Relationship Between Corticosteroid use and Incidence of Ventilator-associated Pneumonia in COVID-19 Patients

A Retrospective Multicenter Study

Ouriel Saura; Anahita Rouzé; Ignacio Martin-Loeches; Pedro Povoa; Louis Kreitmann; Antoni Torres; Matthieu Metzelard; Damien Du Cheyron; Fabien Lambiotte; Fabienne Tamion; Marie Labruyere; Claire Boulle Geronimi; Charles-Edouard Luyt; Martine Nyunga; Olivier Pouly; Arnaud W. Thille; Bruno Megarbane; Anastasia Saade; Eleni Magira; Jean-François Llitjos; Iliana Ioannidou; Alexandre Pierre; Jean Reignier; Denis Garot; Jean-Luc Baudel; Guillaume Voiriot; Gaëtan Plantefeve; Elise Morawiec; Pierre Asfar; Alexandre Boyer; Armand Mekontso-Dessap; Fotini Bardaka; Emili Diaz; Christophe Vinsonneau; Pierre-Edouard Floch; Nicolas Weiss; Adrian Ceccato; Antonio Artigas; David Nora; Alain Duhamel; Julien Labreuche; Saad Nseir

Disclosures

Crit Care. 2022;26(292)

Abstract and Introduction

Abstract

Background: Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP.

Methods: Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox's proportional hazard models with adjustment on pre-specified confounders.

Results: Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p= 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17–1.31) at day 2, 0.95 (0.63–1.42) at day 7, 1.48 (1.01–2.16) at day 14 and 1.94 (1.09–3.46) at day 21.

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Patient characteristics at ICU admission
	No corticosteroids (n = 354)	Corticosteroids (n = 191)
Age, years	64 (53–72)	65 (57–72)
Men	256 (72.3)	134 (70.2)
BMI (Kg/m)*	28.4 (25.4–33.0)	29.6 (26.9–34.3)
Severity scores
SAPS II†	41 (32–54)	43 (33–60)
SOFA Score‡	6 (3–8)	7 (3–9)
Comorbidity scores
MacCabe classification
Non-fatal	296/336 (88.1)	157/186 (85.3)
Fatal < 5 years	36/336 (10.7)	25/186 (13.6)
Fatal < 1 year	4/336 (1.2)	2/186 (1.1)
Charlson comorbidity index^§	3 (1–4)	3 (2–4)
Chronic diseases
Diabetes mellitus	109/353 (30.9)	52/189 (27.5)
Chronic renal failure	17/349 (4.9)	15/187 (8.0)
Heart disease	70/351 (19.9)	30/187 (16.0)
Chronic heart failure	13/350 (3.7)	8/186 (4.3)
COPD	19/350 (5.4)	18/188 (9.6)
Chronic respiratory failure	15/350 (4.3)	5/186 (2.7)
Cirrhosis	4/350 (1.1)	4/187 (2.1)
Immunosuppression	25/350 (7.1)	27/187 (14.4)
Active smoking	17/350 (4.9)	11/188 (5.9)
Alcohol abuse	23/349 (6.6)	10/187 (5.3)
Location before ICU admission
Home	163/354 (46.0)	95/191 (49.7)
Hospital ward	136/354 (38.4)	70/191 (36.6)
Another ICU	55/354 (15.5)	26/191 (13.6)
Recent hospitalization (< 3 months)	24/354 (6.8)	18/189 (9.5)
Recent antibiotics (< 3 months)	45/354 (12.7)	26/190 (13.7)
Causes for ICU admission
Shock	63/348 (18.1)	39/187 (20.9)
Acute respiratory failure	327/354 (92.4)	172/190 (90.5)
ARDS	244/352 (69.3)	125/188 (66.5)
Neurological failure	14/344 (4.1)	12/182 (6.6)
Cardiac arrest	2/343 (0.6)	1/182 (0.5)
Acute renal failure	58/344(16.9)	37/182 (20.3)

