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Managing invasive fungal disease: empirical vs pre-emptive

In this video, Dr Varun Mehra discusses pre-emptive vs empirical approaches during management of invasive fungal diseases.
Hello. In this session, we’ll be looking at what strategy for managing invasive fungal disease is better, preemptive or empirical approach. These are the learning objectives of this session in which we’ll assess the changing paradigm of the risk factors, understanding local epidemiology, and available diagnostics. And also, a quick word on resistance and toxicity issues that we have to face when deciding treatment strategies. This is the spectrum of host conditions and angio-invasive aspergillosis. For example, back in 2000 and again in 2006, the majority of the invasive aspergillosis infections were noted in hemato-oncology and bone marrow transplant patients, and less commonly in other disease settings, like solid-organ transplants, pulmonary disease, or HIV, for example.
But come in 2018 and beyond, we now have access to different novel biologics for treatment of a variety of ecological conditions, including agents like B-cell receptor inhibitors, TKIs, BTKis small molecules, and now more exciting immunomodulatory therapies like CAR-T therapies and checkpoint inhibitors. Equally increasing number of novel indications for transplants, including autoimmune diseases, are now being used, which does play a role in expanding this host population, which otherwise, not at risk in the past. But the increasing use of these novel immunomodulatory agents are bringing in new challenges for the immunosuppressed patients. In terms of diagnostics, more centres will have access to microscopy culture or direct methods to look for invasive fungal disease.
But often, these tests are quite late to diagnose invasive fungal disease and worry is that early diagnostics may play a better role with improvement in patient outcomes. Clearly, the antigen-based methods, like galactomannan and beta-d-glucan are commonly available. However, there is secondary concerns around sensitivities and specifities of these assays as less time to turn around these results. Increasingly, bedside test like lateral flow device are being used. However, they still require clinical validation in trials as well as known molecules like gliotoxin are being used, but there are still remaining research tests.
There are nucleic acid tests, like PCRs, are now becoming standard of care in diagnosing invasive fungal disease and advocated as one of the key tests that should be used for screening or diagnosing these infections. Radiological methods, with CT scan, for example, are commonly available. However, this remains very much a subjective issue in relation to sensitivity and specificity of these scans as you will be able to acquire an expert radiologist to help you define these fungal disease in a more structured manner than normally would be available. It’s also important to think of azole therapeutic drug monitoring because these clearly are important areas for deciding about the efficacy of azole for treatment or prophylaxis purposes.
If, for example, there is under therapeutic effect of azoles, the breakthrough infection could just be a failure of azoles rather than resistance. And that is an important part of also looking at azole resistance screening using molecular methods to help identify patients at risk of developing significant fungal disease because of azole resistance. And this is the world wide map of azole resistance. For example, in red, in many countries across the globe reporting positive clinical isolates, which remains a big concern and potentially related to widespread agriculture industrial use of azoles that leads to further resistance in clinical situations.
Equally, the assays itself suffer from sensitivity issues, especially if we are using triazoles or active azoles that reduces the sensitivity by a third, which becomes a problem in terms of falsely negative assay reports in presence of azoles. And clearly, more is to be done to improve sensitivity of these assays. And this is where combined diagnostic methods might come in handy to improve the sensitivity of these assays. For example, this work done by Dr.
Ceesay at King’s College Hospital showed that combining diagnostics like galactomannan or beta-d-glucan tissue biopsies, PCRS, and CT imaging do improve sensitivity of these tests by increasing the incidence to 21% when using a combined modality versus 11% if you were to use only a single assay, for example. And this is important because these patients will eventually– who are picked up as a high incidence at 21% were found to be doing quite worse in terms of survival outcomes. And any early intervention in terms of early diagnostics could have an impact in improving their survival. And this brings the question as, what is the best strategy for treating fungal disease?
And the numbers needed to treat clearly if you would use prophylaxis models, you’re giving it to a large population to reduce a small number of these infections, which does mean increasing toxicity burden at the same time. However, you are protecting a larger population at high risk for developing fungal disease. In terms of a empirical or preemptive approaches, these remain debatable. But clearly, empirical approach require persistent fever with no specific signs of symptoms and treatment on suspicion only, which again, requires a good size individuals be treated before any change in therapies. And preemptive approaches, you need to wait for specific signs and symptoms or diagnostics to be positive before you treat these patients.
And this study looked– a few years ago between empirical and preemptive fungal approaches in high risk neutropenic patients. And randomising between empirical and preemptive approach and day two of the fevers despite antibiotics. And clearly, this showed there was no overall survival between the two strategies. However, there was concern that this lead to increased risk of fungal disease in the preemptive approach despite reduced antifungal therapy used in this setting. This was clearly used as a main reason for considering empirical approaches that is still being practised in most centres with the fear that if that is not used, there is a risk of missing out on patients and causing additional morbidity for these patients with invasive fungal disease.
And this brings to the question of where does our strategy should sit. And it’s a careful balance between also controlling infection and the burden of infection and clearly early diagnosis will always be the best strategy forward. But this does require strong, reliable, sensitive, and specific diagnostics that can help achieve this goal. Versus an empirical approach where you would need to treat on suspicion only without waiting for diagnostics, but does risk increasing toxicity and over-treating of some of these patients.
And at the same time, we need to keep in mind the severity of these infections that we wish to treat the spectrum of coverage of our antifungal drugs, previous azole exposure, which may decide which class of drugs you may need to treat at the time of breakthrough infections. Duration of therapy is important. And of course, therapeutic drug monitoring is equally important to help improve the strategy you wish to undertake in your own centre.

In this video, Dr Varun Mehra will discuss whether a pre-emptive or empirical approach is better when managing invasive fungal disease.

As discussed in previous steps, most diagnostic tests fall into two categories: Culture or direct methods (e.g. microscopy which is available in most labs) and non-direct methods (e.g. molecular methods such as ELISA assays).

An empirical approach to managing fungal diseases involves treating patients with a persistent fever, no specific signs or symptoms, and treating on suspicion only. A pre-emptive approach, on the other hand, requires you to wait for specific signs and symptoms or diagnostics to be positive before treating these patients.

In a study comparing empirical and pre-emptive antifungal strategies in high-risk neutropenic patients, results showed the overall survival rate to be very similar but there was an increased risk of fungal disease when taking a pre-emptive approach. The evidence from this study was one of the main reasons why empirical approaches are favoured in most centres, with the fear that if an empirical approach was not used, there would be a risk of missing out on patients and causing additional morbidities.

Which strategy to use depends on a careful balance between ‘Odds of controlling the infection’ and the ‘Burden of the infection’. Early diagnosis for a pre-emptive approach will always be the best strategy, but this requires strong, reliable, sensitive and specific diagnostic tests. As opposed to an empirical approach, where you would need to treat on suspicion only without waiting for diagnostics but risking increased toxicity and potentially overtreating patients.

If you would like to read more on this subject, take a look at the Cordonnier et al 2009 paper on empirical and pre-emptive antifungal therapy for high-risk, febrile, neutropenic patients.

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Fungal Diagnostics in Critically Ill Patients

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