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Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation

Open AccessPublished:May 20, 2022DOI:https://doi.org/10.1016/j.jinf.2022.05.015

      Highlights

      • In COVID-19 ARDS superinfections were strongly associated with the use of dexamethasone.
      • Invasive fungal infections were found exclusively in dexamethasone treated patients.
      • Unadjusted survival rate was decreases in patients treated with dexamethasone.

      Abstract

      Objectives

      To determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients, and the impact of dexamethasone as standard therapy.

      Methods

      This multicentre, observational, retrospective study included patients ≥ 18 years admitted from March 1st 2020 to January 31st 2021 with COVID-19 infection who received mechanical ventilation. Patient characteristics, clinical characteristics, therapy and survival were examined.

      Results

      155/156 patients (115 men, mean age 62 years, range 26-84 years) were included. 67 patients (43%) had 90 superinfections, pneumonia dominated (78%). Superinfections were associated with receiving dexamethasone (66% vs 32%, p<0.0001), autoimmune disease (18% vs 5.7%, p<0.016) and with longer ICU stays (26 vs 17 days, p<0,001). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [8/67 (12%) vs 0/88 (0%), p<0.0001]. Unadjusted 90-day survival did not differ between patients with or without superinfections (64% vs 73%, p=0.25), but was lower in patients receiving dexamethasone versus not (58% vs 78%, p=0.007). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 3.7 (1.80–7.61), p<0.001], pre-existing autoimmune disease [OR 3.82 (1.13–12.9), p=0.031] and length of ICU stay [OR 1.05 p<0.001].

      Conclusions

      In critically ill COVID-19 patients, dexamethasone as standard of care was strongly and independently associated with superinfections.

      Keywords

      Abbreviations:

      ARDS (Acute Respiratory Distress Syndrom)

      Introduction

      Bacterial or fungal superinfections following viral infections are well known from seasonal influenza epidemics, mostly in hospitalized patients and in particular in those needing treatment in an intensive care unit (ICU).
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      After the introduction of this therapy in Norway, the impression was that more COVID-19 patients acquired superinfections. In particular, we observed more cases of suspected pneumonia with findings of enterobacteriaceae and fungus in patients receiving mechanical ventilation. At present, data on the impact of dexamethasone therapy on the incidence of superinfections in hospitalized severely ill COVID-19 patients is limited. A multicentre retrospective study was therefore performed in the south-eastern region of Norway to examine if superinfections in hospitalized COVID-19 patients on mechanical ventilation had increased during the COVID-19 pandemic, and whether the incidence of such complications was influenced by the introduction of dexamethasone as standard care.

      Patients and Methods

      Study characteristics and data collection

      This was a national, multicentre, observational, retrospective study with seven participating hospitals in the south-eastern region of Norway. The protocol was approved by the Regional Committee for Health and Research Ethics for South-East Norway (REK: 219370). The study population included all patients at or above 18 years of age admitted from March 1st 2020 until January 31st 2021 who fulfilled the following inclusion criteria: (1) SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR), (2) clinically diagnosed ARDS, and (3) treatment during hospitalization included invasive mechanical ventilation and/or extra-corporal membrane oxygenation (ECMO). Exclusion criteria were withdrawal of consent following distribution of a written summary of the study protocol to living eligible patients. In deceased patients, consent was waived. The main objective was to examine whether the incidence of superinfections remained stable during the pandemic. Secondary aims were the characterisation of these infections, their relation to dexamethasone use, length of ICU and hospital stay and outcome.
      Data were manually collected from electronic medical records and charts and plotted into an electronic database (Ledidi.com, Oslo, Norway). Variables included gender, age, co-morbidities, blood values and clinical characteristics on admission and during ICU stay, date of ICU admission, date of intubation and invasive mechanical ventilation, duration of invasive mechanical ventilation, need for extra-corporal mechanical ventilation (ECMO), superinfections with microbiological documentation and recurrences, use of dexamethasone and other immune-modulating drugs, targeted and/or empirical use of antimicrobial agents, length of stay (LOS) in the ICU and hospital, and 90-day survival (obtained from hospital records automatically updated from the Norwegian National Population Registry). In Norway, the pandemic`s first wave ended late in May 2020 coinciding with dexamethasone being implemented as standard of care.

