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What are the risk factors of IFD?

Here, we talk about the risk factors of IFD in immune-compromised hosts and how this can pose challenges for diagnostics.
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Hello. In this session, we’ll be discussing the risk factors for Invasive Fungal Disease in immunocompromised hosts and how this could pose challenges for diagnostics. It’s important, the first instance, to understand where these risk factors currently sits, in terms of the high risk versus intermediate and low risk categories. And disease areas like chronic granulomatous disease, therapies like allogenic transplants, AM and MDS treatments for induction chemotherapy, or prolonged neutropenia or high dose steroids poses the highest risk of invasive fungal disease. But increasingly, the intermediate risk category is expanding with inclusion of additional risk factors. For example, ICU patients with severe influenza infection and little primary complications, are quite likely to develop fungal disease. And we’ll discuss that in a minute.
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Additionally, new therapies, novel biologics, ibrutinib for example, are posing additional risk factors for an otherwise low risk disease indication like CLL, by virtue of affecting macrophage function and immune modulation that leads to poor infection surveillance and increasing risk of fungal disease. Additionally, new or exciting therapies like, CAR-T therapies, checkpoint inhibitors, which are revolutionising treatment for relapsing and refractory logical malignancies, are increasingly becoming a potential breeding ground for fungal disease, by virtue of lymphodepletion as well as prolonged aplasia-phase post therapies.
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And this is where the early reports for treatments like ibrutinib, for example, highlighted the risk for fungal disease, especially in the first few months of the therapy, when their macrophage function and inmodation is at its peak and leads to a risk of serious disseminator-type infections in these patients. And often, the risk factors are mainly to do with older patients with underlying comorbidities or heavily treated patients. With these immunilogical diseases, it’s quite important to screen these patients for any persistent signs of infections and look for underlying fungal disease. With the advent of CAR-T therapies, for example, this has also become an increasing challenge.
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These therapies are re-engineered T-cells, which leads to a directed immunological response to tumour antigens, but requires a significant degree of depletion and hormonal suppression initially, which leads to increased risk of bacterial and viral infections, but also early- and late-aspergillus, as it is known aspergillus infections in these patients. And then there is clearly an increasing concern and respective reports are coming across for defining these instances of fungal disease in these patients. Additional risk factors, like respiratory viral illness and flu infection has not been recognised. It’s an important risk factor of fungal disease, especially in ICU settings. And these patients are admitted with primary complications.
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And in this study, published a few years ago, it clearly showed a high incidence of around 20% of fungal disease in patients with Influenza A, when they compared that to patients admitted to ICU without any Influenza A infection. And this risk was even higher in the immunocompromised settings, going up to 32% in invasive fungal disease incidence, which is quite remarkable. And this definitely led to increasing mortality in the influenza cohort, up to 50% of patients, as well as going up to 70% in immunocompromised sub-group.
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And this is where there are now set definitions for aspergillus infection-related pulmonary aspergillosis, which takes into account certain clinical criterias, for example, persistent fevers, dyspnoea, haemoptysis, worsening respiratory insufficiency, as well as radiological criteria like palatal infiltrates on the imaging, but also taking into account mycological criteria with serum isolates, bronchoalveolar lavage, galactomannan, positive but also diagmatics to confirm influenza associated pulmonary aspergillosis. In the current era of COVID-19 related pandemic, this is also quite important and has some similarities with severe Influenza A, for example, in terms of Acute Respiratory Distress Syndromes, Lymphopenia effects, bilateral pulmonary infiltrates on imaging, and systemic pro-inflammatory cytokine responses and sepsis leading to multiple organ figure.
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And this has a striking similarities in terms of incidences that are currently being seen in these patients with COVID-19. And there are now certain criteria now being adopted. And one of our studies suggests this diagnostic algorithm published last year, taking into account clinical risk factors and also likelihood of fungal disease based on bronchial fluid lavage and serum biomarkers, leading to potential suggestion of antifungal therapy, if they had underlying risk factors in the modulation, treatments, and worsening clinical detribation with no other explanation, for example, where you could consider giving them antifungal therapy. And this is where it’s important to understand these new risk factors.
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It poses additional challenges, in terms of the further expansion of this patient group, how the current diagnostic serum biomarkers are not validated in this new risk settings, especially with CAR-T settings, Influenza A, or COVID-19-related fungal disease, for example. And perhaps combined diagnostics methods, like serum biomarkers and PCR techniques, could be useful in bronchial samples amd may allow early diagnosis of invasive aspergillosis. However, we do need prospective studies to evaluate these targeted diagnostics in these three new risk profiles, evaluating prophylaxis strategies and optimal management of these fungal diseases.

Here, we talk about the risk factors of IFD in immune-compromised hosts and how this can pose challenges for diagnostics. We start by explaining the importance of understanding where the risk factors sit on the scale of low, intermediate and high risk.

Who is high risk?

Patients experiencing chronic granulomatous disease, allogeneic transplant therapies, AML/MDS treatments for induction chemotherapy, prolonged Neutropenia and/or high dose steroids are at the highest risk of developing fungal disease. However, the intermediate risk category is expanding with additional risk factors such as in ICU patients with severe influenza and chronic lymphocytic leukaemia patients. Additionally, new therapies like CAR-T therapies and Checkpoint inhibitors are increasingly becoming potential breeding grounds of fungal disease.

The challenges

Opportunistic infections during CAR-T therapies have become an increasing challenge. These therapies use re-engineered T-cells which leads to directed immunological responses to tumour antigens but the patient will be immunosuppressed as a side effect. Initially, the patient will be at risk of fungal infection from Candida species, and later will be at risk from Aspergillus and non-aspergillus moulds, and Pneumocystis.

New definitions

There are now set definitions for Influenza-Associated Pulmonary Aspergillosis (IAPA) which take into account clinical criteria, such as persistent fever, Dyspnoea and Haemoptysis, radiological criteria, such as bilateral infiltrates on pulmonary imaging, and mycological criteria such as positive Aspergillus cultures from a bronchoalveolar lavage (BAL).

New risks

New risk factors, in the form of immuno-modulating drugs and cellular therapies, are leading to a further expansion in immuno-modulating drugs and cellular therapies. Current diagnostics for serum biomarkers are not validated in new risk settings, especially with CAR-T therapies, influenza A or SARS-CoV-2 viral related secondary invasive fungal diseases. Combined diagnostics including serum biomarkers & molecular assays (RT-PCR) are still considered useful in bronchial samples and may allow early rapid diagnosis of IA. However, prospective studies evaluating targeted diagnostics, prophylaxis strategies and optimal management are needed.

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Fungal Diagnostics in Critically Ill Patients

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