gautier M, Vidal P, Burrel S, Pineton de Chambrun M, Chommeloux J, Desnos C, Arzoine J, Nieszkowska A, Bréchot N, Schmidt M, Hekimian G, Boutolleau D, Robert J, Combes A, Chastre J. Ventilator-associated pneumonia in patients with SARS-CoV-2-associated acute respiratory distress syndrome requiring ECMO: a retrospective cohort study. Ann Intensive Care. 2020;10:158. doi: 10.1186/s13613-020-00775-4.
    1. Llitjos J-F, Bredin S, Lascarrou J-B, Soumagne T, Cojocaru M, Leclerc M, Lepetit A, Gouhier A, Charpentier J, Piton G, Faron M, Stoclin A, Pène F. Increased susceptibility to intensive care unit-acquired pneumonia in severe COVID-19 patients: a multicentre retrospective cohort study. Ann Intensive Care. 2021;11:20. doi: 10.1186/s13613-021-00812-w.
    1. Melsen WG, Rovers MM, Groenwold RHH, Bergmans DCJJ, Camus C, Bauer TT, Hanisch EW, Klarin B, Koeman M, Krueger WA, Lacherade JC, Lorente L, Memish ZA, Morrow LE, Nardi G, van Nieuwenhoven CA, O’Keefe GE, Nakos G, Scannapieco FA, Seguin P, Staudinger T, Topeli A, Ferrer M, Bonten MJM. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis. 2013;13:665–671. doi: 10.1016/S1473-3099(13)70081-1.
    1. Safdar N, Dezfulian C, Collard HR, Saint S. Clinical and economic consequences of ventilator-associated pneumonia: a systematic review. Crit Care Med. 2005;33:2184–2193. doi: 10.1097/01.CCM.0000181731.53912.D9.
    1. Nseir S, Di Pompeo C, Soubrier S, Cavestri B, Jozefowicz E, Saulnier F, Durocher A. Impact of ventilator-associated pneumonia on outcome in patients with COPD. Chest. 2005;128:1650–1656. doi: 10.1378/chest.128.3.1650.
    1. Rouzé A, Boddaert P, Martin-Loeches I, Povoa P, Rodriguez A, Ramdane N, Salluh J, Houard M, Nseir S. Impact of chronic obstructive pulmonary disease on incidence, microbiology and outcome of ventilator-associated lower respiratory tract infections. Microorganisms. 2020;8:165. doi: 10.3390/microorganisms8020165.
    1. Robba C, Rebora P, Banzato E, Wiegers EJA, Stocchetti N, Menon DK, Citerio G. Collaborative European NeuroTrauma effectiveness research in traumatic brain injury participants and investigators: incidence, risk factors, and effects on outcome of ventilator-associated pneumonia in patients with traumatic brain injury: analysis of a large, multicenter, prospective, observational longitudinal study. Chest. 2020;158:2292–2303. doi: 10.1016/j.chest.2020.06.064.
    1. Papazian L, Klompas M, Luyt C-E. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med. 2020;46:888–906. doi: 10.1007/s00134-020-05980-0.
    1. Martin-Loeches I, Povoa P, Rodríguez A, Curcio D, Suarez D, Mira J-PJ-PJ-P, Cordero MLML, Lepecq R, Girault C, Candeias C, Seguin P, Paulino C, Messika J, Castro AGAGAG, Valles J, Coelho L, Rabello L, Lisboa T, Collins D, Torres A, Salluh J, Nseir S, Fernández RO, Arroyo J, Gabriela M, Alvarez R, Reyes AT, Dellera C, Molina F, Franco DM, et al. Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicentre, prospective, observational study. Lancet Respir Med. 2015;3:859–68. doi: 10.1016/S2213-2600(15)00326-4.
    1. Guidelines for the management of adults with hospital-acquired ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388–416. doi: 10.1164/rccm.200405-644ST.
    1. Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother. 2010;54:4851–4863. doi: 10.1128/AAC.00627-10.
    1. Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation. 2016;133:601–609. doi: 10.1161/CIRCULATIONAHA.115.017719.