      Definition of superinfections

      A superinfection, synonymous with secondary infection, was defined as an incident when the following occurred: 1) Clinical deterioration, 2) A positive specimen obtained >3 days after hospital admission, 3) Findings of pathogenic microorganisms other than SARS-Cov-2 (bacterial, fungal or viral) by cultures (bacteria and fungus), Galactomannan antigen assay (GM-EIA) (BioRad, Hemel, Hempstead, UK) or PCR (in-house methods for fungus and virus) in clinical specimens and, 4) The introduction of targeted antimicrobial therapy or the continuation of empiric antimicrobial therapy in agreement with the findings while the patients was admitted to the ICU. Findings of coagulase-negative staphylococci in a single blood-culture and Candida spp. in airways were considered contaminators or commensal flora and not superinfections. Co-infections, i.e. clinical signs of infection with findings of microbial agents diagnosed on Day 0-2 after admission, were excluded from this study.

      Definition of pulmonary infection

      The definition of ventilator-associated pneumonia (VAP) includes new radiographic infiltrates ≥ 48 hours after intubation.
      • Horby P
      • Lim WS
      • Emberson JR
      • Mafham M
      • Bell JL
      • Linsell L
      • et al.
      Dexamethasone in hospitalised patients with Covid-19.
      However, the radiological presentation of COVID-19 ARDS precluded use of new pulmonary findings as an indication of VAP. Pulmonary infection was therefore in our dataset based on: 1):Respiratory deterioration and/or an increase in inflammatory biochemical markers > 3 days after ICU entry and 2) Microbiological findings in airway secretion and, 3) The introduction of targeted antimicrobial therapy or the continuation of empiric antimicrobial therapy in agreement with the findings.

      Statistical analysis

      Reported values represent counts (%) and medians (25th-75th centiles) unless otherwise noted. Chi square test and Wilcoxon rank sum test were used to compare demographic and clinical characteristics among patients with and without superinfection, and to compare infections, microbiological findings and outcome with and without dexamethasone therapy.
      Factors associated with presence of superinfection were analysed using backwards stepwise multiple logistic regression with p-value thresholds 0.20 to enter and 0.10 to leave the model (Fit Model platform, Personality Stepwise, SAS-JMP 13.2.0 software for Mac, SAS Institute, Cary, NC, USA). Potential dichotomous (yes/no) predictors of superinfection explored included gender, hypertension, diabetes, chronic heart disease, chronic lung disease, chronic kidney disease, autoimmune disease, malignancy, ongoing immunosuppression prior to COVID-19 infection, dexamethasone administered related to COVID-19, and other immune-modulating drugs administered. Potential continuous predictors of superinfection included age by decile, body mass index (BMI), C-reactive protein (CRP), neutrophil and lymphocyte counts on hospital admission and ICU length of stay (LOS). Results are reported as odds ratio (OR) with 95% confidence levels (95% CI) for having an infection versus no infection. The statistical significance level was set at p<0.05.

      Results

      Patient characteristics

      156 patients fulfilled inclusion criteria, of which one declined to participate. A total of 155 patients were included from seven participating hospitals, with median 36 patients (range 5-50) per centre (Table 1). Time from symptom start to hospital admission was median 7 days (IQR 5-10). Time from hospital admission to administration of dexamethasone was median 0 day (IQR 0-4). Time from hospital admission to ICU admission was median 2 days (IQR 1-4). All patients received invasive mechanical ventilation; seven received ECMO therapy. Risk factors for COVID-19, clinical data at admission and peak or lowest point, use of immune-modulating drugs, LOS in the ICU and hospital, and outcome are shown in Table 1. Seventy-two patients received Dexamethasone i.v. 6 mg x 1 or equivalent dose of methylprednisolone (nine patients) for a median of 11 d (8-16) (Table 1). Seven of the 72 patients who received dexamethasone were admitted during the first pandemic wave and 65 patients during the second wave, i.e. after the implementation of dexamethasone as standard care for COVID-19.
      Table 1Demographics, clinical characteristics, use of immunomodulatory drugs and outcome in 155 COVID-19 ARDS patients with or without superinfection
      Full cohortSuperinfectionNo superinfectionP value*
      N = 155N = 67N = 88
      Male gender115 (74)50 (75)65 (74)0.914
      Age (years)62 (54–70)62 (57–71)61 (52–70)0.257
      BMI27.8 (24.5–31.1)27.7 (24.4–31.9)28.1 (25.1–30.9)0.987
      Hypertension69 (45)32 (48)37 (43)0.517
      Diabetes38 (25)15 (22)23 (26)0.591
      Chronic heart disease23 (15)9 (13)14 (16)0.609
      Chronic lung disease36 (23)17 (25)19 (22)0.581
      Chronic kidney disease12 (7.7)7 (10)5 (5.9)0.271
      Malignancy7 (4.5)3 (4.5)4 (4.6)0.560
      Autoimmune disease17 (11)12 (18)5 (5.7)0.016
      Primary Immunodeficiency000NA
      Prior immunosuppressive therapy17 (11)9 (13)8 (9.0)0.392
      Dexamethasone given**72 (46)44 (66)28 (32)<0.0001
      Duration (days)11 (8–16)11 (8–16)12 (8–16)0.705
      Time from Admission (days)0 (0–4)0 (0–4)0 (0–4)0.811
      Hydroxychloroquine43 (28)11 (16)32 (36)0.005
      Anakinra29 (19)11 (16)18 (20)0.589
      CRP Admission Highest129 (70–217)

      280 (200–358)
      128 (60–191)

      273 (188–343)
      129 (80–244)

      280 (205–373)
      0.297

      0.261
      Neutrophils Admission Highest5.8 (3.8–8.8)

      12.8 (9.2–18.1)
      5.0 (3.8–8.5)

      14 (10–19)
      6.1 (3.8–8.8)

      12 (8.3–17)
      0.758

      0.027
      Lymphocytes Admission Lowest0.8 (0.6–1.2)

      0.7 (0.5–0.9)
      0.9 (0.6–1.3)

      0.7 (0.5–1.0)
      0.8 (0.6–1.1)

      0.7 (0.5–0.9)
      0.358

      0.585
      PaO2/FiO2 ratio (Worst)14 (9–20)12 (8.0–19)15 (9.8–22)0.070
      Noradrenaline ≥0.1 µg/kg/min77 (50)33 (49)44 (50)0.927
      Haemodialysis in ICU27 (17)8 (12)19 (22)0.117
      Symptoms–Admission (days)7 (5–10)7 (6–10)8 (5–11)0.731
      Symptoms–Intubation (days)12 (9–15)12 (9–16)12 (9–15)0.509
      Hospital LOS (days)27 (20–42)32 (25–54)23 (18–33)<0.0001
      ICU LOS (days)19 (14–31)26 (16–42)17 (12–22)<0.0001
      Time on ventilator (days)16 (10–26)21 (12–34)13 (9–19)<0.0001
      90-day survival***107 (69)43 (64)64 (73)0.254
      Values are N (%) and medians (25th–75th centile). *Chi square tests or Wilcoxon test; **Dexamethasone 6 mg x 1 or equivalent dose methylprednisolone (nine patients); ***All-cause out-of-hospital survival; BMI: Body mass index (kg/m2); ICU: intensive care unit; CRP: C-reactive protein (mg/L); Neutrophils and lymphocytes: x10^9/L; LOS: length of stay.

