Can a Blood Test Find Invasive Fungal Infection Without a Biopsy?
Diagnosing invasive fungal infection can be difficult. Symptoms may be non-specific, scans can resemble other illnesses and traditional tests sometimes require samples from the lungs or another affected organ.
New research is exploring whether fragments of fungal DNA found in the bloodstream could help doctors make a diagnosis more quickly and with fewer invasive procedures.
Paper of the week: plasma sequencing in children and young adults
A study investigated plasma metagenomic next-generation sequencing, usually shortened to mNGS, in children and young adults being assessed for invasive fungal infection.
The test looks for small fragments of microbial DNA circulating in the blood. Unlike a conventional test designed to detect one particular fungus, mNGS can search broadly for genetic material from many different bacteria, viruses and fungi at the same time.
This could be valuable because invasive fungal infection is often difficult to diagnose. Obtaining a sample directly from the lungs or another infected site may require bronchoscopy, biopsy or another invasive procedure.
However, a blood-based sequencing test cannot yet replace conventional investigation. The amount of fungal DNA in the blood may be very small, and a positive result still needs to be interpreted alongside symptoms, scans, immune status and other laboratory tests.
Finding two infections at the same time
A case report describes a person with mantle cell lymphoma who developed lung infection involving both cytomegalovirus and Aspergillus tamarii.
CT scans showed widespread ground-glass changes in both lungs. Metagenomic sequencing of blood and bronchoalveolar lavage fluid detected both infections simultaneously.
This is important because people with severely weakened immune systems may develop more than one infection at the same time. If testing only looks for one suspected cause, another infection may be missed.
The report is a single case, so it does not show how often mNGS will detect multiple infections reliably. It does, however, demonstrate the breadth of information that one sequencing test can potentially provide.
Read the case report on PubMed
Can sequencing also detect resistance?
Another study assessed mNGS in people with cancer, looking not only for infectious organisms but also for antimicrobial-resistance genes.
In principle, this could provide two pieces of information at the same time:
- which organisms may be causing the infection; and
- whether they carry genes associated with resistance to commonly used treatments.
This could help doctors choose treatment more quickly, particularly when conventional cultures are negative or take several days.
There are important limitations. Detecting a resistance gene does not always prove that the organism is clinically resistant to a particular drug. The genetic information still needs to be interpreted alongside culture, susceptibility testing and the patient’s clinical condition.
Why mNGS is not a simple replacement for culture
Metagenomic sequencing is powerful, but it has several challenges.
- Human DNA can overwhelm the small amount of microbial DNA in a sample.
- The test may detect organisms that are colonising the airways rather than causing disease.
- Contamination can sometimes be difficult to distinguish from genuine infection.
- Results require specialist laboratory and clinical interpretation.
- The technology remains expensive and is not available everywhere.
For these reasons, mNGS is best viewed as an additional tool rather than a replacement for culture, microscopy, antigen testing, PCR, imaging and clinical assessment.
New ways to improve sequencing
Two other studies explored ways of making metagenomic testing more sensitive.
One used probe-capture technology to enrich microbial genetic material before sequencing. This may help when there is very little pathogen DNA in a blood or respiratory sample.
Another investigated methods for enriching microbial cell-free DNA in plasma. The aim is to remove some of the background human DNA and make it easier to detect fragments released by infectious organisms.
These are technical developments rather than tests that most patients can currently request. They show, however, how researchers are trying to overcome one of the central problems of mNGS: finding a small microbial signal in a large amount of human genetic material.
Other research: biomarkers, imaging and prediction
A review of invasive mould infections in intensive-care patients emphasised that diagnosis usually depends on combining several types of evidence.
These may include:
- CT or other imaging;
- galactomannan and other fungal biomarkers;
- PCR testing;
- culture and microscopy; and
- the patient’s underlying illness and immune status.
Another study developed a clinical prediction model, or nomogram, to identify people at higher risk of invasive pulmonary aspergillosis.
Prediction tools may eventually help clinicians decide who needs urgent fungal testing. However, this model still requires testing in other hospitals and patient groups before it can be considered reliable for routine use.
Read the intensive-care review and read the prediction-model study.
A specialised example: cerebral aspergillosis and ibrutinib
The final paper examined cerebral aspergillosis in people receiving ibrutinib, a drug used to treat some blood cancers.
The study found that this form of aspergillosis often spread through the bloodstream and that serum galactomannan was less frequently positive than in some other groups.
This is a useful reminder that the performance of a diagnostic test can depend on:
- where the infection is located;
- the type of immune problem;
- the treatment the person is receiving; and
- the amount of fungal material present in the blood or tissues.
A negative test result therefore does not always exclude invasive aspergillosis when clinical suspicion remains high.
What does this mean for patients?
The research points towards a future in which fungal diagnosis uses several complementary tests rather than relying on one method.
Blood-based sequencing could be particularly useful when:
- the infection is difficult to sample directly;
- more than one pathogen may be present;
- standard cultures are negative; or
- rapid information is needed to guide treatment.
But mNGS is not yet a universal fungal test. A positive result does not automatically prove that a fungus is causing disease, and a negative result cannot always rule infection out.
For now, the best diagnosis usually comes from combining the patient’s symptoms and immune status with imaging, culture, antigen tests, PCR, antibody tests and—when available and appropriate—metagenomic sequencing.
The direction of travel is clear: fungal diagnosis is moving beyond culture alone. The challenge will be making these newer tests affordable, widely available and straightforward to interpret.