Risk factors for developing ventilator-associated lower respiratory tract infection in patients with severe COVID-19: a multinational, multicentre study, prospective, observational study

Abstract

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes.Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.

Figure 1

Flow chart of patients included in the analysis.

Figure 2

Aetiological pathogens. Here is presented the frequency (in counts) of the etiological isolations in the whole cohort of patients with VA-LRTI. (A) Shows microorganisms isolated in the general cohort. (B) Represents the VAP cohort and Panel C depicts the VAT cohort. Within the “Other” group are microorganisms with less than five isolates (Achromobacter xylosoxidans, Acinetobacter lwoffii, Citrobacter koseri, Hafnia alvei, Moraxella catharralis, Neisseria cinerea, Providencia rettgeri, Raoultella planticola, Raoultella ornithinolytica, Streptococcus anginosus, and Streptococcus pyogenes).

Figure 3

An automatized model to determine the impact of ventilator-associated lower respiratory tract infection on hospital mortality. (A) Presents variables more strongly associated with hospital mortality according to the Gini importance. (B) Represents the contribution of the variables to the output; the red values indicate a high-value contribution of the variable, and the blue values are a low-value contribution. The positive values in the plot indicate a high probability of hospital mortality, and negative values indicate a low likelihood of hospital mortality. (C) Presents each cross-validation trial’s receiver operative curve (ROC) for the subset of the selected variables. The blue curve represents the average of the ROC curves of each test, and the average area under de ROC is also presented. The most significant variables associated with hospital mortality according to their Gini importance and contribution to the output were Hospital-LOS, higher days under IMV, old age, higher creatinine levels on admission, and lower PaO2/FiO2 on ICU admission. Also, the development of AKI during ICU stays and VA-LRTI were risk factors associated with hospital mortality.

Figure 4

Logistic regression models to identify factors associated with ventilator-associated lower respiratory tract infection (VA-LRTI) (A) and the impact of VA-LRTI on hospital mortality (B). Logistic regression was performed with the optimal subset of variables obtained with the random forest model for the two outcomes (VA-LRTI and hospital mortality). The odds ratios (OR) are graphically represented in the Forest plot for better medical interpretability. (A) Presents the odd proportions of the risk for VA-LRTI, and (B) is shown the odds ratios for the hospital mortality.