Summary Invasive pulmonary aspergillosis is emerging as a secondary infection in patients with COVID-19, which may present as alveolar disease, airway disease (i.e., 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 the aggregation of predisposing factors (e.g., factors defined by the Education and Research Consortium of the European Organization for Research and Treatment of Cancer and Mycoses or genetic polymorphisms), viral factors (e.g., Tropism and lytic effects), immune defense factors and the effects of concomitant therapies will determine if and when the angioinvasion threshold is reached. Treatment of invasive Aspergillus tracheobronchitis should include reduction of viral lytic effects, rebalancing of immune dysregulation , and systemic and local antifungal therapy. Future study designs should include approaches that aim to develop better diagnostics for tissue invasion and airway involvement and identify patient immune status to guide personalized immunotherapy. |
Invasive aspergillosis is well recognized as a complication of treatment for patients with acute leukemia or who have had a solid organ transplant or stem cell transplant. The risk of invasive aspergillosis is strongly associated with neutropenia as a prominent host factor, but infection is increasingly seen in critically ill patients.
Among the increase in patients with invasive aspergillosis in the intensive care unit (ICU), patients with infection secondary to severe viral illness, particularly influenza pneumonia, represent an important group.
Studies noted that influenza was an independent risk factor for invasive aspergillosis, and influenza-associated pulmonary aspergillosis (IPAS) was observed both in patients with host susceptibility factors, as defined by the European Organization for Research and Development. Treatment of Cancer (EORTC) and the Mycosis Study Group Education and Research Consortium (MSGERC), and in previously healthy individuals that critically ill patients with COVID-19 are also at high risk of developing invasive aspergillosis.
COVID-19-associated pulmonary aspergillosis (CAPA) was observed in 3–33% of patients (mostly mechanically ventilated) admitted to the ICU, although various case definitions for CAPA were used. The mortality rates reported for patients with CAPA (i.e., 44-74%) are substantially higher than those observed in critically ill COVID-19 patients without CAPA (i.e., 19-39%) and are similar to the rates Mortality rates reported for patients with influenza-associated pulmonary aspergillosis.
Panel Factors from the Education and Research Consortium of the European Organization for Research and Treatment of Cancer and Mycoses
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An important clinical manifestation of invasive aspergillosis in patients with severe viral pneumonia is invasive Aspergillus tracheobronchitis (BIAI), which is characterized by plaques in the large airways (i.e., trachea and bronchi). Although it is a known manifestation of invasive aspergillosis in lung transplant recipients, it has been reported that up to 56% of patients with influenza-associated aspergillosis present BIAI.
Epithelial erosion due to virus replication is most likely an important predisposing factor for developing BIAI, as this factor may provide a portal of entry for Aspergillus to cause invasive airway disease. BIAI has been reported in 10-20% of critically ill patients with COVID-19. The frequency of BIAI in patients with COVID-19 and COVID-associated critical illness (CAPA) could be lower than that observed in patients with influenza, but could also be underreported due to the reluctance of physicians to perform bronchoscopy in patients with COVID-19 during the first wave of the pandemic (i.e., approximately December 2019 to June 2020).
The diagnosis of BIAI is very relevant since the mortality associated with this manifestation was reported to be 90% (9 of 10) in patients with CAPA compared to 44% (11 of 25) in patients with other pulmonary manifestations, while that mortality data are scarce. for patients with severe COVID-19.
Key messages
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Pathophysiology of invasive Aspergillus tracheobronchitis (BIAI)
Invasive aspergillosis is an opportunistic infection that requires a defect in host defense to develop.
Predisposing factors that increase the risk of invasive aspergillosis have been well described in patients with hematologic malignancies and include intrinsic factors, such as acute myeloid leukemia, and extrinsic factors, such as intensive chemotherapy. Both of these factors lead to severe mucositis and a reduction in neutrophil count (i.e. granulocytopenia) and therefore pose a high risk of developing invasive aspergillosis. Additionally, impairment of neutrophil function (e.g., caused by corticosteroid treatment or chronic granulomatous disease) predisposes individuals to the development of invasive aspergillosis.
