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

Summary

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.

IntroductionInvasive aspergillosis is well recognised as a complication of treatment for patients with acute leukaemia or who have had solid organ transplantation or stem cell transplantation.Aspergillus fumigatus and aspergillosis in 2019. The risk for invasive aspergillosis is strongly associated with neutropenia as a prominent host factor, but the infection is increasingly observed in critically ill patients. Among the increase of patients with invasive aspergillosis in the intensive care unit (ICU), patients with the infection secondary to severe viral illness, notably influenza pneumonia, represent an important group.Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Studies noted that influenza was an independent risk factor for invasive aspergillosis, and influenza-associated pulmonary aspergillosis (IAPA) was observed both in patients with susceptibility host factors (panel), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) and Mycoses Study Group Education and Research Consortium (MSGERC),Donnelly JP Chen SC Kauffman CA et al.Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. and in previously healthy individuals.Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study.Wauters J Baar I Meersseman P et al.Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study.van de Veerdonk FL Kolwijck E Lestrade PP et al.Influenza-associated aspergillosis in critically ill patients. 90-day mortality after ICU admission for patients with IAPA was 51% (42 of 83) compared with 28% (99 of 349) for patients with influenza without IAPA.Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Cohort studies show that critically ill patients with COVID-19 are also at high risk of developing invasive aspergillosis.Alanio A Dellière S Fodil S Bretagne S Mégarbane B Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19.van Arkel ALE Rijpstra TA Belderbos HNA van Wijngaarden P Verweij PE Bentvelsen RG COVID-19-associated pulmonary aspergillosis.Bartoletti M Pascale R Cricca M et al.Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study.White PL Dhillon R Cordey A et al.A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU.Rutsaert L Steinfort N Van Hunsel T et al.COVID-19-associated invasive pulmonary aspergillosis.Salmanton-García J Sprute R Stemler J et al.COVID-19-associated pulmonary aspergillosis, March–August 2020. COVID-19-associated pulmonary aspergillosis (CAPA) was observed in 3–33% of (mostly mechanically ventilated) patients who were admitted to ICUs, although various case definitions for CAPA were used.Koehler P Bassetti M Chakrabarti A et al.Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Reported mortality rates for patients with CAPA (ie, 44–74%) are substantially higher than those observed in critically ill patients with COVID-19 without CAPA (ie, 19–39%) and are similar to mortality rates that are reported for patients with IAPA.Bartoletti M Pascale R Cricca M et al.Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study.White PL Dhillon R Cordey A et al.A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU.European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium factors

History of neutropenia (ie, <0·5 × 109 neutrophils per L [<500 neutrophils per mm3] for >10 days) that is temporally related to the onset of invasive fungal disease

Haematological malignancy

Receipt of an allogeneic stem-cell transplant

Receipt of a solid organ transplant

Prolonged use of corticosteroids (excluding among patients with allergic bronchopulmonary aspergillosis) at a therapeutic dose of more than 0·3 mg/kg for at least 3 weeks in the past 60 days

Treatment with other recognised T-cell immunosuppressants, such as calcineurin inhibitors, TNF blockers, lymphocyte-specific monoclonal antibodies, or immunosuppressive nucleoside analogues, during the past 90 days

Treatment with recognised B-cell immunosuppressants, such as BTK inhibitors (eg, ibrutinib)

Inherited severe immunodeficiency (eg, chronic granulomatous disease, STAT3 deficiency, or severe combined immunodeficiency)

Acute graft-versus-host disease grade 3 or 4, involving the gut, lungs, or liver, that is refractory to first-line treatment with steroids