      Occurrence of superinfections

      In 67/155 (43%) of patients a total of 90 superinfections were detected. The first superinfections occurred 11 (range 7–17) days after admission and included 57 monomicrobial and 10 polymicrobial infections. Sixteen patients (24%) developed a second superinfection (11 with monomicrobial and 5 with polymicrobial findings) 10 (range 3-42) days after the first infection, of which four were recurrences. Six patients (9% of total) experienced a third superinfection (5 monomicrobial and 1 polymicrobial) 16 (6-26) days after the second infection and four were recurrences. One patient had a fourth new infection while in the ICU.  The predominant location for superinfections was the lower respiratory tract (78% of infections), followed by 10% bloodstream infections, 8.4% urinary tract infections, and 2% each of positive cultures of faeces and intravascular lines.
      Microbes, specimens and the relation to dexamethasone treatment are presented in Figure 1. In some patients, findings of the same microbe in more than one specimen occurred. Gram-negative rods were the dominant pathogens identified, while Staphylococcus aureus was the most common subspecies detected. Fungal infection was diagnosed in 8 patients, five fulfilling the defined criteria for possible or probable COVID-19 associated pulmonary aspergillosis (CAPA) at a median of 14 days (9-27) from admittance, and three with Pneumocystis jirovecii pneumonia at 27 days (3-33) after admittance.
      • Koehler P
      • Bassetti M
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      • Chen SCA
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      • Hoenigl M
      • et al.
      European Confederation of Medical Mycology; International Society for Human Animal Mycology; Asia Fungal Working Group; INFOCUS LATAM/ISHAM Working Group; ISHAM Pan Africa Mycology Working Group; European Society for Clinical Microbiology; Infectious Diseases Fungal Infection Study Group; ESCMID Study Group for Infections in Critically Ill Patients; Interregional Association of Clinical Microbiology and Antimicrobial Chemotherapy; Medical Mycology Society of Nigeria; Medical Mycology Society of China Medicine Education Association; Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology; Association of Medical Microbiology; Infectious Disease Canada. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.
      Two patients had reactivation of HSV and CMV and were treated with antiviral drugs.
      Figure 1
      Figure 1Superinfections in COVID-19 patients: Microbial agents and specimens Data from 155 COVID-19 patients on invasive mechanical ventilation. The definition of superinfection (N=90) included a positive specimen obtained >3 days after hospital admission. Red columns show findings in patients having received dexamethasone or an equipotent dose of methylprednisolone as COVID-19 treatment (72 of 155 patients); blue columns are findings in non-corticosteroid treated patients.
      Comparing the patient groups with and without superinfections, we found that patients with superinfections more often had received corticosteroids (Table 1). Patients with superinfections also more often had pre-existing autoimmune diseases, and had higher maximum neutrophil count, a trend towards lower minimum PaO2/FiO2 ratio and longer hospital stay, ICU-stay and time on ventilator support. However, 90-day survival rates for patients with superinfections were not significantly lower than for those without superinfections (64% versus 73%, p=0.25). Moreover, high CRP levels or low number of lymphocytes, other co-morbidities than autoimmune disorders, or use of immunosuppressive drugs at the time of hospital admission were not significantly associated with the occurrence of superinfections. Use of hydroxychloroquine was statistically associated with a lower number of superinfections, but importantly, in our patient cohort, hydroxychloroquine use stopped abruptly at the same time as dexamethasone was introduced as standard therapy.
      Use of dexamethasone was independently associated with the occurrence of superinfections in COVID-19 patients on invasive mechanical ventilation Superinfections were observed in 44/72 (61%) patients who did receive dexamethasone, while in patients who did not receive dexamethasone 23/83 (28%) had superinfections (p<0.0001). All invasive fungal infections were found in dexamethasone-treated patients [8/72 (11%) vs 0/83 (0%), p<0.001] (Table 3). Survival rates were lower in patients receiving dexamethasone (58% vs 78%).
      Table 2Demographics, clinical characteristics, use of immunomodulatory drugs and outcome in 155 COVID-19 patients treated with or without dexamethasone
      Full cohortDEXA yesDEXA noP value*
      N = 155N = 72N = 83
      Male gender115 (74)53 (74)62 (75)0.877
      Age (years)62 (54–70)62 (54–71)62 (53–70)0.711
      BMI27.8 (24.5–31.1)28.5 (25.0–32.1)27.2 (24.2–30.5)0.104
      Hypertension69 (45)36 (50)33 (40)0.225
      Diabetes38 (25)20 (28)18 (22)0.379
      Chronic heart disease23 (15)8 (11)15 (18)0.214
      Chronic lung disease36 (23)20 (28)16 (19)0.211
      Chronic kidney disease12 (7.7)7 (9.7)5 (6.0)0.390
      Malignancy7 (4.5)7 (10)0 (0)0.003
      Autoimmune disease17 (11)10 (14)7 (8.4)0.278
      Primary Immunodeficiency000NA
      Immunosuppression pre-admission17 (11)13 (18)4 (4.8)0.009
      Dexamethasone given**72 (46)72 (100)0NA
      Duration (days)11 (8–16)NA
      Time from Admission (days)0 (0–4)NA
      Hydroxychloroquine43 (28)1 (1.4)42 (51)<0.001
      Anakinra29 (19)5 (7.0)24 (30)<0.001
      Superinfection after 72 h67 (43)44 (61)23 (28)<0.001
      CRP Admission Highest129 (70–217)

      280 (200–358)
      126 (65–184)

      265 (187–326)
      130 (80–225)

      293 (235–380)
      0.398

      0.019
      Neutrophils Admission Highest5.8 (3.8–8.8)

      12.8 (9.2–18.1)
      5.1 (3.5–8.7)

      15 (10.4–20)
      6.1 (4.0–8.8)

