Novel insights in prevention and diagnosis of non-bacterial infections during critical illness

Patients who survive an acute life-threatening event do not always rapidly recover but are at risk for prolonged organ failure and dependency on organ support. During this phase of ‘persistent critical illness’, patients are prone to acquire opportunistic infections, among which viral reactivation and invasive fungal infections (IFIs). These infections are associated with higher mortality, longer ICU-dependency and higher costs. In this thesis, we focused on the prevention and diagnosis of these infections with the aim to improve the outcome of critically illness.

In the first part, we investigated the association between CMV serology and ICU outcome. Critically ill patients who were previously infected with CMV are prone to viral reactivation in the ICU, which is associated with worse clinical outcome. Patients with this latent CMV infection can be identified by the presence of CMV antibodies in their serum. We assessed the relation between CMV serology and clinical outcome in a large post-hoc analysis of two RCTs. Because reactivation occurs late during critical illness, we included non-immunocompromised patients who stayed in the ICU for three days or more. In this group of 1504 patients, we assessed ICU and hospital mortality, ICU and hospital length of stay, and the duration of organ support. There were no differences in the outcome parameters of CMV seropositive versus CMV seronegative patients. We defined several high-risk groups, in whom CMV reactivation has been shown to occur more frequently. Also in these high-risk patients, CMV serology was no independent risk factor for ICU or hospital mortality. We concluded that the performance of interventional studies with antiviral treatment to prevent reactivation in CMV seropositive patients is premature.

In the second part, we studied the impact of early macronutrient restriction on the incidence of newly acquired IFIs during critical illness. We showed that withholding parenteral nutrition to supplement insufficient enteral nutrition, and thereby accepting a macronutrient deficit during the first week of ICU stay, significantly reduced the incidence of IFIs as compared to early supplemental parenteral nutrition. In a time-to-event analysis, we showed that IFIs occur more frequently and earlier in patients assigned to early supplemental parenteral nutrition as compared to the patients in whom a macronutrient deficit is accepted up till one week in the ICU. The risk to acquire an IFI over time was associated with the total daily mean caloric intake, suggesting that the amount of administered calories is probably more important than the route of macronutrient administration.

In the third part, we focused on new tools to diagnose IFIs during critical illness. As a first tool, we investigated the accuracy of (1,3)-b-D-glucan (BG) to diagnose IA during critical illness. We showed that BG has a high negative predictive value for IA in ICU patients, but a low specificity due to false positive results. In our studied ICU population, the optimal cutoff to diagnose IA is higher than the cutoff suggested by the manufacturer. But even at a higher cutoff, GM detection on BAL performed better than BG detection in serum. We concluded that the test properties are insufficient to use the test as a diagnostic tool in the studied population.

As a second diagnostic tool, we investigated the serum concentration of the soluble mannose receptor (sMR) in ICU patients with an IFI, and a propensity-score matched group of ICU patients with a bacterial infection or without new infection during ICU stay. We found that serum sMR concentrations are significantly higher in patients with IFI as compared to patients with a bacterial infection or with no new infection during ICU stay. However, there was a high overlap in the serum concentration of patients with an IFI and patients with a bacterial infection. Consequently, the accuracy of sMR to diagnose IFI during critical illness is insufficient and we do not advise this test as a diagnostic tool in critically ill patients. Interestingly, macronutrient restriction during the first week of critical illness was significantly associated with lower sMR concentrations.

To conclude, we have demonstrated that nutritional support during the early phase of critical illness affects the risk of acquiring fungal infections in the prolonged phase, adding to the previously demonstrated increased risk for newly acquired infections in the ICU supplemental parenteral nutrition is initiated early. It is of interest to evaluate whether this effect is also present for viral reactivation. Also, the underlying mechanism of this increased infectious risk remains to be illuminated. Autophagy, the ‘housekeeping cellular function’ that is responsible to remove damaged cell organelles, is inhibited by nutrition and also plays a role in combating infections. The impact of nutrition on autophagy of immune cells, and its relation to clinical outcome, may shed light on the underlying pathophysiology of the increased infectious risk that is found when nutrition is administered early during critical illness.