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Invasive Aspergillosis and COVID-19

The COVID-19 pandemic has revealed an emerging predisposing factor for invasive aspergillosis that healthcare professionals should consider. COVID-19 associated pulmonary aspergillosis - abbreviated to CAPA - is a type of invasive aspergillosis that is increasingly recognised as a threat to COVID-19 patients admitted to intensive care, or who develop acute respiratory distress syndrome (ARDS).1-3


In these patients, respiratory and ICU healthcare professionals may need to raise the index of suspicion to identify an invasive fungal infection and manage it early. Careful consideration of fungal diagnostics, the characteristics of the therapy and the status of the patient is required when choosing a suitable antifungal treatment to combat COVID-19 associated pulmonary aspergillosis.

COVID-19 patients who develop ADRS may be at risk of invasive aspergillosisa

Increasing evidence suggests that COVID-19 patients with severe ARDS are at risk of invasive pulmonary aspergillosis.1​​​​

    Up to 40% of hospitalised patients with COVID-19 develop ARDS1

    The estimated rate of COVID-19 associated pulmonary aspergillosis in patients with ARDS is 19.4-35%1

    Aspergillosis in these patients is associated with high mortality rates and may prolong the acute phase of COVID-191

    However, monitoring and diagnosis are difficult due to the non-typical presentation of  non-neutropenic patients, including those with COVID-19.1  In addition, Aspergillus diagnostic testing is commonly done on BALF and tracheal aspirate samples, but bronchoscopy can aerosolise virus in patients with COVID-19, posing a risk to patients and hospital personnel.1​​​​​​​


    When to suspect COVID-19 associated pulmonary aspergillosis

    COVID-19 associated pulmonary aspergillosis is a recently reported phenomenon, and as such data are currently limited. Clinical associations are difficult to ascertain due to small population numbers, and contributory factors identified in some studies have been found to be non-significant in others.1,2,4,5 

    However, potential risk factors predisposing COVID-19 patients to develop secondary pulmonary aspergillosis have been identified:
    ​​​​​​​

    Severe lung damage during the course of COVID-191,6

    Molecular epithelial damage in COVID-19 may provide an opportunity for Aspergillus species to invade tissues in a way that is at least partially distinct from other respiratory viruses.
    ​​​​​​​

    Use of corticosteroids1​​​​​​​

    In those with ARDS, systemic corticosteroids are used to alleviate immune responses, but may at the same time increase vulnerability for developing secondary infections.
    ​​​​​​​

    Widespread use of broad-spectrum antibiotics in the ICU1​​​​​​​​​​​​​​

    The administration of antibiotics allows fungi to thrive in the human gut microbiome,  which may predispose the host to invasive fungal infections once the immune system becomes impaired.

    ​​​​​​​

    Presence of comorbidities, particularly those causing structural lung damage1​​​​​​​

    Hypertension and diabetes are thought to increase the risk of overall infections. Structural lung damage caused by COPD or asthma may particularly predispose patients to developing invasive pulmonary aspergillosis.
    ​​​​​​​

    Immune dysregulation associated with COVID-191,6,7​​​​​​​

    Inflammation resulting from immune dysregulation may result in an environment favouring fungal pathogenesis. Examples associated with SARS-CoV-2 infection include IL-1 hyperactivity, increased levels of IL-6, potential damage to T-cells and leukopenia.
    ​​​​​​​

    Considerations when treating COVID-19 associated pulmonary aspergillosis

    Suspicion and early diagnosis are critical determinants of outcomes for invasive pulmonary aspergillosis.1,8

    While there are approved treatments for invasive aspergillosis, differences in coverage,  tolerability and PK1,9-11 mean that a considered, individualised assessment should be made for every patient, with particular attention given to the following:

    ​​​​​​​

    Drug-drug interactions

    Interactions with concomitant medications in COVID-19 patients should be considered1