      11.3 (8.3–16.6)
      0.613

      0.002
      Lymphocytes Admission Lowest0.8 (0.6–1.2)

      0.7 (0.5–0.9)
      0.8 (0.6–1.1)

      0.6 (0.4–0.9)
      0.8 (0.6–1.2)

      0.7 (0.5–0.9)
      0.220

      0.055
      PaO2/FiO2 ratio (Worst)14 (9–20)11 (8.0–20)15 (10–23)0.015
      Noradrenaline ≥0.1 ug/kg/min77 (50)36 (50)41 (49)0.940
      Haemodialysis in ICU27 (17)13 (18)14 (17)0.846
      Symptoms–Admission (days)7 (5–10)7 (5–10)8 (6–11)0.086
      Symptoms–Intubation (days)12 (9–15)13 (10–16)11 (9–15)0.013
      Hospital LOS (days)27 (20–42)30 (22–49)25 (18–36)0.017
      ICU LOS (days)19 (14–31)21 (15–37)18 (13–26)0.044
      Intubation time (days)16 (10–26)16 (10–31)15 (10–21)0.256
      90-day survival***107 (69)42 (58)65 (78)0.007
      Values are N (%) and medians (25th–75th centile). *Chi square tests or Wilcoxon test. BMI: Body mass index (kg/m2); ICU: intensive care unit; **Dexamethasone 6 mg x 1 or equivalent dose methylprednisolone (nine patients); CRP: C-reactive protein (mg/L); Neutrophils and lymphocytes: x10^9/L; LOS: length of stay; ***All-cause out-of-hospital survival. NOTE: In this cohort, 98% of patients not receiving dexamethasone arrived during the first wave of the pandemic, when early intubation was recommended and hydroxychloroquine was still in use.
      Table 3Possible invasive fungal infections in eight critically ill Covid-19 patients on invasive mechanical ventilation
      Patients NoSex and AgeRisk Factors for COVID-19 or IFIDEXAPathogensSpecimensDiagnosticsTherapyOutcome
      1F 54Autoimmune disease, Immunosuppressive drugs IMV 3 dYesP. jirovecii*BALPCR+TMP/SMX 21 dAlive
      2M 58IMV 9 dYesAspergillus sp.TRACHCulture+, GM: nd, PCR: ndVoriconazole 13 dAlive
      3M 61Autoimmune disease, Immunosuppressive drugs IMV 19 dYesA. fumigatusTRACHCulture+, GM: nd, PCR: ndMicafungin 1 dDeceased
      4M 76Autoimmune disease, COPD, Hypertension IMV 14 dYesA. fumigatusTRACHCulture+, GM: nd PCR+Anidulafungin 15 dDeceased
      5M 82MDS? Hypertension, IMV 11 dYesA. fumigatusTRACHCulture+, PCR+, GM+Anidulafungin 17 dDeceased
      6M 60BMI 30 IMV 27 dYesP. jirovecii*TRACHPCR+TMP/SMX 38 d + Anidulafungin 6 dDeceased
      7F 62Autoimmune disease, Hypertension, ECMO 33 dYesP. jirovecii*BALPCR+TMP/SMX 5 dDeceased
      8M 58ECMO 27 dYesA. fumigatusTRACHCulture+, PCR+, GM+Isavuconazole 18 dDeceased
      IFI: invasive fungal infection; DEXA: Dexamethasone; F: female; M: male; IMV: invasive mechanical ventilations; d: days; COPD: chronic obstructive pulmonary disease; MDS: myelodysplastic syndrome; BAL: bronchioalveolar lavage; SPUT: induced sputum; TRACH: tracheal secretion; TMP/SMX: Trimeptoprim/Sulfamethoxazole; PCR: polymerase chain reaction; GM: galactomannan; neg: negative; nd: not done.
      *HIV-negative
      Backwards stepwise multiple logistic regression adjusting for demographics, comorbidities, admission lab values and ICU LOS showed that detected superinfection was independently associated with having received dexamethasone (OR 3.7 (1.80–7.61), p<0.001) and having autoimmune disease (OR 3.82 (1.13–12.9), p=0.031). Longer ICU LOS increased the occurrence of superinfections (OR 1.05 per day LOS, p<0.001). The combined predictive value of the full regression model was moderate (AUROC 0.786).

