This study shows a 33% crude prevalence rate of VAP and an overall incidence density of 13.48 episodes per 1000 days of MV, higher than the incidence in non-COVID patients from the report of the Italian project GiViTi of 2019 (with an incidence of 9.8 events per 1000 ventilator days) [7] and of the European intensive care units (report of ECDC) in 2019 (9.5 episodes per 1000 ventilator days) [6]. However, the incidence of VAP is quite similar compared to studies including only ARDS patients as reported by Guerin et al. for PROSEVA trial in 2016 (between 11.8 and 15.4 VAP per 1000 ventilator days) [16].
VAP did not significantly increase the ICU mortality rate in our cohort, consistently with previous reports in COVID-19 [12], and non-COVID-19 patients, even with severe ARDS [7]. Improvement have occurred in the past few years in the management of ARDS patients in the ICU. Lung-protective ventilation strategies have been widely used in ARDS patients the past few decades and especially in the last 2 years of pandemic with COVID-19 ARDS patients [17, 18]. These strategies together with prompt antibiotic treatment may contribute to explaining this finding, as also some evidence indicates that cyclic stretch of pulmonary epithelial cells may represent an important pathogenic mechanism of VAP, promoting bacterial growth [19].
The sequential organ failure assessment (SOFA) score at ICU admission ≥ 4 and ICU length of stay > 28 days were independently associated with higher risk of VAP, although ICU length of stay could be as much a cause as a consequence. SOFA score has been developed to assess the acute morbidity of critical illness and is widely used in predicting mortality and ICU length of stay in septic patients [20], as in some studies, it has been shown that it can also be a predictor for ventilator-associated pneumonia [21].
Ventilated patients in OTI had a 1.7-fold higher incidence of VAP than those in tracheostomy, 16.46 and 9.8 episodes per 1000 days on MV, respectively. Indeed, tracheostomy has many beneficial effects in MV patients, facilitating the weaning process, reducing the need for sedative and analgesics, reducing dead space and airway resistance, and finally, helping to maintain easier oral hygiene [22].
In our cohort, the most frequently isolated microorganisms were Pseudomonas aeruginosa (39.8%), Klebsiella spp. (16.5%), Staphylococcus aureus (7.7%), Stenotrophomonas maltophylia (7.7%), Acinetobacter baumanii (7.7%), and Escherichia coli (5.8%). Although some of the isolated microorganisms of our study are overlapping with those of the 2019 ECDC report, others such as P. aeruginosa, Klebsiella spp, and A. baumanii have higher incidence. This is likely to be due to the SARS-CoV-2-related upper respiratory tract microbiome dysbiosis reported in some studies, correlated to a profoundly altered microbiome profile through different mechanisms, as known for other respiratory viruses, including alteration of the respiratory epithelium, promotion of adhesion of respiratory pathogens, and increase of local inflammation [23, 24].
Carbapenem resistance resulted in all Acinetobacter spp. and in 41.4% of P. aeruginosa isolates with a 56% and 60% increase over the ECDC report in 2019 (63.9% and 25.9%, respectively). Instead, carbapenem resistance in Klebsiella spp. isolates was 17.6%, which is slightly higher to that reported by ECDC in 2019 (15.2%). Half of S. aureus were methicillin-resistant (MRSA) with a 113% increase over ECDC report in 2019 (23.5%). Widespread and inappropriate prescription of broad-spectrum antibiotics as prophylaxis for COVID-19 (usually beta-lactams, macrolides, and fluoroquinolones) has been observed during the pandemic, as discussed in the 32nd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), presented on April 23–26, 2022 [25], showing high rates of antimicrobial resistance in COVID-19 patients. As expected, also in our study, a high percentage of our patients (52.4%) used broad-spectrum antibiotics prior to ICU admission and often started before admission to hospital. The overuse of empirical antibiotics before intubation could have led to an unfavorable development of multidrug resistant bacteria, as a high proportion of carbapenem resistance and MRSA microorganisms.
Late-onset VAP were more likely to be caused by multidrug-resistant (MDR) pathogens (Table 2, Supplemental Material).
Demographics (age, sex), comorbidities, renal placement therapy, PaO2/FiO2 at ICU admission, and empirical antibiotic therapy prior OTI were not associated with a higher risk of VAP, consistently with the data reported by Blonz et al. [11]. Barotrauma, as pneumothorax or pneumomediastinum, in our ICU COVID-19 patients had a relatively low incidence [26], and it was not associated with a higher risk of VAP. Moreover, blood transfusion during the ICU stay had an independent higher risk of developing VAPs, as reported in a multicenter study including 284 intensive care units in the USA in non-COVID-19 population, by Shorr et al. [27]. An experimental hypothesis is that blood transfusion promotes the release of cytokines, which enhances various cytokine cascades producing pulmonary inflammation, as well as bronchoalveolar activation of coagulation [28].
The patient’s body position is an important aspect in ICU. A semi-recumbent position (i.e., elevation of the head of bed to 30–45°) has been widely used in our ICU as a strategy for patients undergoing MV as a recommendable measure in several clinical practice guidelines for preventing VAP [29]. This position can help reduce gastroesophageal reflux and avoid the entry of gastric contents and contaminated oropharyngeal secretions into the lower airway [29]. An early application of prone position seems to have a survival benefit in patients with moderate-severe ARDS, promoting the distribution of the gas–tissue ratios along the dependent–nondependent axis and a more homogeneous distribution of lung stress and strain [30]. Indeed, during the pandemic prone position has been a common strategy in COVID-19 patients with refractory hypoxemia [31]. Although the prone position appears not to be associated with a higher risk of VAP, as reported as well by Ayzac et al. in the PROSEVA trial in 2016 and in a recent review by Pozuelo‑Carrascosa et al. in 2022, in intubated patients with severe ARDS, and our results are consistent with them [16, 29].
Interleukin-6 acts as a fundamental cytokine in organizing T cell responses to infections and, eventually, may protect against superinfection. Tocilizumab or Sarilumab are anti IL-6 receptor monoclonal antibodies, approved for the treatment of multiple inflammatory diseases, and have been considered for off-label use in the treatment of COVID-19 [32, 33]. We found that Tocilizumab/Sarilumab had a significant association with a twofold higher risk of VAP at both univariate and multivariate analysis, consistently with data reported by Martinez et al. [34].
This study has a major limitation. This is an observational study conducted in a single center with a 6-month observation period on a limited population of approximately 300 MV COVID-19 patients; however, our prevalence and incidence rate are in line with literature data, and it represent a first step to formulate hypothesis to design of larger clinical studies.