    CYP3A4-metabolised treatments may limit the use of voriconazole9

    Renal insufficiency

    SARS-CoV-2 has renal tropism1

    Commonly used antifungals require renal function monitoring9,12-14

    Pharmacokinetic profile

    Treating seriously ill COVID-19 patients can be challenging – addressing their invasive aspergillosis with an antifungal that has predictable PK and low requirement for drug monitoring may be beneficial1

    QTc prolongation

    COVID-19 can significantly affect cardiac function and multiple medications used in COVID-19 patients are pro-arrythmic15

    Minimising the risk of QT prolongation may therefore be an important treatment consideration

    ECMM recommendations for treating COVID-19 associated pulmonary aspergillosis:16

    The ECMM has recommended CRESEMBA® as a first-line treatment option for the management of COVID-19/influenza-associated pulmonary aspergillosisb

    ​​​​​​​

    Footnotes

    ARDS, acute respiratory distress syndrome; CAPA, COVID-19 associated pulmonary aspergillosis; COVID, coronavirus disease; ICU, intensive care unit; BALF, bronchoalveolar fluid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COPD, chronic obstructive pulmonary disease; IL, interleukin; IV, intravenous; PK, pharmacokinetics; TDM, therapeutic drug monitoring; ECMM, European Confederation of Medical Mycology.

    a. Cresemba® is not indicated for the treatment of COVID-19
    b. Voriconazole is also recommended as a first-line treatment option. Please refer to the full guidance document for further information

    ​​​Prescribing Information for Cresemba (isavuconazole)

    Great Britain
    Cresemba (isavuconazole) 100mg hard capsules
    Cresemba (isavuconazole) 200mg powder for concentrate for solution for infusion 

    Northern Ireland
    Cresemba (Isavuconazole) 100mg hard capsules and Cresemba (Isavuconazole) 200mg powder for concentrate for solution for infusion

    Prescribing Information for Vfend (voriconazole)

    Great Britain
    ​​​​​​​Vfend (voriconazole) 50mg film coated tablets
    Vfend (voriconazole) 200mg film coated tablets
    Vfend (voriconazole) 200mg powder for solution for infusion
    Vfend (voriconazole) 40mg/ml powder for oral suspension


    Northern Ireland
    ​​​​​​​
    Vfend (voriconazole): 50mg film coated tablets, 200mg film coated tablets, 200mg powder for solution for infusion & 40mg/ml powder for oral suspension ​​​​​​​

    References: 

    1. Arastehfar A et al. J Fungi (Basel) 2020;6(2):91. 
    2. Alanio A et al. Lancet Respir Med 2020;8(6):e48–e49. 
    3. Rutsaert L, et al. Ann Intensive Care 2020;10(1):71. 
    4. Zhu XJ, et al. Virus Res 2020;285:198005. 
    5. Wang J, et al. Crit Care 2020;24:299. 
    6. Thompson GR, et al. Open Forum Infect Dis 2020;7(7):ofaa242. 
    7. Zheng HY, et al. Cell Mol Immunol 2020;17(5):541–543. 
    8. Ullmann AJ, et al. Clin Microbiol Infect 2018;24:e1–38. 
    9. VFEND Summary of Product Characteristics. 
    10. Noxafil Summary of Product Characteristics. 
    11. AmBisome Summary of Product Characteristics. 
    12. Donnelley MA et al. Infect Drug Resist 2016;9:79–86. 
    13. Patel GP et al. J Med Toxicol 2011;7(1):12–15. 
    14. Shigemi A et al. Int J Antimicrob Agents 2011;38(5):417–420. 
    15. Wang Y et al. J Arrhythm 2020;36:827–836. 
    16. ECMM. Covid-19/Influenza-Associated Pulmonary Aspergillosis – Management. Available from: https://www.ecmm.info/wp-content/uploads/CAPA-IAPA-ICU-management-algorithm-2020_06_05PKfin_DOI.pdf. Accessed February 2021.
    PP-CRB-GBR-1218. August 2021

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