      Empiric antimicrobial therapy

      Empiric antimicrobial therapy was administered to 147 (95%) patients at some time point, a median of 3 (2-5) courses during the ICU stay. The proportion of patients starting such therapy on hospital admission was higher during the first pandemic wave than later in the study period (98% vs. 81%, p=0.004). Predominant empiric antibiotics started on hospital days 0, 1 and 2 were penicillins (15%), cephalosporins (50%), fluorokinolones (25%), meropenem and gentamicin (3% each).

      Discussion

      In this study of 155 consecutively treated COVID-19 patients requiring invasive mechanical ventilation, we demonstrate that 43% experienced 1-4 superinfections according to our definition throughout their ICU stay. Use of dexamethasone in these patients was strongly and independently associated with the occurrence of superinfections, with an adjusted odds ratio of 3.7. Having an autoimmune disease and a long ICU stay also demonstrated a similar independent association. However, the association of superinfections with dexamethasone was strongly present also after adjusting for these two factors. In this small study we could not demonstrate a statistically significant effect of superinfections on 90-day survival. Examining the patients receiving dexamethasone vs. not, the same association with infections, in particular invasive fungal infections, and longer ICU stay persisted. Furthermore, the use of dexamethasone demonstrated a significant association with mortality. Our findings suggest that whereas dexamethasone has been shown to increase survival in critically ill COVID-19 patients, it also appears to increase the risk of clinically relevant superinfections. In this Norwegian study, although observational, its use also have an impact on outcome.
      While it is not surprising that use of corticosteroids increases the risk of infections in COVID-19 patients, available data on the incidence of superinfections in COVID-19 patients in the dexamethasone era is scarce. In initial studies on dexamethasone use in COVID-19, superinfections were not included as secondary outcome.
      • Collaborative Group RECOVERY
      • Horby P
      • Lim WS
      • Emberson JR
      • Mafham M
      • Bell JL
      • Linsell L
      • et al.
      Dexamethasone in hospitalized patients with Covid-19 – preliminary report.
      ,
      • Sterne JAC
      • Murthy S
      • Diaz JV
      • et al.
      Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis.
      A later meta-analysis suggested a possible increase in secondary infections following corticosteroid therapy, but occurrence of secondary infection was not a pre-defined endpoint in the majority of the studies included, so the results should be interpreted with caution.
      • van Passen J
      • Vos JS
      • Hoekstra EM
      • Neuman KM
      • Boot PC
      • Arbous SM
      Corticosteroid use in COVID-19 patients: a systemic review and meta-analysis on clinical outcomes.
      In a single-centre study on severely ill patients, Saade et al. reported that dexamethasone was associated with increased risk of superinfection, but importantly, this population had a high prevalence of underlying immune defects due to malignancies and organ transplantation (34%).
      • Saade A
      • Moratelli G
      • Dumas G
      • Mabrouki A
      • Tudesq J-J
      • Zafrani L
      • et al.
      Infectious event in patients with severe COVID-19: results of a cohort of patients with high prevalence of underlying immune defects.
      A recent study of ICU patients from three French ICUs reported a higher incidence of superinfections than that of the present study, but they found no association between the occurrence of VAP and the use of dexamethasone.
      • Gragueb-Chatty I
      • Lopez A
      • Hamidi D
      • Guervilly C
      • Loundou A
      • Daviet F
      • et al.
      Impact of dexamethasone on the incidence of ventilator-associated pneumonia and blood stream infections in COVID-19 patients requiring invasive mechanical ventilation: a multicenter retrospective study.
      One possible contributor to the discrepancies between our findings and these studies is differences in the utilization of broad-spectrum antibiotics, previously demonstrated to be independently associated with superinfections in COVID-19.
      • Grasselli G
      • Scaravilli V
      • Mangioni D
      • Scudeller L
      • Alagna L
      • Bartoletti M
      • et al.
      Hospital-acquired infections in critically ill patients with COVID-19.
      Although 95% of our patients received empiric antibiotics, this involved to a large extent the use of relatively narrow-spectrum agents due to moderate levels of antimicrobial resistance in Norway, as demonstrated in EARS-Net.

      www.http://www.ecdc.europa.eu/en/about-us/partnerships-and-networks/disease-and-laboratory-networks/ears-net. Accessed Octobre 14th 2021.