Values are as no./No.(%) or median (interquartile range). * 31 missing values (n = 10 in corticosteroid group); † 42 missing values (n = 17 in corticosteroid group); ‡ 21 missing values (n = 8 in corticosteroid group); § 19 missing values (n = 8 in corticosteroid group)
McCabe classification of comorbidities and likelihood of survival, likely to survive > 5 years, 1–5 years, < 1 year; Chronic kidney disease, KDOQI CKD classification stage 4 or 5 (creatinine clearance < 30 ml/mn); Chronic heart failure, NYHA class III or IV; Heart disease, ischemic heart disease or atrial fibrillation; Cirrhosis, Child–Pugh score B or C; Immunosuppression if hematological malignancy, allogeneic stem cell transplant, solid cancer, organ transplant, HIV or immunosuppressive drugs; More than one cause for ICU admission is possible
ARDS Acute respiratory distress syndrome, COPD chronic obstructive pulmonary disease, ICU intensive care unit, SAPS II Simplified Acute Physiology Score II, SOFA Sequential Organ Failure Assessment

Table 2. Patient characteristics during ICU stay
	No corticosteroids (n = 354)	Corticosteroids (n = 191)
Corticosteroids
Hydrocortisone	–	52/187 (27.8)
Dexamethasone	–	46/187 (24.6)
Methylprednisolone	–	90/187 (48.1)
Highest daily dose, mg	–	100 (50–133)
Exposure period, days	–	6 (3–8)
Antibiotic treatment	308/328 (93.9)	177/182 (97.3)
Duration, days	12 (7–18)	14 (9–20)
Prone positioning	228/353 (64.6)	143/191 (74.9)
ECMO	39/354 (11.0)	22/190 (11.6)
28-day outcomes
MV duration, days	14 (8–22)	17 (10–25)
28-day mortality	93/354 (26.3)	70/191 (36.6)
ICU length of stay, days	17 (11–27)	20 (13–28)

Values are as no./No.(%) or median (interquartile range)
Highest daily dose of corticosteroids is reported as prednisone equivalent. Exposure period is defined from the day of initiation of corticosteroids until the occurrence of VAP or MV withdrawal or death within the 28-day of follow-up
ECMO extracorporeal membrane oxygenation, ICU intensive care unit, MV mechanical ventilation

Table 3. Association between corticosteroid treatment use and outcomes in all study patients
	Unadjusted analysis		Adjusted analysis^b
	Unadjusted analysis		Multiple imputation analysis^c		Complete case-analysis
	cHR (95%CI)	P Value	cHR (95%CI)	P Value	cHR (95%CI)	P Value
VAP
Overall effect		0.13^a		0.082^a		0.056^a
At day 2	0.43 (0.15–1.17)		0.47 (0.17–1.31)		0.43 (0.14–1.24)
At day 7	0.86 (0.58–1.28)		0.95 (0.63–1.42)		0.95 (0.63–1.44)
At day 14	1.34 (0.92–1.94)		1.48 (1.01–2.16)		1.59 (1.05–2.38)
At day 21	1.75 (0.99–3.08)		1.94 (1.09–3.46)		2.16 (1.16–4.02)
28-day mortality	2.01 (1.46–2.75)	< 0.0001	1.67 (1.20–2.33)	0.002	1.47 (1.02–2.10)	0.034
MV duration	1.14 (0.89–1.45)	0.30	1.25 (1.01–1.54)	0.036	1.18 (0.88–1.56)	0.25
Length of ICU stay	0.71 (0.54–0.95)	0.017	1.00 (0.80–1.24)	0.99	0.77 (0.56–1.07)	0.12

ARDS acute respiratory distress syndrome, BMI body mass index, cHR cause-specific hazard ratio, CI confidence interval, ICU intensive care unit, SAPS II Simplified Acute Physiology Score II, VAP ventilator-associated pneumonia
^a P Value for the effect of corticosteroids assessed by including corticosteroids and time*corticosteroids terms into Cox's regression model to account the violation of proportional hazard assumption
^bAdjusted for age, sex, BMI, SAPS II, MacCabe classification, immunosuppression, recent hospitalization, recent antibiotics, shock, ARDS, cardiac arrest (^cafter handling missing values by multiple imputation (m = 20)

