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Managing invasive fungal infections in a COVID-19 era

HOW HAS IFI MANAGEMENT
BEEN IMPACTED BY COVID-19?

Highlights from the Gilead-organised and funded promotional symposium at TIMM 2021

COVID-19 is associated with an increased risk of invasive fungal infections (IFIs), particularly in severely ill patients admitted into the Intensive Care Unit (ICU). The most common of these are caused by Aspergillus and Candida auris, but increasing numbers of infections caused by Mucorales have also been reported.1

The Trends in Medical Mycology (TIMM) congress took place in October 2021. As part of this event, and in response to the issues faced by clinicians as a result of the pandemic, Gilead led a symposium to discuss the challenges of identifying and managing IFIs in COVID-19 patients. It was chaired by Prof George Dimopolous* and featured presentations by Prof Paul Verweij**, Prof Souha Kanj and Prof Pierluigi Viale - these are the highlights.

MEET THE SPEAKERS

What have we learnt about invasive fungal infections in critically-ill COVID-19 patients?

In this first presentation, Prof Dimopolous explained that since the start of the COVID-19 pandemic, superinfections have been frequently observed in hospitalised patients. IFIs represent a significant threat to these patients, but comorbidities, risk factors (length of stay in ICU, invasive procedures, use of broad-spectrum antibiotics, use of corticosteroids) and COVID-19 specific mechanisms (dysregulation of inflammatory and immune responses) make managing these infections a challenge. As such, “it is essential to maintain a high index of suspicion in order to facilitate early diagnosis and appropriate treatment”.1

To help identify patients with suspected COVID-19-associated pulmonary aspergillosis (CAPA), influenza-associated pulmonary aspergillosis (IAPA) definitions could be adapted given the small differences between them. These similarities and differences, when used alongside other diagnostic algorithms, can contribute towards a diagnosis of suspected IFI.2 In cases where there is clinical suspicion of an IFI, an empirical approach to treatment in eligible patients needs to be taken as setbacks in initiation of treatment associated with diagnostic delay increase the risk of poor outcomes.3

Diagram showing decision tree for the management of CAPA

In terms of other IFIs, clinicians should be aware of steroid use and uncontrolled diabetes as risk factors of infections such as COVID-19 associated mucormycosis (CAM). In these patients, adjunctive surgical debridement has been associated with improved outcomes.4 T-cell deficiency may be a useful indicator of Pneumocystis jirovecii pneumonia (PJP) due to overlapping symptoms with COVID-19.5,6 Immune dysregulation, including T-cell depletion, and cumulative risk factors in COVID-19 patients may also increase the risk of cryptococcal infection along with other secondary opportunistic infections.7 Cases of histoplasmosis and fusariosis have also been reported in COVID-19 patients, highlighting the need for clinicians to be aware of these infections.8,9

Prof Dimopolous concluded that IFIs represent a serious threat to patients with COVID-19 in the ICU.1 Clinicians therefore need to be aware of their similarities and differences, so they can use various diagnostic tools to identify suspected cases and treat them empirically.2,3

To see the full presentation, watch the video below.

EARLY IDENTIFICATION OF PATIENTS
AT HIGH RISK OF AN IFI

In this session by Prof Verweij, the challenges of identifying patients at high risk of CAPA were discussed. These patients are more difficult to diagnose versus other Aspergillus infections. This is because host factors, clinical factors and mycology that typically aid diagnosis are often absent in patients with COVID-19.1

EORTC/MSGERC host factors10 are commonly absent and radiology non-specific in patients with COVID-19.1 Prof Verweij introduced a set of factors involved in different stages of the infection, from inhalation to angioinvasion, that contribute to the risk of CAPA.11

Diagram showing angioinvasion threshold model

Clinical characteristics of aspergillosis, such as the halo or air crescent sign, are also more difficult to see using imaging techniques.12-14 In his opinion, serum galactomannan and beta-D-glucan levels may be useful in staging the infection rather than diagnosis, as a positive result is indicative of angioinvasion and poorer outcomes.15

Discussing the advantages and disadvantages of different sampling techniques, Prof Verweij summarised by stating that “Bronchoscopy and bronchoalveolar lavage seem to be the best approach to diagnosing a mould infection.”16 The main challenge in diagnosing CAPA is making the distinction between colonisation and tissue invasion. Biopsies are difficult to obtain and the race is now on to find a more suitable biomarker.

Although less common than CAPA, CAM infections pose a serious threat to patients, and clinicians should be aware of key risk factors, such as uncontrolled diabetes mellitus and systemic corticosteroids use.17 Due to its aggressive nature, it is important to take every case seriously, even if the patient already has a positive Aspergillus culture.14,17-18

In summary, patients with COVID-19 in the ICU are at risk of developing IFIs with high mortality rates.1 These infections can be difficult to diagnose and have variable clinical presentations, therefore, early diagnosis and therapy are important to improve outcomes in these patients.1,14,17-18

To see the full presentation, watch the video below.