      Furthermore, in the French study, the non-dexamethasone treated “first wave” patients were almost twice as likely to be on a ventilator at ICU admission and had 50% longer ventilator and ICU time than the dexamethasone treated “second wave” COVID-19 patients, potentially influencing their results. Our findings of length of stay having an independent association with superinfections could support this.
      Pneumonia was the most frequent form of infection observed, and eight patients (5%), increasing to 11% in the dexamethasone treated population, had possible or probable invasive fungal infection with a 75% mortality rate. Early in the pandemic, CAPA was reported with varying incidence, with a median of 13.5%, ranging from 2.5% to 35% in a review.
      • Chong WH
      • Neu KP.
      Incidence, diagnosis and outcomes of Covid-19-associated pulmonary aspergillosis (CAPA): a systematic review.
      In three prospective trials, the incidence was somewhat higher, 14% to 38%.
      • Bartoletti M
      • Pascale R
      • Cricca M
      • Rinaldi M
      • Maccaro A
      • Bussini L
      • et al.
      for the PREDICO Study Group. Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study.
      ,
      • van Biesen S
      • Kwa D
      • Bosman RJ
      • Juffermans NP.
      Detection of invasive pulmonary aspergillosis in COVID-19 with non-directed bronchioalveolar lavage.
      ,
      • White PL
      • Dhillon R
      • Cordey A
      • Hughes H
      • Faggian F
      • Soni S
      • et al.
      A National Strategy to Diagnose Coronavirus Disease 2019–Associated Invasive Fungal Disease in the Intensive Care Unit.
      In ICU patients receiving mechanical ventilation, Marr et al. suggested an incidence of 20-30%.
      • Marr KA
      • Platt A
      • Tornheim JA
      • Zhang SX
      • Datta K
      • Cardozo C
      Garcia-Vidal. Aspergillosis complicating severe coronavirus disease.
      Two recent studies from ICU populations with COVID-19 reported 15% and 9% incidence of CAPA and both demonstrated an independent association to dexamethasone.
      • Gangneux J-P
      • Dannaoui E
      • Fekkar A
      • Luyt C-E
      • Botterel F
      • de Prost N
      • et al.
      Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicenter MYCOVID study.
      ,
      • Leistner R
      • Schroteter L
      • Adam T
      • Poddubnyy D
      • Stegemann M
      • Siegmund B
      • et al.
      Corticosteroid as risk factor for COVID-19-associated pulmonary aspergillosis in intensive care patients.
      A recent multicentre study by Perner et al. using differing doses of dexamethasone in critically ill COVID-19 patients demonstrated only 3-4% of invasive fungal infections depending on dexamethasone dose.
      The COVID STEROID 2 Trial Group
      Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial.
      These findings support the fact that CAPA is a real threat in COVID-19 ARDS, particularly when anti-inflammatory regimens are used.
      We demonstrated a frequent use of empirical antimicrobial agents and its use diminished over time possibly making a positive contribution to the microbial yield in the dexamethasone era. However, the differences of empiric use at admission was small, 98% vs 81%, and 95% of all our patients received empiric therapy at some point during the ICU stay, making this a less plausible explanation for increased superinfection rate by time.
      Having demonstrated a strong association with superinfections and dexamethasone without affecting survival rates, we examined the impact of dexamethasone on the same parameters and demonstrated a significant impact on unadjusted survival rates. As this is a small study, the findings should be interpreted carefully. Furthermore, survival rates might have been even lower at this time of the pandemic without dexamethasone.
      A clear limitation of this study is its observational, retrospective design. However, it was a multicentre study and included most Norwegian hospitals where COVID-19 patients were treated both before and after dexamethasone was implemented as standard therapy in patients with ARDS. Due to the limited value of radiological diagnostics in assessing VAP in COVID-19 ARDS, the diagnosis was based solely on perceived clinical deterioration and microbiological findings, possibly leading to an overestimation of true superinfections. Finally, patient numbers were relatively low; this might have influenced some sub-analyses such as the occurrence of fungal infection.

      Conclusion

      We report that mechanically ventilated COVID-19 patients receiving dexamethasone had an over three times higher odds ratio for contracting superinfections while in the ICU. These superinfections were associated with autoimmune disease and longer ICU and hospital stays. Other anti-inflammatory and immunosuppressive agents are being tested in COVID-19 patients, often in combination with dexamethasone. Based on the present findings, a particular focus on superinfections is warranted.

      Funding

      This study was funded by the authors’ institutions.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We thank Ledidi.com for their generous contribution in allowing us to use their data platform for the collection and partly analysing data from multiple centres.

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