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Review
. 2021 Jul;9(7):795-802.
doi: 10.1016/S2213-2600(21)00138-7. Epub 2021 May 26.

COVID-19-associated Aspergillus tracheobronchitis: the interplay between viral tropism, host defence, and fungal invasion

Frank L van de Veerdonk  1 , Roger J M Brüggemann  2 , Shoko Vos  3 , Gert De Hertogh  4 , Joost Wauters  5 , Monique H E Reijers  6 , Mihai G Netea  1 , Jeroen A Schouten  7 , Paul E Verweij  8
Affiliations
Review

COVID-19-associated Aspergillus tracheobronchitis: the interplay between viral tropism, host defence, and fungal invasion

Frank L van de Veerdonk et al. Lancet Respir Med. 2021 Jul.

Abstract

Invasive pulmonary aspergillosis is emerging as a secondary infection in patients with COVID-19, which can present as alveolar disease, airway disease (ie, invasive Aspergillus tracheobronchitis), or both. Histopathology of invasive Aspergillus tracheobronchitis in patients with severe COVID-19 confirms tracheal ulcers with tissue invasion of Aspergillus hyphae but without angioinvasion, which differs from patients with severe influenza, where early angioinvasion is observed. We argue that aggregation of predisposing factors (eg, factors that are defined by the European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium or genetic polymorphisms), viral factors (eg, tropism and lytic effects), immune defence factors, and effects of concomitant therapies will determine whether and when the angioinvasion threshold is reached. Management of invasive Aspergillus tracheobronchitis should include reducing viral lytic effects, rebalancing immune dysregulation, and systemic and local antifungal therapy. Future study designs should involve approaches that aim to develop improved diagnostics for tissue invasion and airways involvement and identify the immune status of the patient to guide personalised immunotherapy.

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Conflict of interest statement

Declaration of interests RJMB reports grants from and consultancy for MSD, Pfizer, Mundipharma, F2G, Gilead Sciences, Astellas Pharma, and Amplyx Pharmaceuticals, outside of the submitted work. JW reports grants and personal fees from MSD, Gilead Sciences, and Pfizer during the study. PEV reports grants from Mundipharma, F2G, Pfizer, Thermo Fisher Scientific, Gilead Sciences, and Cidara Therapeutics and non-financial support from IMMY, outside of the submitted work. FLvdV reports personal fees from Gilead Sciences and Swedish Orphan Biovitrum, outside of the submitted work. SV, GDH, MHER, MGN, and JAS declare no competing interests.

Figures

Figure 1
Figure 1
Biopsy images with Grocott stain from two patients with COVID-19 and invasive Aspergillus tracheobronchitis (A) Bronchial biopsy showing an ulcer with necroinflammatory debris and septate Aspergillus hyphae (black; original magnification ×40). Hyphae are superficially located and there is no evidence for angioinvasion. (B) Image of the trachea showing tissue invasion by fungal hyphae (black), consistent with Aspergillus (original magnification ×200). There is no evidence for angioinvasion.
Figure 2
Figure 2
Histopathology of invasive Aspergillus tracheobronchitis in a patient with severe influenza shown with Grocott stain (A) Trachea showing extensive ulceration and necrosis with presence of multiple Aspergillus hyphae (black; original magnification ×40). The hyphae infiltrate the submucosa of the trachea. (B) Aspergillus hyphae (black) showing invasion of a tracheal artery vessel with thrombus formation (original magnification ×100).
Figure 3
Figure 3
The angioinvasion threshold model Factors that contribute to invasive Aspergillus tracheobronchitis disease progression ultimately leading to angioinvasion in patients with severe COVID-19 and influenza pneumonia. The arrows indicate invasive Aspergillus tracheobronchitis disease progression, where the infection has surpassed the angioinvasion threshold in a case of influenza.
Figure 4
Figure 4
Interventions that might contribute to reducing the severity and mortality associated with invasive Aspergillus tracheobronchitis IL=interleukin. *Can have both beneficial and harmful effects on reaching threshold.
See this image and copyright information in PMC

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