The presence of host factors has become an important criterion for the classification of patients with invasive aspergillosis and is part of case definitions.
Invasive aspergillosis secondary to severe viral infection can occur in patients with EORTC and MSGERC. host factors, but 30 to 78% of patients do not have these host factors.
Role of the virus
Human-adapted influenza A viruses preferentially bind to α2,6-linked sialic acids. Using lectins that were specific for the sialic acid α2,6-galactose sialyloligosaccharides, one study showed that epithelial cells of the trachea and bronchi, including terminal and respiratory. Bronchioles primarily express sialic acid α2,6-galactose sialyloligosaccharides (rather than sialic acid α2,3-galactose sialyloligosaccharides).
Histopathological findings of influenza A patients at autopsy showed multifocal desquamation of the epithelium, congestion, hemorrhage, and necrotrochitis. Histopathological changes involving the trachea and bronchi were observed in two-thirds of fatal cases of 2009 H1N1 influenza, indicating that the airway epithelium is commonly affected during influenza pneumonia.
Autopsy studies of patients who died from COVID-19 showed plaques in the trachea and large bronchi and microscopy showed mucosal ulceration with infiltration of mixed inflammatory cells, including neutrophils and fibrin.
Role of host defense
Lytic infection caused by influenza and SARS-CoV-2 viruses results in local innate immunodeficiency due to the loss of mechanical barrier function and the ability to produce defensins by epithelial cells. Influenza has been observed to cause more extensive lysis compared to SARS-CoV-2 which could play a role in the severity of influenza-associated tracheobronchitis.
Both COVID-19 and influenza share signs of hyperinflammation , which in some patients has features of macrophage activation syndrome , characterized by hemophagocytosis (among other features), defects in immune cell numbers (i.e., pancytopenia), and increased of ferritin concentration. This severe innate inflammatory response could play a role in tissue damage and necrosis at the site of infection, increasing the risk of invasive aspergillosis of the trachea.
COVID-19 patients and influenza patients also share an impaired adaptive immune response reflected by lymphopenia 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 usually present.
Steroids are an independent risk factor in patients with SIP ; have been associated with CAPA and may affect the ability of monocytes and macrophages to kill fungi, but may reduce the detrimental effects caused by cytokine storm syndrome. Unlike influenza pneumonia, for which steroid use is 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 trial data RECOVERY.
Fungus role
A fumigatus has been the main species reported to cause invasive aspergillosis in association with influenza and COVID-19, but other Aspergillus species can cause SIP and CAPA. Aspergillus species that may be involved in CAPA include Aspergillus flavus, Aspergillus niger, Aspergillus terreus, and Aspergillus calidoustus, but confirmed cases of BIAI due to species other than A. fumigatus have not yet been reported.
Although virulence traits have been identified in A. fumigatus, allowing the fungus to better resist environmental stressors, there is no evidence to support that specific Aspergillus genotypes cause invasive aspergillosis or IATB. Rather than the fungus itself, the effects of virus infection (e.g., local cell lysis and subsequent effects on the host, including suppression of the NADPH oxidase complex in influenza) that are caused by the initial viral infection, they are likely to determine the host’s ability to resist fungal invasion.
Angioinvasion threshold model
Insights from histopathology and observations from patient cohort studies suggest that host-virus-fungal interactions are crucial determinants of clinical disease progression and subsequently the performance of diagnostic tests.
Angioinvasion is a central feature of the pathogenesis of invasive aspergillosis leading to intravascular thrombosis and tissue infarction causing tissue necrosis and reduced leukocyte influx. Furthermore, angioinvasion is an important condition for fungal cell wall components, such as galactomannan, to be released into the circulation. The ability to reach the angioinvasion threshold can be further accelerated by treatment with neuraminidase inhibitors, ultimately leading to the increased fungal burden seen in patients with influenza compared to COVID-19.
