Ventilator-Associated Pneumonia in Critically Ill Patients With COVID-19

Mailis Maes; Ellen Higginson; Joana Pereira-Dias; Martin D. Curran; Surendra Parmar; Fahad Khokhar; Delphine Cuchet-Lourenco; Janine Lux; Sapna Sharma-Hajela; Benjamin Ravenhill; Islam Hamed; Laura Heales; Razeen Mahroof; Amelia Solderholm; Sally Forrest; Sushmita Sridhar; Nicholas M. Brown; Stephen Baker; Vilas Navapurkar; Gordon Dougan; Josfin Bartholdson Scott; Andrew Conway Morris

Disclosures

Crit Care. 2021;25(25) 

In This Article

Discussion

COVID-19 is a new disease in the human population and this has led to an increase in the number of patients in need of mechanical ventilation, which in turn introduces the risk of VAP. COVID-19 can present in various severe manifestations and reports of co-infections vary.[7–9] However, often these reports suffer from a lack of clarity around the severity of illness, location of patients (critical care vs non-critical care), timing of sampling relative to onset of disease and, where applicable, the use of mechanical ventilation. Here, we report on the most severely affected COVID-19 patients who required ICU admission with mechanical ventilation. We found that relative to patients without COVID-19, the hazard of VAP was significantly elevated.

Conventional surveillance for VAP uses incidence density, which we calculated to allow comparison with previously published reports. We found a high incidence density of confirmed VAP (28/1000 ventilator days) amongst patients with COVID-19, whilst those without COVID-19 had rates closer to those reported from other units in the pre-COVID-19 era, where incident densities were 6–14/1000 ventilator days for confirmed VAP were reported.[23] As sessional use of personal protective equipment remained in place until the end of July 2020, for management of both COVID-19 and non-COVID-19 patients, we do not think that this influenced the differential acquisition of VAP amongst these two groups.

The distribution of infecting organism was similar between patients with and without COVID-19, and reflects that reported in the literature from previous surveys of ICU-acquired infections from before the COVID era.[3,19] The use of the TAC allowed more rapid identification of organisms, most of which were subsequently identified by culture. Notably there were a few organisms the TAC did not detect, largely because sequences for these organisms were not present on the card, these were distributed between both the COVID-19 and non-COVID patients.

At the lung microbiome level, we observed no difference in the composition of organisms between COVID-19 positive and non-COVID patients who developed VAP. Reassuringly, antibiotic susceptibility of the causative pathogens was similar in the two groups (data not shown) and this meant that conventional antimicrobial regimens could be used.

There is increasing recognition of fungal infections amongst patients with viral pneumonitides and VAP.[11,21,22] Although debate continues regarding the differences and similarities between influenza and COVID-associated aspergillosis,[10] in keeping with our findings in bacterial VAP it appears that IPA is more common in COVID-19 patients than in ICU patients without COVID-19. It has been suggested that CAPA may relate to the use of immunosuppressive medications.[10] As can be seen from Table 1, steroids were relatively rarely used in this cohort of COVID-19 patients who were largely admitted before the results of the RECOVERY trial had been announced[24] and indeed none of the 3 CAPA patients we identified had received steroids prior to their diagnosis or had underlying immunosuppressive conditions.

More broadly, in our setting immunomodulatory medications were not commonly used at the time of the peak of the COVID-19 admissions, yet there remains a high prevalence of bacterial VAP in these patients. Although VAP in COVID-19 may present problems of quantity, we did not find evidence in this report of a qualitative difference in terms of the organisms causing infection, although as noted above aspergillosis may be more common although this needs to be seen in the context of a significantly higher rate of VAP overall. In the subset where we undertook microbiome profiling, our patients demonstrated similar profiles to those reported by other groups investigating the pulmonary microbiome of ventilated patients.[25,26] The factors which lead to pulmonary dysbiosis in critical illness remain incompletely understood, but may include intercurrent antibiotic use, enteric translocation, pulmonary immune dysfunction and altered clearance.[27]