Table 4. Description of patients at the day of VAP diagnosis
	No corticosteroids (n = 138)	Corticosteroids (n = 74)
Total number of VAP
1	103/138 (74.6)	66/74 (89.2)
2	29/138 (21.0)	6/74 (8.1)
3	5/138 (3.6)	1/74 (1.4)
4	1/138 (0.7)	1/74 (1.4)
5	0/138 (0.0)	1/74 (1.4)
SOFA score^a	8 (5–11)	8 (5–11)
Diagnostic procedure
Endotracheal aspirates	83/137 (60.6)	47/73 (64.4)
Bronchoalveolar lavage	54/137 (39.4)	26/73 (35.6)
Modified CPIS^a	6 (5–7)	6 (4–7)
PaO₂/FiO₂ ^b	130 (91–180)	139 (95–188)
Antibiotic treatment	122/138 (88.4)	71/74 (95.9)
Appropriate antibiotic treatment	94/133 (70.7)	48/73 (65.8)

Values are as no./No.(%) or median (interquartile range)
VAP ventilator-associated pneumonia, SOFA Sequential Organ Failure Assessment, CPIS clinical pulmonary infection score
^a8 missing values (1 in corticosteroids group)
^b13 missing values (3 in corticosteroids group)

Table 5. Microorganisms responsible for VAP
	No corticosteroids (n = 138)	Corticosteroids (n = 74)
Gram-positive cocci	22 (15.9)	13 (17.6)
MSSA	12 (8.8)	7 (9.5)
MRSA	5 (3.6)	0 (0.0)
Enterococcus spp.	3 (2.2)	4 (5.4)
Streptococcus pneumoniae	2 (1.5)	2 (2.7)
Gram-negative bacilli	83 (60)	44 (59.5)
Pseudomonas aeruginosa	24 (17.5)	17 (23)
Enterobacter spp.	20 (14.6)	14 (18.9)
Klebsiella pneumoniae	6 (4.4)	5 (6.8)
Escherichia coli	12 (8.8)	2 (2.7)
Acinetobacter baumannii	9 (6.6)	2 (2.7)
Stenotrophomonas maltophilia	2 (1.5)	0 (0.0)
Serratia marcescens	2 (1.5)	2 (2.7)
Citrobacter freundii	4 (2.9)	0 (0.0)
Proteus mirabilis	1 (0.7)	1 (1.4)
Haemophilus influenza	2 (1.5)	0 (0.0)
Morganella morganii	1 (0.7)	1 (1.4)
Other*	17 (12.3)	9 (12.1)
Polymicrobial	15 (10.9)	8 (10.8)
Multidrug-resistant isolates	26 (19.0)	21 (28.4)

VAP Ventilator-associated pneumonia
Values are as no. (%)
Missing values n = 1 (in the no-corticosteroid group)
MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus
*Contains other Streptococcus Spp., other Klebsiella Spp., other Citrobacter Spp. and other bacteria

Table 6. Association between corticosteroid use and mortality, MV duration and ICU length of stay according to VAP
	Unadjusted analysis			Adjusted analysis^a
	Unadjusted analysis			Multiple imputation analysis^b			Complete case-analysis
	cHR (95%CI)	P Value	P Het	cHR (95%CI)	P Value	P Het	cHR (95%CI)	P Value	P Het
All-cause 28-day mortality
No VAP	2.36 (1.60–3.46)	< 0.0001	0.18	1.95 (1.31–2.90)	0.001	0.15	1.61 (1.03–2.51)	0.034	0.44
VAP	1.50 (0.87–2.59)	0.14		1.18 (0.66–2.10)	0.56		1.21 (0.67–2.17)	0.51
MV duration
No VAP	1.20 (0.90–1.61)	0.27	0.40	1.29 (0.96–1.73)	0.086	0.19	1.46 (1.03–2.05)	0.03	0.050
VAP	0.96 (0.62–1.50)	0.68		0.90 (0.57–1.42)	0.66		0.81 (0.49–1.31)	0.39
Length of ICU stay
No VAP	0.68 (0.48–0.96)	0.027	0.82	0.76 (0.53–1.07)	0.11	0.78	0.84 (0.56–1.26)	0.40	0.46
VAP	0.73 (0.44–1.19)	0.21		0.69 (0.42–1.14)	0.15		0.65 (0.38–1.12)	0.12

