(Beta-D-)Glucan Insensitivity

You are taking care of a patient that is s/p heart transplant that has been complicated by intestinal rupture, abdominal surgery, need for dialysis and prolonged stay in the ICU. The individual has been on piperacillin-tazobactam for more than 10 days due to the abdominal sepsis. Over the past 24 hours the blood pressure has dropped, and the patient has been less responsive.

Should you start anti-fungal therapy?

Is there any other testing that you could do that will alter you to a fungal infection?

Beside sending blood cultures, you wonder about sending a 1,3-Beta-D-Glucan. Would this be the test that tells you a fungal infection is present?

This is not an uncommon scenario or issue or problem we face in medicine (general medicine, critical care, and ID), when to start anti-fungal therapy. Over the past 30 years there has been an increase in the incidence in invasive candidal infections (ICI), especially in the ICU. Unfortunately, outcomes have not changed and in some patient populations may have worsened. Empirical antifungal therapy has failed to demonstrate a survival benefit, even in patients with sepsis that is acquired in the ICU, Candidal colonization and multi-organ failure. Prophylactic antifungal therapy in the surgical setting has been ineffective at reducing mortality in the immune competent. One approach is assessing risk factors (prolong ICU stay, invasive devices, TPN, abdominal surgery in the past 7 days, prior antimicrobial use for >48 hours and renal replacement therapy) and assessing the 1,3-Beta-D-Glucan (BDG). The BDG is a cell wall polysaccharide found in most fungi.  The pooled sensitivity is 74-86% and the pooled specificity is 49-71%, so not a great test. With a low pre-test probability, a BDG <80 pg/ml has a good NPV, but a very low PPV.

This brings us to the recent advanced published study by Bloos et al (1-3)-Beta-D-Glucan guided antifungal therapy in adults with sepsis, Int Care Med 2022. The aim of this study was to test whether BDG-guidance shortens time to antifungal therapy and there by reduces mortality of sepsis in persons at high risk for invasive candida infections (ICI). And an Editorial.

Methods:

Open, randomized multi-site trial form Sept 2016 to Sept 2019.

P: Adult patients with sepsis and increased risk for ICI

– TPN, abdominal surgery in the past 7 days, prior antimicrobial use for >48 hours and renal

replacement therapy

I: BDG group

• Clinical informed of the results
• If >/=80 pg/mlà start antifungal
• If only 1 result >/= 80 & cultures negative, antifungal stopped
• If both >/=80 and cultures negative, antifungals continue

C: Controlà BDG measured but clinicians blinded to the results. Treat according to local standard of care

Both: Antifungals started if cultures positive in blood, sterile body fluid or biopsy of sterile body site.

Both: BDG checked 1-hour after enrollment and at 24-hours after enrollment

O: Primary outcomeà All cause mortality by 28-days after inclusion

Secondary outcomesà

-antifungal free survival at day 28

-Candida colonization index

-Time to antifungal therapy

-Costs of antifungals

-Duration of organ support

-Mean SOFA score

-ICU and hospital LOS

-ICU mortality

-Frequency of adverse events

Results:

2324 eligibleà 324 randomized, 3 withdrew consent

339 total: 172 BDG group, 167 control

Patients well balanced, recent abdominal surgery most common RF for ICI.

Initial blood cultures: +Candida 15 pt (4.4%)

ICI: Diagnosed 48 pt (14.2%) within 96-hours

Candida albicans #1 species

Sensitivity and specificity of the BDG to:

–Predict candidemia: Sens-64.3% Spec- 63.7%

–Predict ICI: Sens- 54.4% Spec- 65.2%

Antifungal regimen:

BDG group- 48% started an antifungal with 43% starting because of positive BDG

Control group- 5% started on antifungal, 9/10 due to positive microbiology

 

 

Primary Outcome:

Death- 33.7% in BDG vs 30.5% Control (NS)

Secondary outcomes:

BDG groupà had earlier start of antifungal (1.1d vs 4.4d), higher frequency antifungal use, lower antifungal free survival

Conclusion:

BDG guidance in critically ill patients led to earlier start of antifungal and more frequent initiation of antifungal but did not offer a benefit in terms of 28-dat mortality. In fact, BDG measurement led to longer hospital stay and higher costs. There are recommendations (as stated above) to start empiric antifungal for those at risk for ICI, but the benefit has not been clearly demonstrated in clinical trials. The lack of specificity of the BDG plays a role in its use as a guide to antifungal therapy. Many different situations can lead to a positive result. A potential way to optimize the specificity of the BDG is to increase a positive cut-off to >/=200 pg/ml.

 

Bottom-line (my take):

BDG is not a good, independent measure of ICI in septic patients. For the patient I presented, a BDG would most likely not be of benefit. There are multiple factors that could lead to a positive result (HD, receipt of antibody therapy, and recent abdominal surgery. Utilizing all the risk factors the patient has plus establishing a likelihood of ICI is at least just as good as adding a BDG. Would I start antifungal therapy on this individual that is developing new sepsis/septic shock, yes (based on risk factors of transplant, sepsis in the ICU, antibacterial therapy, HD and recent abdominal surgery). But I would not rely on the BDG to dictate whether to start or stop therapy