Although patients without COVID-19 developed proportionately more 'early' VAP, being VAP within the first 4 days of ventilation (Additional file 1: Table S2), examination of the VAP-free survival curves (Figure 2) reveals the hazard of early VAP is similar between the two groups. What is striking, however, is the ongoing risk of VAP seen in patients with COVID-19 which is greater than that seen in patients without COVID. This ongoing risk is reminiscent of the effect we reported previously in critically ill patients with marked immunoparesis.[5]

Although from our observational study we cannot be certain why ventilated patients with COVID-19 have such a significantly increased risk of infection, previous work has indicated that the strongest predictor of nosocomial infection in critically ill patients is impaired immune cell function.[5,28] Patients with COVID-19, in keeping with other critical illness syndromes such as bacterial sepsis and major trauma, experience a complex dysregulation of their immune function with features of both hyperinflammatory activation and organ damage as well as impaired antimicrobial functions.[6,29] Notably, one of the key drivers of neutrophil impairment in critical illness is the complement component C5a[30,31] and high levels of complement activation and C5a release have been reported in COVID-19.[32] Other recent reports on the immunology of COVID-19 highlight marked increases in markers of immune cell functional suppression in the most severely unwell patients.[29] Damage to the alveolar membrane, although not specific to COVID-19, may also facilitate invasion of bacterial species.[33] The estimates of the prevalence of invasive pulmonary aspergillosis and herpesvirade reactivation are limited to those patients investigated by broncho-alveolar lavage and therefore represent only a subset of those investigated for VAP. In the case of invasive aspergillosis it also required senior clinician ordering of galactomannan, and as a retrospective study we cannot be sure clinicians had a common threshold for requesting this test. We therefore acknowledge that these data may underestimate the prevalence of these conditions, however the trend towards higher prevalence amongst patients with COVID-19 adds some support to the hypothesis that these patients suffer from a considerable burden of immunoparesis. It is notable, if not surprising, that patients with COVID-19 were much more likely to present with acute respiratory distress syndrome (ARDS) (Table 1) and consequently had more severe oxygenation defects and were much more likely to be ventilated prone. ARDS is an established risk factor for VAP,[34] and the intense pulmonary inflammation can lead to immunologic reprogramming which can impair anti-microbial responses.[35] Prone positioning may increase risk of microaspiration, however dissecting out the specific effects of proning as opposed to the severity of the underlying lung inflammation remains challenging.[36] Whilst previous broad-spectrum antimicrobial therapy is an acknowledged risk factor for VAP[15] we did not find evidence of substantial differences in either antibmicrobial use or spectrum in patients with and without COVID19.

VAP remains difficult to definitively confirm without histological confirmation, which is seldom practical nor desirable in ventilated patients, we therefore cannot be certain that the patients with positive microbiology had definite pneumonia, although the use of quantitative cultures reduces the risk of detection of colonisation as opposed to infection.[17,37] We used a clinically relevant definition similar to that used in previous studies[17,37] and applied this consistently across the two groups. We note that diagnostic technique can alter the rate of diagnosis,[37] and therefore think it is reassuring that the proportion of bronchoscopic diagnoses was consistent across both groups (Table 1). Similarly, the use of the more sensitive TAC molecular diagnostic could increase the apparent rate of microbiologically confirmed VAP, it is reassuring that TAC was used marginally more frequently in the non-COVID patients and this also suggests the difference seen is due to biological rather than technical reasons.

Reports of rates of VAP amongst ventilated patients with COVID-19 vary, with rates of 40–86% reported[38–40] and our reported rate of 49% is in keeping with reports from other centres. Although some reports, not focussed specifically on VAP, indicate lower rates of 10%,[8] it is unclear how many of the ICU patients in that cohort were ventilated for at least 48 h. The rates of VAP between centres managing COVID-19 are likely to vary depending on the clinical characteristics of the patients managed, differential ICU admissions policies and clinical factors such as use of immunosuppressive therapies. Although we managed to maintain one to one nursing ratios throughout the first wave of COVID-19, it is possible that the increased numbers of nurses with only brief training in critical care led to increased rates of VAP. However, the continued high compliance with the ventilator care bundle which includes key nursing interventions such as oral hygiene and head of bed elevation argues against this being a major factor. We acknowledge the sample size and single centre limitations with our observations and suggest larger studies from distinct geographic locations may help fully understand the risk of developing secondary bacterial infections in patients with severe COVID-19.

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