Is Ventilator-Associated Pneumonia More Frequent in Patients With Coronavirus Disease 2019?

Ventilator-associated pneumonia (VAP) has been one of the most challenging infections before the coronavirus disease 2019 (COVID-19) pandemic (1), and with the growing number of hospital and ICUs being overwhelmed with the complex and prolonged acute care of patients with COVID-19, VAP has become a larger issue during this pandemic, with a crude overall incidence ranging from 40% to 60% (2–7). Nonetheless, the variation on VAP definitions used in different countries makes difficult to compare the incidence rates (8).

Vacheron et al (9), in this issue of Critical Care Medicine, address the epidemiology of VAP among patients with COVID-19. The study was multicentric and evaluated a cohort of patients with COVID-19 compared with another without COVID-19 to search for the incidence of VAP and if the presence of COVID-19 resulted in a difference in the development of VAP in the ICU. Notably, the two cohorts were matched by age, sex, hospital center, presence of antibiotics, time from ICU admission to mechanical ventilation, and Simplified Acute Physiology Score II score at admission. The sample size was large (n = 1,879), and the study found a significant 66% increase in the incidence of VAP in patients with COVID-19: VAP incidence was 15.4 per 1,000 ventilation days in the non-COVID-19 group, which increased to 25.5 per 1,000 ventilation days in the COVID-19 group. The cumulative incidence was higher for the first VAP episode, with a subdistribution hazard ratio of 1.70 (95% CI, 1.46–1.97;p < 0.001). The microbial etiology and resistance patterns did not differ between groups, with most VAPs caused by Gram-negative microorganisms (77%), but methicillin-resistant Staphylococcus aureus VAP was less frequent in the COVID-19 group. Even after all matching factors at baseline, the COVID-19 patients still had a significant longer duration of mechanical ventilation (11 vs 6 d; p > 0.001), longer ICU stay (15 vs 9 d; p < 0.001), and higher ICU case fatality (31% vs 26%; p < 0.001). As a current comparison to other populations with COVID-19, two other cohorts from different countries showed similar to higher VAP incidence rates: United Kingdom (10): 28 per 1,000 ventilation days; Italy (11): 26 per 1,000 ventilation days; in fact, the hazard ratio shown in Maes et al (10) (2.01; 95% CI, 1.14–3.54; p = 0.001) was similar to that from Vacheron et al (9).

The pre-pandemic known risk factors for VAP, such as long hospital and ICU stay, prolonged invasive mechanical ventilation, older age, chronic lung disease, acute respiratory distress syndrome (ARDS), trauma, major surgery, patient positioning, sedation and neuromuscular blocking agents, and immunosuppressive status, are all individually or in combination present in patients with COVID-19 (12). However, the most relevant risk factor in both pre-pandemic and peri-pandemic remains the prolonged need for mechanical ventilation since the probability of developing VAP goes up for every day the patient remains intubated. The large utilization of prone positioning (13), as well as of immunosuppressive drugs to treat COVID-19, has further increased the incidence of hospital-acquired infections caused by bacterial or fungal etiologies secondary to the use of steroids (4, 14–16) and tocilizumab (4, 17); however, baricitinib was not associated with more secondary infections in two large studies (18, 19). In addition, the fact most world ICUs have been run close to or at capacity, adds another major risk of hospital-acquired infections like VAP because the lower healthcare provider to patient ratio and the higher need for personal protective equipment (already limited in many hospitals) can further lead to suboptimal infection control measures and its consequent higher incidence of hospital-acquired infections (20). Among the limitations of this new study by Vacheron et al (9), it is notable that there was no collection of concomitant medications, such as steroids, other immunosuppressive drugs, nor the description of hospital/ICU capacity levels at each enrolling site, both of which could have affected the incidence of VAP; for example, the use of concomitant immunosuppressive drugs was likely more frequent in the COVID-19 patients, and this could have further increased the VAP rate in patients with COVID-19. Also, severe lymphopenia due to COVID-19 increases the risk of secondary infections (20, 21), and the more frequent use of extracorporeal membrane oxygenation in patients with COVID-19 is also associated with VAP (2, 15, 22).

Similar to Vacheron et al (9), other studies have also reported a predominance of Gram-negative etiology in 60–70% of VAPs (6, 11), and more concerning is the high prevalence of multidrug resistant organisms (MDROs) as frequent as one-third of the hospital-acquired infections in patients with COVID-19 (11). This issue shows another elephant in the room, that is, the potential for an additional increase in the development of MDROs due to the overuse of unnecessary empirical antibiotics during this pandemic. The challenges to clinically distinguish COVID-19 progression from bacterial and fungal infections has brought difficulties not only for the bedside clinical care, but also for antimicrobial stewardship programs, particularly when the hospitals are at capacity, and isolation rooms for MDRO infection are even more scarce during the pandemic. Recent studies have already shown that the utilization of antibiotics has been several folds above the actual rate of bacterial infections (11, 23), thus if this trend continues, it is possible that soon (during or after the pandemic) a larger part of hospital-acquired infections will be caused by MDROs. Thus, unless we keep our guard up to prevent the unnecessary use of empiric antimicrobials, we may end up with a different type of problem after this pandemic: outbreaks of MDRO hospital-acquired infections.

A recent study showed that the ventilator-associated events (VAEs) rates per 100 episodes of mechanical ventilation and per 1,000 ventilator days were higher among COVID-19 positive versus negative patients, but most of these VAEs were due to progressive ARDS, while the rate of infection-related ventilator-associated complications was similar between both groups (24). The rates of primary coinfections have been relatively low in patients with COVID-19 (7, 25) compared with coinfection rates before the pandemic (26); however, the rate of secondary infections has varied according to different VAP definitions. The study findings by Vacheron et al (9) suggest that secondary hospital-acquired infections such as VAP are more prevalent with COVID-19 than with other respiratory infections.