ARDS acute respiratory distress syndrome, BMI body mass index, cHR cause-specific hazard ratio, CI confidence interval, ICU intensive care unit SAPS II Simplified Acute Physiology Score II, VAP ventilator-associated pneumonia
^aAdjusted for age, gender, BMI, SAPS II, McCabe classification, immunosuppression, recent hospitalization, recent antibiotics, shock, ARDS, cardiac arrest
^bAfter handling missing values by multiple imputation (m = 20)
P Het: P Value for the heterogeneity test of effects according to occurrence of VAP

Authors and Disclosures

Ouriel Saura¹, Anahita Rouzé^1,2, Ignacio Martin-Loeches^3–5, Pedro Povoa^6–8, Louis Kreitmann³⁰, Antoni Torres¹², Matthieu Metzelard¹¹, Damien Du Cheyron¹³, Fabien Lambiotte¹⁴, Fabienne Tamion¹⁵, Marie Labruyere¹⁶, Claire Boulle Geronimi¹⁷, Charles-Edouard Luyt¹⁸, Martine Nyunga¹⁹, Olivier Pouly²⁰, Arnaud W. Thille²¹, Bruno Megarbane²², Anastasia Saade²³, Eleni Magira²⁴, Jean-François Llitjos²⁵, Iliana Ioannidou²⁶, Alexandre Pierre²⁷, Jean Reignier²⁸, Denis Garot²⁹, Jean-Luc Baudel³¹, Guillaume Voiriot³², Gaëtan Plantefeve³³, Elise Morawiec^34,35, Pierre Asfar³⁶, Alexandre Boyer³⁷, Armand Mekontso-Dessap^38–40, Fotini Bardaka⁴¹, Emili Diaz^9,10, Christophe Vinsonneau⁴², Pierre-Edouard Floch⁴³, Nicolas Weiss^44–46, Adrian Ceccato⁴⁷, Antonio Artigas⁴⁸, David Nora⁶, Alain Duhamel^49,50, Julien Labreuche⁵⁰ and Saad Nseir^1,2* and coVAPid Study Group