    1. Therneau T-M, Grambsch P-M. Modeling survival data: extending the Cox model. New-York: Springer; 2000.
    1. Willke RJ, Zheng Z, Subedi P, Althin R, Mullins CD. From concepts, theory, and evidence of heterogeneity of treatment effects to methodological approaches: a primer. BMC Med Res Methodol. 2012;12:185. doi: 10.1186/1471-2288-12-185.
    1. van Burren S, Groothuis-Oudshoorn K. Multivariate imputation by chained equations in R. 2011. J Stat Softw 2011;45:1–24.
    1. Gladitz J, Rubin DB. Multiple imputation for nonresponse in surveys. Biom J. 1989;31:131–2. doi: 10.1002/bimj.4710310118.
    1. Makris D, Desrousseaux B, Zakynthinos E, Durocher A, Nseir S. The impact of COPD on ICU mortality in patients with ventilator-associated pneumonia. Respir Med. 2011;105:1022–1029. doi: 10.1016/j.rmed.2011.03.001.
    1. Bercault N, Boulain T. Mortality rate attributable to ventilator-associated nosocomial pneumonia in an adult intensive care unit: a prospective case-control study. Crit Care Med. 2001;29:2303–2309. doi: 10.1097/00003246-200112000-00012.
    1. Martin-Loeches I, Povoa P, Rodríguez A, Curcio D, Suarez D, Mira J-P, Cordero ML, Lepecq R, Girault C, Candeias C, Seguin P, Paulino C, Messika J, Castro AG, Valles J, Coelho L, Rabello L, Lisboa T, Collins D, Torres A, Salluh J, Nseir S. Incidence and prognosis of ventilator-associated tracheobronchitis (TAVeM): a multicentre, prospective, observational study. Lancet Respir Med. 2015;3:859–868. doi: 10.1016/S2213-2600(15)00326-4.
    1. Melsen WG, Rovers MM, Bonten MJM. Ventilator-associated pneumonia and mortality: a systematic review of observational studies. Crit Care Med. 2009;37:2709–2718.
    1. Bekaert M, Timsit JF, Vansteelandt S, Depuydt P, Vésin A, Garrouste-Orgeas M, Decruyenaere J, Clec’h C, Azoulay E, Benoit D. Attributable mortality of ventilator-associated pneumonia: a reappraisal using causal analysis. Am J Respir Crit Care Med. 2011;184:1133–1139. doi: 10.1164/rccm.201105-0867OC.
    1. Steen J, Vansteelandt S, De Bus L, Depuydt P, Gadeyne B, Benoit DD, Decruyenaere J. Attributable mortality of ventilator-associated pneumonia: replicating findings, revisiting methods. Ann Am Thorac Soc. 2021;18(5):830–7.
    1. Barbier F, Lisboa T, Nseir S. Understanding why resistant bacteria are associated with higher mortality in ICU patients. Intensive Care Med. 2016;42(12):2066–9.
    1. Martin-Loeches I, Torres A, Povoa P, Zampieri FG, Salluh J, Nseir S, Ferrer M, Rodriguez A. TAVeM study Group: the association of cardiovascular failure with treatment for ventilator-associated lower respiratory tract infection. Intensive Care Med. 2019;45:1753–1762. doi: 10.1007/s00134-019-05797-6.
    1. Nair GB, Niederman MS. Ventilator-associated pneumonia: present understanding and ongoing debates. Intensive Care Med. 2014;41:34–48. doi: 10.1007/s00134-014-3564-5.
    1. Papazian L, Forel J-M, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal J-M, Perez D, Seghboyan J-M, Constantin J-M, Courant P, Lefrant J-Y, Guérin C, Prat G, Morange S, Roch A. ACURASYS Study Investigators: neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–1116. doi: 10.1056/NEJMoa1005372.
    1. Shintani AK, Girard TD, Eden SK, Arbogast PG, Moons KGM, Ely EW. Immortal time bias in critical care research: application of time-varying Cox regression for observational cohort studies. Crit Care Med. 2009;37:2939–2945. doi: 10.1097/CCM.0b013e3181b7fbbb.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner