Measuring galactomannan in lung-washing fluid to diagnose invasive aspergillosis in patients with an impaired immune system

Why is improving the accuracy of the diagnosis of invasive fungal disease important?

Some people have a weakened immune system; they are said to be 'immunocompromised'. People can be immunocompromised when they have leukaemia, or HIV/AIDS, and when using some forms of medication.

Immunocompromised means that the immune system is less able to fight infections. This can result in an infection that does not occur under normal conditions. This is called an opportunistic infection. An example is aspergillosis, an infection caused by a fungus. As the fungal infection is not stopped by the immune system, it spreads through the body. The fungus 'invades' the body - hence we call this invasive aspergillosis. This may be lethal. Early diagnosis allows timely treatment and stops the fungus from further invading the body.

What diagnostic test was studied in the review?

We wanted to find out how good 'galactomannan detection' is for diagnosing an infection of invasive aspergillosis.

Galactomannan detection is a diagnostic procedure. It works by passing an instrument through the mouth or nose into the airways. Fluid is flushed into a part of the lung. This fluid washes fungi and other microbes from the lungs and is collected and analysed. This process is called bronchoalveolar lavage (lung-washing), shortened to BAL. One of the things that may be in the collected BAL fluid is galactomannan, a component of the fungal cell wall.

The result of the BAL galactomannan test is part of international criteria used to differentiate between patients who are likely to have invasive aspergillosis and patients who are less likely to have invasive aspergillosis. If multiple criteria are fulfilled (e.g. imaging tests and clinical signs and symptoms), then the patients will be treated with antifungal medication.

What is the aim of this review?

The aim of this review was to determine the error rate of galactomannan testing on BAL. To this end, we searched for studies on this subject. The galactomannan test results in an 'optical density index' (ODI), not a yes or no answer. The studies differed with respect to the cut-off value above which a result was considered positive. Most considered a result above an ODI of 0.5 or 1.0 as positive.

What are the main results of this review?

Imagine a group of 1000 people with an impaired immune system where 120 (12%) have invasive aspergillosis. The results of this review indicate that in theory, if the BAL galactomannan test were to be used using an ODI of 0.5 or higher to decide which results are positive:

- an estimated 273 will have a test result indicating that they probably have invasive aspergillosis, and of these 167 will be incorrectly classified as having invasive aspergillosis; and

- of the 727 people with a result indicating that invasive aspergillosis is not likely to be present, 14 will be incorrectly classified as not having invasive aspergillosis.

If a higher cut-off value is used to determine test positivity, then more patients will have a false-negative result and fewer patients will have a false-positive result.

How reliable are the results of the studies in this review?

In the included studies, the diagnosis of invasive aspergillosis was made by assessing all patients with international criteria (known as the reference standard). This is likely to have been a reliable method for deciding whether patients really had invasive aspergillosis. The results of the various studies differed and had small numbers of patients with invasive aspergillosis. Therefore, the numbers are an average across the studies in the review and we cannot be sure that the test will always produce these results.

Who do the results of this review apply to?

The results are mainly applicable to adults who undergo intensive chemotherapy or a stem cell transplant for a form of cancer of the blood cells.

How up-to-date is this review?

The review authors searched for and used studies published up to 9 September 2016.

Authors' conclusions: 

The optimal cut-off value depends on the local incidence and clinical pathway. At a prevalence of 12% a hypothetical population of 1000 patients will consist of 120 patients with IA. At a cut-off value of 0.5 14 patients with IA will be missed and there will be 167 patients incorrectly diagnosed with IA. If we use the test at a cut-off value of 1.0, we will miss 26 patients with IA. And there will be 62 patients incorrectly diagnosed with invasive aspergillosis. The populations and results were very heterogeneous. Therefore, interpretation and extrapolation of these results has to be performed with caution. A test result of 1.5 ODI or higher appears a strong indicator of IA.

Read the full abstract...
Background: 

Invasive aspergillosis (IA) is a life-threatening opportunistic mycosis that occurs in some people with a compromised immune system. The serum galactomannan enzyme-linked immunosorbent assay (ELISA) rapidly gained widespread acceptance as part of the diagnostic work-up of a patient suspected of IA. Due to its non-invasive nature, it can be used as a routine screening test. The ELISA can also be performed on bronchoalveolar lavage (BAL), allowing sampling of the immediate vicinity of the infection. The invasive nature of acquiring BAL, however, changes the role of the galactomannan test significantly, for example by precluding its use as a routine screening test.

Objectives: 

To assess the diagnostic accuracy of galactomannan detection in BAL for the diagnosis of IA in people who are immunocompromised, at different cut-off values for test positivity, in accordance with the Cochrane Diagnostic Test Accuracy Handbook.

Search strategy: 

We searched three bibliographic databases including MEDLINE on 9 September 2016 for aspergillosis and galactomannan as text words and subject headings where appropriate. We checked reference lists of included studies for additional studies.

Selection criteria: 

We included cohort studies that examined the accuracy of BAL galactomannan for the diagnosis of IA in immunocompromised patients if they used the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) classification as reference standard.

Data collection and analysis: 

Two review authors assessed study quality and extracted data. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used for quality assessment.

Main results: 

We included 17 studies in our review. All studies except one had a high risk of bias in two or more domains. The diagnostic performance of an optical density index (ODI) of 0.5 as cut-off value was reported in 12 studies (with 1123 patients). The estimated sensitivity was 0.88 (95% confidence interval (CI) 0.75 to 1.00) and specificity 0.81 (95% CI 0.71 to 0.91). The performance of an ODI of 1.0 as cut-off value could be determined in 11 studies (with 648 patients). The sensitivity was 0.78 (95% CI 0.61 to 0.95) and specificity 0.93 (95% CI 0.87 to 0.98). At a cut-off ODI of 1.5 or higher, the heterogeneity in specificity decreased significantly and was invariably >90%.

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