One important clinical manifestation of invasive aspergillosis in patients with severe viral pneumonia is invasive Aspergillus tracheobronchitis (IATB), which is characterised by plaques in the large airways (ie, trachea and bronchi). Although a known manifestation of invasive aspergillosis in recipients of lung transplants,Mehrad B Paciocco G Martinez FJ Ojo TC Iannettoni MD Lynch 3rd, JP Spectrum of Aspergillus infection in lung transplant recipients: case series and review of the literature. up to 56% of patients with IAPA have been reported to present with IATB.Wauters J Baar I Meersseman P et al.Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study.Nyga R Maizel J Nseir S et al.Invasive tracheobronchial aspergillosis in critically ill patients with severe influenza. A clinical trial. Epithelial erosion due to virus replication is most likely an important predisposing factor to developing IATB, as this factor can provide a portal of entry for Aspergillus to cause invasive airway disease. IATB has been reported in 10–20% of critically ill patients with COVID-19 and CAPA.Bartoletti M Pascale R Cricca M et al.Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study.Rutsaert L Steinfort N Van Hunsel T et al.COVID-19-associated invasive pulmonary aspergillosis. The frequency of IATB in patients with COVID-19 and CAPA might be lower than is observed in patients with IAPA, but it might also be under-reported due to the reluctance of clinicians to do bronchoscopy in patients with COVID-19 during the first wave of the pandemic (ie, approximately December, 2019, to June, 2020). Diagnosing IATB is highly relevant as mortality that is associated with this manifestation was reported to be 90% (9 of 10) in patients with IAPA compared with 44% (11 of 25) in patients with other pulmonary manifestations,Nyga R Maizel J Nseir S et al.Invasive tracheobronchial aspergillosis in critically ill patients with severe influenza. A clinical trial. whereas mortality data are scarce for patients with severe COVID-19.Key messages

Invasive Aspergillus tracheobronchitis represents airways disease occurring in up to 56% of patients with severe influenza and in up to 20% of patients with severe COVID-19.

The ability of Aspergillus to cause angioinvasion is hypothesised as a crucial step in the pathophysiology of invasive Aspergillus tracheobronchitis (ie, angioinvasion threshold model), which determines diagnostic test performance and disease progression.

Invasive Aspergillus tracheobronchitis presents a highly lethal Aspergillus disease manifestation in patients with severe influenza, which occurs early after intensive care unit admission, whereas most invasive Aspergillus tracheobronchitis cases develop later after intensive care unit admission in patients with COVID-19-associated pulmonary aspergillosis and often present a less progressive course of disease.

The aggregation of predisposing factors (eg, presence of European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium factors or genetic polymorphisms), viral factors (eg, tropism and lytic effects), immune dysregulation, and effects of antiviral or immunosuppressive therapies will determine whether the angioinvasion threshold is reached and when.

Future study design should involve approaches that are aimed to develop improved diagnostics for tissue invasion and airways involvement and identify the immune status of the patient to guide personalised immunotherapy.

Histopathology of illustrative casesTo understand the pathophysiology of IATB in patients with COVID-19, the histology of some patients with proven COVID-19 and IATB was compared with that of patients with influenza and IATB. Figure 1A shows a tissue fragment from a bronchial biopsy that was obtained from an endobronchial plaque that was observed at bronchoscopy. The patient had no EORTC and MSGERC risk factors and bronchoscopy was done 8 days after ICU admission. Before bronchoscopy, the patient had received dexamethasone at a dose of 6 mg/day for 8 days. The epithelial lining showed partial ulceration, which is most likely due to SARS-CoV-2 replication. ACE2 receptor expression, which serves as an entry point for SARS-CoV-2, is seen in the pre-existent, reactive respiratory epithelium (appendix p 1) and the metaplastic epithelium near the ulcer (appendix p 2). At the ulcer, necroinflammatory debris and several septate hyphae can be identified that are consistent with Aspergillus infection (figure 1A). The hyphae show superficial tissue invasion but no deep invasion in the underlying tissue. Furthermore, there was no evidence for angioinvasion. In the stroma, nuclear debris, neutrophils, some macrosialin-positive histiocytes (appendix p 3), and a few CD8-positive cytotoxic T lymphocytes are seen (appendix p 4). A tracheal biopsy from a second patient with COVID-19 and proven IATB shows similar histopathological features (figure 1B). Similar to the first patient, this patient had no EORTC and MSGERC risk factors, and the CAPA diagnosis was made 17 days after ICU admission. Before the biopsy, the patient had received dexamethasone for 10 days at a dose of 6 mg/day and methylprednisolone for 1 day at a dose of 60 mg. Compared with patient 1, more advanced ulceration was found reaching into the perichondral tissue (figure 1B). Staining for the SARS-CoV-2 spike protein did not show any viral protein (appendix p 5). Invasive growth of Aspergillus hyphae is seen in figure 1B, but again, there was no evidence for angioinvasion. Furthermore, numerous macrosialin-positive histiocytes and few CD8-positive cytotoxic T cells were found lining the edge of the ulcerative lesion (appendix p 5).Figure thumbnail gr1

Figure 1Biopsy 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.

