Measurement of β-D-glucans to detect invasive fungal infection in immunocompromised people

Why is improving the diagnosis of invasive fungal infections important?
Fungal infections occur in people who are unable to fight infection, and these infections can be life-threatening in this group of people. Fungal infections are difficult to diagnose. Failure to recognize a fungal infection when it is present (a false-negative test result) leads to delayed treatment and poorer outcomes. An incorrect diagnosis of infection (a false-positive result) may result in wasted resources and unnecessary investigation and treatment.

What is the aim of this review?
The aim of this review is to find out how accurate a blood test is for diagnosis of fungal infections in people who are unable to fight infection. Review authors included 49 studies to answer this question.

What was studied in this review?
Five kinds of blood tests were compared. All of these tests use similar biochemical methods to detect the presence of a sugar molecule (β-D-glucan) that is a component of the fungal cell wall. This molecule does not normally occur in blood, so its detection indicates that fungi are present. The tests require a blood sample, which is then sent to a laboratory for analysis. Diagnosis of fungal infections is difficult, and the diagnosis is often made only after the disease has advanced. Blood tests can provide an earlier diagnosis, so they would offer an advantage over current methods.

What are the main results of the review?
This review included studies of 6244 people who were at risk of getting fungal infections. Study results show that accuracy varied widely across studies. The variation was so great that it was not possible to obtain a reliable estimate of the accuracy of the various tests.

How reliable are results of the studies in this review?
In the included studies, the diagnosis of invasive fungal infection was made using criteria developed by the European Organization for Research and Treatment of Cancer (EORTC)*. The EORTC criteria are considered reliable and the studies were generally well conducted, so it is likely that the reference diagnoses were accurate. Accuracy of blood tests for invasive fungal infections varied widely. Some studies found that the blood test was accurate, but others found that the blood test was not very accurate. The reason for this variation is not understood.

*The EORTC criteria provide the reference diagnosis. Results of the blood test are compared to the reference diagnosis.

Who do the results of this review apply to?
Most included studies were performed at academic medical centers or public hospitals in the United States, Germany, and Italy. The most common underlying conditions were cancer (47%) and admission to intensive care (33%). A majority of participants were adults. The overall prevalence of invasive fungal infection was 28%.

What are the implications of this review?
Accuracy of the diagnosis varied widely across studies. It is not clear whether testing can accurately detect invasive fungal infections. Testing accurately detects disease in some studies, but in others it does not. The reasons for the variation in accuracy are not understood.

How up-to-date is this review?
The review authors searched for and reviewed studies published up to June 2019.

Authors' conclusions: 

We noted considerable heterogeneity between studies, and these differences precluded a formal meta-analysis. Because of wide variation in the results, it is not possible to estimate the diagnostic accuracy of the BDG test in specific settings. Future studies estimating the accuracy of BDG tests should be linked to the way the test is used in clinical practice and should clearly describe the sampling protocol and the relationship of time of testing to time of diagnosis.

Read the full abstract...
Background: 

Invasive fungal infections (IFIs) are life-threatening opportunistic infections that occur in immunocompromised or critically ill people. Early detection and treatment of IFIs is essential to reduce morbidity and mortality in these populations. (1→3)-β-D-glucan (BDG) is a component of the fungal cell wall that can be detected in the serum of infected individuals. The serum BDG test is a way to quickly detect these infections and initiate treatment before they become life-threatening. Five different versions of the BDG test are commercially available: Fungitell, Glucatell, Wako, Fungitec-G, and Dynamiker Fungus.

Objectives: 

To compare the diagnostic accuracy of commercially available tests for serum BDG to detect selected invasive fungal infections (IFIs) among immunocompromised or critically ill people.

Search strategy: 

We searched MEDLINE (via Ovid) and Embase (via Ovid) up to 26 June 2019. We used SCOPUS to perform a forward and backward citation search of relevant articles. We placed no restriction on language or study design.

Selection criteria: 

We included all references published on or after 1995, which is when the first commercial BDG assays became available. We considered published, peer-reviewed studies on the diagnostic test accuracy of BDG for diagnosis of fungal infections in immunocompromised people or people in intensive care that used the European Organization for Research and Treatment of Cancer (EORTC) criteria or equivalent as a reference standard. We considered all study designs (case-control, prospective consecutive cohort, and retrospective cohort studies). We excluded case studies and studies with fewer than ten participants. We also excluded animal and laboratory studies. We excluded meeting abstracts because they provided insufficient information.

Data collection and analysis: 

We followed the standard procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened studies, extracted data, and performed a quality assessment for each study. For each study, we created a 2 × 2 matrix and calculated sensitivity and specificity, as well as a 95% confidence interval (CI). We evaluated the quality of included studies using the Quality Assessment of Studies of Diagnostic Accuracy-Revised (QUADAS-2). We were unable to perform a meta-analysis due to considerable variation between studies, with the exception of Candida, so we have provided descriptive statistics such as receiver operating characteristics (ROCs) and forest plots by test brand to show variation in study results.

Main results: 

We included in the review 49 studies with a total of 6244 participants. About half of these studies (24/49; 49%) were conducted with people who had cancer or hematologic malignancies. Most studies (36/49; 73%) focused on the Fungitell BDG test. This was followed by Glucatell (5 studies; 10%), Wako (3 studies; 6%), Fungitec-G (3 studies; 6%), and Dynamiker (2 studies; 4%). About three-quarters of studies (79%) utilized either a prospective or a retrospective consecutive study design; the remainder used a case-control design.

Based on the manufacturer's recommended cut-off levels for the Fungitell test, sensitivity ranged from 27% to 100%, and specificity from 0% to 100%. For the Glucatell assay, sensitivity ranged from 50% to 92%, and specificity ranged from 41% to 94%. Limited studies have used the Dynamiker, Wako, and Fungitec-G assays, but individual sensitivities and specificities ranged from 50% to 88%, and from 60% to 100%, respectively. Results show considerable differences between studies, even by manufacturer, which prevented a formal meta-analysis. Most studies (32/49; 65%) had no reported high risk of bias in any of the QUADAS-2 domains. The QUADAS-2 domains that had higher risk of bias included participant selection and flow and timing.

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