TIMELY INITIATION OF ANTIFUNGAL TREATMENT:
WHO AND WHEN TO TREAT

In this session, Prof Kanj presented the challenges of diagnosing and treating CAPA, Candida auris and CAM infections in patients with COVID-19. “The literature on CAPA is confusing with conflicting observations”, she explained, before reviewing the literature on the incidence, mortality, onset and diagnosis of CAPA. Due to overlapping clinical features of CAPA and COVID-19-associated acute respiratory distress syndrome (ARDS), she added, the European Confederation of Medical Mycology (ECMM) and International Society for Human and Animal Mycology (ISHAM) jointly defined the diagnostic criteria and management protocol.16

“CAPA is proposed to be defined as possible, probable or proven, and considered as invasive Aspergillosis in temporal proximity to a preceding SARS-CoV-2 infection, depending on histological, microbiological, imaging and clinical criteria.”16

She explained there was no data to suggest treatment would be different from recommendations for patients without COVID-19 except in severe cases where azoles aren’t appropriate - such as where resistance is present. Cases of azole resistance have now been reported all over the world, including several countries affected by the COVID-19 pandemic.19-21 As such, clinicians need to be aware of the drivers of resistance in Aspergillus spp and use recommended alternatives, such as liposomal amphotericin B, where appropriate.16,22,23

Prof Kanj went on to discuss reported cases of Candida auris in patients with COVID-19, stating that there is an exacerbated threat, which has infection control implications. She highlighted CAM as an emerging problem that necessitates vigilance in COVID-19 patients, closing her presentation by underlining the importance of early diagnosis and treatment of IFIs in order to improve patient outcomes.

To see the full presentation, watch the video below.

THE ROLE OF LIPOSOMAL AMPHOTERICIN B
IN CURRENT ICU PRACTICE

In the final presentation by Prof Viale, the limitations of current treatment options were discussed. Although azoles are widely used, the emergence of resistance threatens their efficacy.24 Inhibition of CYP450 by azoles also increases the potential for drug-drug interactions.24 Furthermore, evidence suggests that Aspergillus fumigatus is able to overcome the fungicidal effects of echinocandins, such as caspofungin.25

Prof Viale went on to present the evidence supporting the use of liposomal amphotericin B in patients with IFIs, stating that liposomal amphotericin B is effective as first-line treatment for invasive fungal infections in the ICU.26 Studies have demonstrated the effectiveness of liposomal amphotericin B in treating invasive fungal infections, including within an ICU setting.27-30

Liposomal amphotericin B shows reduced levels of nephrotoxicity vs. conventional amphotericin B deoxycholate.27-29§ Prof Viale went on to state that liposomal amphotericin B is also effective against non-Aspergillus moulds and is suitable in cases of intolerance to other antifungal agents or suspected resistance within the ICU.30-31

To see the full presentation, watch the video below.

SUMMARY

IFIs have become a challenging complication in patients with COVID-19.1,4 Clinicians need to be aware of the various risk factors in these patients, including use of corticosteroid, monoclonal antibodies, broad-spectrum antibiotics and invasive procedures.1,32 Maintaining a high level of suspicion of IFIs is crucial to ensure prompt diagnosis and facilitate early empiric treatment in eligible patients with a broad-spectrum antifungal agent.1

Footnotes

  • *Professor of Critical Care at the National and Kapodistrian University of Athens, Greece. Disclosures: Honorarium fee for speaking at this Gilead-sponsored symposium.
  • **Professor of Clinical Mycology Department of Medical Microbiology, Radboud University Medical Center, The Netherlands. Disclosures: Research grants, advisory boards, speaker for Astellas, Basilea Pharmaceutica, Pfizer, F2G, MSD, Gilead.
  • Disclosures: Speaker/advisory member for Pfizer, Astellas, Novartis, Merck, Gilead, Hikma.
  • Disclosures: Honoraria from Pfizer, MSD, Shionogi, Gilead, bioMerieux, Biotest, Advanz Pharma, Angelini Pharma, Novartis, Thermo Fisher and Zambon for participating in accredited educational activities and/or for acting as a consultant/scientific advisor. Research grants from Pfizer, Shionogi and Gilead for coordinating or attending research projects.
  • §Liposomal amphotericin B has been shown to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity; however, renal adverse reactions may still occur. Caution should be exercised when prolonged therapy is required. If clinically significant reduction in renal function or worsening of other parameters occurs, consideration should be given to dose reduction, treatment interruption or discontinuation. Additionally, although infusion-related reactions are not usually serious, consideration of precautionary measures for the prevention or treatment of these reactions should be given to patients who receive liposomal amphotericin B therapy.27-29 Concurrent administration of liposomal amphotericin B with other nephrotoxic agents, such as ciclosporin and tacrolimus, may enhance the potential for drug-induced renal toxicity in some patients. Regular monitoring of renal function is recommended in patients receiving liposomal amphotericin B with any nephrotoxic medications. Concurrent use of corticosteroids may potentiate hypokalaemia.28 For the full list of interactions and information on AmBisome®, please refer to the Summary of Product Characteristics.

References

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Date of preparation: April 2022. Job code: IHQ-AMB-0428.