For comparison, Figure 2 shows the histopathology of IATB in a patient with severe influenza. This patient had no EORTC and MSGERC risk factors and was diagnosed with IAPA 3 days after ICU admission. The infection was rapidly fatal and the patient died on day 5 after ICU admission. He had received corticosteroids for vasopressor-resistant shock in the 4 days before death. Extensive ulceration and necrosis in the trachea were noted at autopsy (figure 2A). Multiple Aspergillus hyphae can be identified infiltrating the tracheal submucosa. Few inflammatory cells are seen at the ulcer level and in the superficial layers of the trachea. In the adventitia, moderate inflammation with neutrophils admixed with macrophages is seen with necrotic debris. There is clear evidence for invasive growth of Aspergillus hyphae in surrounding blood vessels (figure 2B). In addition to invasive growth of hyphae, Aspergillus fumigatus vesicles were found in the lumen of the trachea (appendix p 6). These structures are formed by the fungus to allow sporulation, and Aspergillus conidia are visible on the epithelial cells of the trachea.Figure thumbnail gr2

Figure 2Histopathology 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).

Pathophysiology of IATBInvasive aspergillosis is an opportunistic infection that requires a defect of the host defence to develop. Predisposing factors that increase the risk for invasive aspergillosis have been well described in patients with haematological malignancies and include intrinsic factors, such as acute myeloid leukaemia, and extrinsic factors, such as intensive chemotherapy. Both of these factors lead to severe mucositis and reduction in neutrophil counts (ie, granulocytopenia) and thus present a high risk of developing invasive aspergillosis.Aspergillus fumigatus and aspergillosis in 2019. Additionally, disruption to neutrophil function (eg, caused by corticosteroid treatment or chronic granulomatous disease) predispose people to the development of invasive aspergillosis. The presence of host factors has become an important criterion for classification of patients with invasive aspergillosis and is part of case definitions, such as the EORTC and MSGERC's definition.Donnelly JP Chen SC Kauffman CA et al.Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Invasive aspergillosis that is secondary to severe viral infection can occur in patients with EORTC and MSGERC host factors, but 30–78% of patients with IAPA do not have these host factors.Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study.Wauters J Baar I Meersseman P et al.Invasive pulmonary aspergillosis is a frequent complication of critically ill H1N1 patients: a retrospective study.van de Veerdonk FL Kolwijck E Lestrade PP et al.Influenza-associated aspergillosis in critically ill patients.Nyga R Maizel J Nseir S et al.Invasive tracheobronchial aspergillosis in critically ill patients with severe influenza. A clinical trial. This proportion is even higher in patients with CAPA (86% [123 of 143] of patients do not have these host factors).Koehler P Bassetti M Chakrabarti A et al.Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Although EORTC and MSGERC host factors, and other factors that are not covered by the EORTC and MSGERC case definitions, can contribute to patient susceptibility to CAPA,Fekkar A Lampros A Mayaux J et al.Occurrence of invasive pulmonary fungal infections in patients with severe COVID-19 admitted to the ICU. virus-induced anatomical or immunological changes are likely to have an important role in providing the opportunity to develop invasive aspergillosis.Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Role of the virusHuman adapted influenza A viruses preferentially bind to α2,6-linked sialic acids.Davis AS Chertow DS Kindrachuk J et al.1918 Influenza receptor binding domain variants bind and replicate in primary human airway cells regardless of receptor specificity. By use of lectins that were specific for sialic acid α2,6-galactose sialyloligosaccharides, a study showed that epithelial cells in the trachea and bronchi, including terminal and respiratory bronchioles, mainly express sialic acid α2,6-galactose sialyloligosaccharides (rather than sialic acid α2,3-galactose sialyloligosaccharides).Shinya K Ebina M Yamada S Ono M Kasai N Kawaoka Y Avian flu: influenza virus receptors in the human airway. Histopathological findings from patients with influenza A at autopsy showed multifocal desquamation of the epithelium, congestion, haemorrhage, and necrotising tracheobronchitis.Nakajima N Sato Y Katano H et al.Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection. Histopathological changes involving the trachea and bronchi were observed in two-thirds of fatal 2009 H1N1 influenza cases, indicating that airway epithelium is commonly affected during influenza pneumonia.Shieh W-J Blau DM Denison AM et al.2009 pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in the United States.Autopsy studies of patients who died from COVID-19 showed plaques in the trachea and large bronchi and microscopy showed mucosal ulceration with mixed inflammatory cell infiltration, including neutrophils and fibrin.Borczuk AC Salvatore SP Seshan SV et al.COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City. In one patient, SARS-CoV-2 immunohistochemical staining and electron microscopy confirmed the presence of SARS-CoV-2-like particles in tracheal epithelial cells and the surrounding extracellular space, supporting a direct role of SARS-CoV-2 in the observed tissue damage.Bradley BT Maioli H Johnston R et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series. Furthermore, SARS-CoV-2 RNA has been detected in tracheal tissue.Bradley BT Maioli H Johnston R et al.Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.Evert K Dienemann T Brochhausen C et al.Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation. In the two patients with COVID-19 that were previously described (figures 1A, 1B), epithelial cells from the trachea and bronchi stained positive for ACE2 receptors, but the SARS-CoV-2 spike protein was not detected, possibly due to postmortem autolysis or the long interval between initial SARS-CoV-2 infection and autopsy. In an autopsy study of 38 people with COVID-19, large airway inflammation was noted in 35 (92%) patients, including acute inflammation in 17 patients and chronic inflammation in 18 patients.Borczuk AC Salvatore SP Seshan SV et al.COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City. Role of the host defenceThe lytic infection that is caused by influenza and SARS-CoV-2 viruses results in a local innate immunodeficiency due to loss of the mechanical barrier function and capacity to produce defensins by the epithelial cells. Influenza has been observed to cause more extensive lysis compared with SARS-CoV-2,Varghese FS van Woudenbergh E Overheul GJ et al.Berberine and obatoclax inhibit SARS-CoV-2 replication in primary human nasal epithelial cells in vitro. which might have a role in the severity of the tracheobronchitis that is associated with influenza. Both COVID-19 and influenza share signs of hyperinflammation, which in some patients has features of macrophage activation syndrome, characterised by haemophagocytosis (among other features), defects in immune cell numbers (ie, pancytopenia), and increased ferritin concentration.Tate MD Ong JDH Dowling JK et al.Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition.Swoboda J Wittschieber D Sanft J et al.Bone marrow haemophagocytosis indicates severe infection with severe acute respiratory syndrome coronavirus 2., , van de Veerdonk FL Netea MG Blocking IL-1 to prevent respiratory failure in COVID-19. This severe innate inflammatory response could have a role in tissue damage and necrosis at the site of infection, increasing the risk for invasive aspergillosis from the trachea. An impaired adaptive immune response reflected by lymphopenia is also shared by patients with COVID-19 and patients with influenza and is a well known risk factor for invasive aspergillosis. The severity of hyperinflammation and lymphopenia can vary in patients with COVID-19 or influenza, but both risk factors for aspergillosis are often present. Steroids are an independent risk factor in patients with IAPA; they have been associated with CAPA and can impair the ability of monocytes and macrophages to kill fungiKyrmizi I Gresnigt MS Akoumianaki T et al.Corticosteroids block autophagy protein recruitment in Aspergillus fumigatus phagosomes via targeting dectin-1/Syk kinase signaling. but can reduce the detrimental effects that are caused by cytokine storm syndrome. In contrast to influenza pneumonia, for which the use of steroids in not recommended due to the increased risk of invasive aspergillosis, steroids are now used as standard of care for patients with severe COVID-19 since publication of the data from the RECOVERY trial.Horby P Lim WS Emberson JR et al.Dexamethasone in hospitalized patients with Covid-19. A difference between influenza and SARS-CoV-2 is that influenza can infect monocytes and macrophagesHoeve MA Nash AA Jackson D Randall RE Dransfield I Influenza virus A infection of human monocyte and macrophage subpopulations reveals increased susceptibility associated with cell differentiation.

留言 (0)

沒有登入
gif