The threshold model of angioinvasion. Factors contributing to the progression of invasive Aspergillus tracheobronchitis disease ultimately leading to angioinvasion in patients with severe COVID-19 and influenza pneumonia. Arrows indicate disease progression of invasive Aspergillus tracheobronchitis, where the infection has surpassed the threshold for angioinvasion in a case of influenza.
Management of Invasive Aspergillus Tracheobronchitis (BIAI)
Interventions to prevent the rapid progression of Aspergillus airway disease should target the four determinants that have been described:
- predisposing factors
- virus infection
- host factors
- interventions
Genetic polymorphisms and host factors EORTC and MSGERC inevitably contribute to the risk and clinical course. These aspects must be considered an a priori risk of developing a disease and cannot be modified.
Beyond these predisposing factors, the following strategies may contribute to clinical management: prevention or reduction of the severity of lytic infection with virus-directed strategies, host-directed strategies that aim to balance immune dysregulation, and therapy directed against Aspergillus. Disease-specific interventions are based on pathophysiology that is different between patients with severe COVID-19 and patients with influenza. These strategies targeting the virus, host, and fungus can be implemented as individual interventions, but will most likely be combined.
Interventions may have a beneficial effect on one factor but create a risk for another factor. For example, the neuraminidase inhibitor oseltamivir could reduce the lytic effects that are caused by influenza, but could predispose the patient to invasive aspergillosis through effects on host neuraminidase activity, its use is also has been irrevocably associated with increased risk.
Conclusions and future directions
The current knowledge of the pathophysiology of invasive Aspergillus tracheobronchitis (BIAI) in patients with COVID-19 and patients with influenza has allowed us to hypothesize that the threshold for the indication to start systemic antifungal therapy coincides with the presence or absence of angioinvasion . . It is unknown whether this hypothesis is true for all patients: not all patients present clinically with tracheobronchitis, and patients with tracheobronchitis may still have signs of invasive lung disease (shown by elevated bronchoalveolar lavage of galactomannan) that warrant administration. systemic. treatment.
Although antifungal therapy is recommended for patients with possible, probable, or proven COVID-19-associated pulmonary aspergillosis (CAPA), several studies noted that patients who were diagnosed with CAPA (based on bronchoalveolar lavage positivity) survived without receiving therapy. antifungal, most likely because the angioinvasion threshold was not reached and the risk factors, such as the virus itself, cytokine storm syndrome, and lymphopenia, were resolved.
The progression from Aspergillus colonization to tissue invasion and angioinvasion is likely a continuous process, and available diagnostic tests do not have the ability to be stage-specific. Identification of biomarkers to indicate stages of tissue invasion and airway involvement should be a priority of future studies. Furthermore, the described threshold suggests that the application of various antiviral, immunomodulatory and antifungal drugs (e.g., nebulized antifungals) may help prevent the progression of Aspergillus colonization to tissue and angioinvasive invasion.
The main challenge for future research is the design of clinical trials that take into consideration the complexity of a combined intervention at these three levels (i.e., antiviral, immunomodulatory, and antifungal) of influence on the threshold for angioinvasive disease. Ideally, intervention arms are guided by biomarkers that can be used in daily clinical practice, resulting in a true example of a personalized trial. Unfortunately, there is still no clear data that cytokines or cytokine ratio can guide immunotherapy.
Most guidance is now based on clinically used parameters. Identification of the patient’s predominant immunological status is important to guide personalized immunotherapy. Therefore, patients with an immune status that is characterized by hyperinflammation would likely benefit from anti-inflammatory therapy (e.g., anticytokine biologics) that would reduce tissue damage.
Conversely, in patients in whom immune paralysis prevails , adjuvant stimulatory immunotherapy (eg, recombinant interferon gamma) is likely to be beneficial. Future studies with personalized immunotherapy approaches should be a priority to identify the best therapeutic approaches in patients with COVID-19-associated pulmonary aspergillosis, with and without IATB.
