Invasive Aspergillosis and COVID-19

Prescribing information is available at the bottom of this page

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).2-4
 
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 for invasive aspergillosisa

Increasing evidence suggests that COVID-19 patients with severe ARDS are at risk of invasive pulmonary aspergillosis.2

40% of hospitalised patients Up to 40% of hospitalised patients with COVID-19 develop ARDS2
19.4-35% estimated rate of CAPA in patients with ARDS The estimated rate of COVID-19 associated pulmonary aspergillosis in patients with ARDS is 19.4-35%2
Aspergillosis in these patients is associated with high mortality rates Aspergillosis in these patients is associated with high mortality rates and may prolong the acute phase of COVID-192

 

However, monitoring and diagnosis are difficult due to the non-typical presentation of  non-neutropenic patients, including those with COVID-19.2  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.2

 

When to suspect COVID-19 associated pulmonary aspegillosis

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.2,3,5,6 

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

Severe lung damage during the course of COVID-192,7
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 corticosteroids2
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 ICU2
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 damage2
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-192,7,8
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.2,9

While there are approved treatments for invasive aspergillosis, differences in coverage,  tolerability and PK1,10-12 mean that a considered, individualised assessment should be made for every patient, with particular attention given to the following:

Drug-drug interactions Drug-drug interactions
Interactions with concomitant medications in COVID-19 patients should be considered2
CYP3A4-metabolised treatments may limit the use of voriconazole10
Renal insufficiency Renal insufficiency
SARS-CoV-2 has renal tropism2
Commonly used antifungals require renal function monitoring10,13-15
Pharmacokinetic Profile 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 beneficial2
QTc Prolongation QTc prolongation
COVID-19 can significantly affect cardiac function and multiple medications used in COVID-19 patients are pro-arrythmic16
Minimising the risk of QT prolongation may therefore be an important treatment consideration

 

ECMM recommendations for treating COVID-19 associated pulmonary aspergillosis:17

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

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

 

Prescribing Information

This includes legal category, basic NHS cost and a link to SPC. Please click each relevant SPC link to be directed to EMC webiste. 
 

Cresemba® (isavuconazole) Prescribing Information
Cresemba® 100mg hard capsules – SPC
Legal Category: POM. Basic NHS Cost: 14 caps pack £599.28
Cresemba® 200mg powder for concentrate for solution for infusion – SPC
Legal Category: POM Basic NHS Cost: 1 vial pack £297.84

Vfend® (voriconazole) Prescribing Information
Vfend® 50mg filmed tablets – SPC
Legal Category: POM. Basic NHS Cost: 28 tabs £275.68
Vfend® 200mg filmed tablets – SPC
Legal Category: POM. Basic NHS Cost: 28 tabs £1102.74
Vfend® 200mg powder for solution for infusion – SPC
Legal Category: POM. Basic NHS Cost: 1 vial £77.14
Vfend® 40mg/ml powder for oral suspension – SPC
Legal Category: POM Basic NHS Cost: 75ml £551.37

PP-CRB-GBR-0927.  February 2021