¹Médecine Intensive-Réanimation, CHU de Lille, 59000, Lille, France ²INSERM U1285, Université de Lille, CNRS, UMR 8576 – UGSF – Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France. ³Department of Intensive Care Medicine, Multidisciplinary Intensive Care Research Organization (MICRO), St. James's Hospital, Dublin, Ireland. ⁴Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland. ⁵Hospital Clinic, IDIBAPS, Universidad de Barcelona, Ciberes, Barcelona, Spain. ⁶Polyvalent Intensive Care Unit, Hospital de São Francisco Xavier, CHLO, Lisbon, Portugal. ⁷NOVA Medical School, CHRC, New University of Lisbon, Lisbon, Portugal. ⁸Center for Clinical Epidemiology and Research Unit of Clinical Epidemiology, OUH Odense University Hospital, Odense, Denmark. ⁹Critical Care Department, Hospital Universitari Parc Tauli, Sabadell, Spain. ¹⁰Departament de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain. ¹¹Service de Médecine Intensive Réanimation, CHU Amiens Picardie, 80000, Amiens, France. ¹²Department of Pulmonology, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERES, Barcelona, Spain. ¹³Department of Medical Intensive Care, Caen University Hospital, 14000, Caen, France. ¹⁴Service de Réanimation Polyvalente, Centre Hospitalier de Valenciennes, Valenciennes, France. ¹⁵Medical Intensive Care Unit, Rouen University Hospital, UNIROUEN, Inserm U1096, FHU- REMOD-VHF, 76000, Rouen, France. ¹⁶Department of Intensive Care, François Mitterrand University Hospital, Dijon, France. ¹⁷Service de Réanimation et de Soins Intensifs, Centre Hospitalier de Douai, Douai, France. ¹⁸Service de Médecine Intensive Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique – Hôpitaux de Paris, Paris Cedex 13, France. ¹⁹Service de Réanimation, Centre Hospitalier de Roubaix, Roubaix, France. ²⁰Service de Médecine Intensive Réanimation, Hôpital Saint Philibert GHICL, Université Catholique, Lille, France. ²¹CHU de Poitiers, Médecine Intensive Réanimation, CIC 1402 ALIVE, Université de Poitiers, Poitiers, France. ²²Department of Medical and Toxicological Critical Care, Lariboisière Hospital, INSERM UMRS-1144, Paris Cité University, Paris, France. ²³Service de Médecine Intensive Réanimation, Hôpital Saint-Louis, 75010, Paris, France. ²⁴National and Kapodistrian University of Athens, Evangelismos Hospital, Athens, Greece. ²⁵Medical Intensive Care Unit, Cochin Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France. ²⁶First Department of Pulmonary Medicine and Intensive Care Unit, National and Kapodistrian University of Athens, Sotiria Chest Hospital, Athens, Greece. ²⁷Service de Réanimation Polyvalente, Centre Hospitalier de Lens, Lens, France. ²⁸Service de Médecine Intensive Réanimation, CHU de Nantes, Nantes, France. ²⁹Service de Médecine Intensive Réanimation, CHU de Tours, Hôpital Bretonneau, 37044, Tours Cedex 9, France. ³⁰Service de Médecine Intensive - Réanimation, Hôpital Edouard Herriot, Hospices Civils de Lyon, 69437, Lyon Cedex 03, France. ³¹Service de Médecine Intensive Réanimation, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012, Paris, France. ³²Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Service de Médecine Intensive Réanimation, Hôpital Tenon, Paris, France. ³³Service de Réanimation Polyvalente, CH Victor Dupouy, Argenteuil, France. ³⁴Service de Médecine Intensive-Réanimation et Pneumologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France. ³⁵Sorbonne Université, Inserm UMRS Neurophysiologie Respiratoire Expérimentale et Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié Salpêtrière, Paris, France. ³⁶Département de Médecine Intensive Réanimation, CHU d'Angers, 49933, Angers Cedex 9, France. ³⁷Service de Médecine Intensive Réanimation, CHU de Bordeaux, 33000, Bordeaux, France. ³⁸Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Service de Médecine Intensive Réanimation, 94010, Créteil, France. ³⁹CARMAS, Université Paris Est Créteil, 94010, Créteil, France. ⁴⁰INSERM U955, Institut Mondor de Recherche Biomédicale, 94010, Créteil, France. ⁴¹Intensive Care Unit, University Hospital of Larissa, University of Thessaly, Biopolis, 41110, Larissa, Greece. ⁴²Intensive Care Unit, Hôpital de Béthune, 62408, Béthune, France. ⁴³Service de Réanimation, Hôpital Duchenne, 62200, Boulogne-sur-Mer, France. ⁴⁴Département de Neurologie, Unité de Médecine Intensive Réanimation Neurologique, Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France. ⁴⁵Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et Fibro-Inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France. ⁴⁶Groupe de Recherche Clinique en Réanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE), Sorbonne Université, Paris, France. ⁴⁷Intensive Care Unit, Hospital Universitari Sagrat Cor, Grupo Quironsalud, Barcelona, Spain. ⁴⁸Critical Care Center, Corporacion Sanitaria Universitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain. ⁴⁹Univ. Lille, ULR 2694-METRICS: Evaluation des Technologies de Santé et des Pratiques Médicales, 59000, Lille, France. ⁵⁰Biostatistics Department, CHU de Lille, 59000, Lille, France

*Correspondence
s-nseir@chru-lille.fr

Author Contributions
OS, AR, IML, PP, AD, JL and SN contributed to conception and design of the study. All authors were involved in data acquisition. OS, AR, IML, PP, AT, LK, AD, JL and SN contributed to data analysis and interpretation. All authors were involved in manuscript drafting or critical revision for important intellectual content. All authors contributed to final approval of the submitted version. SN was guarantor of the paper.

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

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Relationship Between Corticosteroid use and Incidence of Ventilator-associated Pneumonia in COVID-19 Patients

A Retrospective Multicenter Study

Abstract and Introduction

Abstract

Tables

Tables

Tables

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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