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The Halo Effect in Invasive Fungi Disease

Learn more about the clinical signs and symptoms of invasive fungal disease and ‘The Halo effect’.
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Hello. In this session, we’ll be discussing the clinical signs and symptoms of invasive fungal disease and the conundrum of the halo effect. The learning objectives of the session basically revolve around typical presentations of invasive fungal disease, the halo effect and the imaging challenges. And what really is the definition of invasive fungal disease. Let’s take an example of a typical presentation of a 65-year-old female, for example, who has a history of being a heavy smoker. She has known emphysema. She presented with two week history of worsening cough symptoms, one episode of hemoptysis, and breathlessness. She had intermittent fevers at home and was admitted with high grade persistent fevers in this admission.
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She was noted with pancytopenic with severe neutropenia and was confirmed to have suffered from acute myeloid leukaemia on marrow biopsy. Now if you would consider doing further investigations for the cough symptoms and you may do a CT scan possibly as your first choice of the diagnostics. And clearly at the chest imaging, science often shows these patterns which often are macronodular or consolidation with these ground lost changes or halo sign as we know it now. And this was first published many years ago in 1985 describing this aspect economic sign of invasive fungal disease.
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For the studies subsequent to that, a few years later it was done in autopsy series in which patients were looked at post-mortem who had previously geological imaging done prior to the deaths looking at evidence of fungal disease in autopsy series. And that would clearly show the usefulness of halo sign described in the CT as quite as trigonomic of an invasive fungal disease in patients who did have invasive primary aspergillosis compared to those who didn’t, as one of the sore signals that potentially reflected as quite strongly linked with evidence of fungal disease. And this is the histological patterns that often are seen with halo signs as you see in the CT with central inflammatory necrotic element with surrounding edoema.
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And it neutrophilic filtrates reflecting the fungus halogens that you see on the CT itself. And that’s how they look back sculpturally and on a CT cam. Then the question is, what does these halo signs really mean in clinical diseases? And it’s clear that this is not only a sign for invasive fungal disease. And you could see these signs in other indications like coccidioidomycosis, Kaposi’s sarcoma, metastatic angiosarcoma. So clearly, these are not a very sensitive signs for a fungal disease and any potential need to consider additional clinical features as well as other diagnostic tests to really hone down the diagnosis. And often you may have to do a typical lung biopsy to confirm what these lesions do mean.
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And then come along the air crescent signs that often also described quite cataclysmic of invasive fungal disease. But we do know that these signs can also present in patients, for example, with TB and pre-recent haemoptysis. Signs our in patients who have neutropenic persistent fevers. And they all can look similar with different etiologies in the background. So it’s again very difficult to assess that they do have a fungal disease. But in the right context, clinical context, you could potentially argue this is more likely to be a fungal disease based on these changes. Major standard imaging techniques as of this day and age, clearly CT imaging are still more commonly available and are useful for detection of primary infections.
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Quite often time and operator dependent may not allow you to differentiate between aspergillus or pathogenic fungi and has again limited specific predictive value. If you use PET imaging for example, which has been proposed as an agent for invasive aspergillosis. However, that added sensitivity may be difficult to confirm because of difficulty in deciding if this is just pure inflammation or true infection. And we have a role in decision to stop antifungals if it’s negative. However, it may not be useful for diagnostics. And for that reason, this specificity is still low in these infections. Come along CTPA.
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And again in some small centres, there has been a clear utility of doing CTPAs in some of these patients which choose a clear signal if there is an obstruction of the contrast through a consolidation, which may suggest a necrosis of that blood vessel, meaning potentially likely invasive fungal disease compared to other scans where the contrast shows through easily to that consolidation lesion, suggesting is unlikely to be fungal disease. And that was quite sensitive way of describing invasive fungal disease using these techniques.
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But this is still operative dependent and centre dependent because the other centres have not been able to show similar results so far and does require quite a trained and motivated radiologist in your centre to be able to do these scans in a timely fashion and report in this manner. So yes, there is some degree of improvement from these additional imaging tools. However, there are additional problems that still remains in terms of subjectivity and sensitivity for these aspergillus, for these tests.
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Come along EORTC which is a group in Europe that was set up in 2002 and again sat down in 2008 and recently in 2019 revising the guidelines of definitions of invasive fungal disease based on the criteria using cost, factors for example, significant neutropenia, transplant patients in the suppressive drugs that are given to these individuals that may put them at risk of invasive fungal disease. And typical clinical features, ideological features that may give you a confidence of saying that this may well be a possible fungal disease. But it does require additional biomarkers to improve that sensitivity of these radiological tests.
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For example, radiological matters like, galactomannan PCRs, or tissue matters that will hopefully give you much more stronger confidence in calling this as a probable invasive fungus disease. These are important steps in defining the true likeliness of invasive fungal disease in these high-risk individuals. But clearly, resting your case on a single typical finding on a CT scan may not necessarily be an invasive fungal disease.
In this video, Dr Varun Mehra will be talking about the clinical signs and symptoms of invasive fungal disease and ‘The Halo effect’.

The Halo sign’ is a characteristic pattern often found when taking CT chest images of Invasive Pulmonary Aspergillosis (IPA) patients, and is defined by a ground-glass opacity encircling a pulmonary nodule or mass. This pattern is caused by an inflammatory necrotic mass with a surrounding oedema and neutrophilic infiltrates.

During a study by Kami M et al. (2002), it was found that the ‘Halo’ was only found in hospitalised patients with haemotological malignancy and neutropenia with IPA, with 13 out of 17 patients showing this pattern on CT chest scans. In patients without IPA, the ‘Halo’ pattern was absent. This shows how useful the ‘Halo’ sign can be in diagnosing IPA. However, the ‘Halo’ sign can be found in other diseases such as Coccidioidomycosis, Kaposi’s Sarcoma, and Metastatic Angiosarcoma, indicating that this a low sensitivity diagnosis tool, and you should consider additional clinical features and other diagnostic tests to hone down the diagnosis.

Other variations of the ‘Halo’ sign include ‘Air Crescent’ signs which can also present themselves in patients with Tuberculosis, Haemoptysis, Neutropenia, and refractory pyrexia. ‘Air Crescent’ usually appears later in the evolution of the IPA lung lesion, with the recovery of the neutrophil count. In the correct context however, it could be argued to be more likely to be a fungal disease.

Current methods in imaging include CT scans, PET scans, and CTPA scans. CT scans are the most common and standard imaging technique for detecting pulmonary infection, though they are time and operator dependent, cannot differentiate between Aspergillus and other pathogenic fungi, and have limited specificity and predictive value. PET scans are more sensitive, though it is still difficult to differentiate from pure inflammation or true infection.

CTPA is a type of CT scan that can identify obstructions in blood vessels. Obstructions in the contrast through the consolidation lesion shown in the scan could suggest thrombosis and necrosis of the blood vessels, indicating a high likelihood of fungal disease. This technique is sensitive to fungal disease. CTPA is still operator and centre dependent however since other centres have not been able to replicate successful results and a highly trained radiologist is required to do these scans.

The guidelines of definitions of invasive fungal disease were revised in 2019 to be based on three criteria.

  • Host factors may put the host more at risk of invasive fungal disease.
  • Typical clinical, radiological, and serological features can give you indications that this is an invasive fungal disease.
  • Mycology. Using additional biomarkers to improve the sensitivity of radiological tests such as Galactomannan and PCRs.
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