Pathogenesis of Respiratory Viral and Fungal Coinfections

Salazar, Fabián; Bignell, Elaine; Brown, Gordon D.; Cook, Peter C.; Warris, Adilia

doi:10.1128/cmr.00094-21

Cited by 89 publications

(81 citation statements)

References 575 publications

(597 reference statements)

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“…It has been suggested that COVID-19-associated pulmonary aspergillosis (CAPA) is a contributing factor to mortality in patients with severe COVID-19 (Salazar et al, 2021). In our series, 7.69% of the patients showed CAPA.…”

Section: Discussionmentioning

confidence: 56%

RNA SARS-CoV-2 Persistence in the Lung of Severe COVID-19 Patients: A Case Series of Autopsies

et al. 2022

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The exact role of viral replication in patients with severe COVID-19 has not been extensively studied, and it has only been possible to demonstrate the presence of replicative virus for more than 3 months in a few cases using different techniques. Our objective was to study the presence of RNA SARS-CoV-2 in autopsy samples of patients who died from COVID-19 long after the onset of symptoms. Secondary superimposed pulmonary infections present in these patients were also studied. We present an autopsy series of 27 COVID-19 patients with long disease duration, where pulmonary and extrapulmonary samples were obtained. In addition to histopathological analysis, viral genomic RNA (gRNA) and viral subgenomic RNA (sgRNA) were detected using RT-PCR and in situ hybridization, and viral protein was detected using immunohistochemistry. This series includes 26 adults with a median duration of 39 days from onset of symptoms to death (ranging 9–108 days), 92% of them subjected to immunomodulatory therapy, and an infant patient. We detected gRNA in the lung of all but one patient, including those with longer disease duration. SgRNA was detected in 11 out of 17 patients (64.7%) with illness duration up to 6 weeks and in 3 out of 9 patients (33.3%) with more than 6 weeks of disease progression. Viral protein was detected using immunohistochemistry and viral mRNA was detected using in situ hybridization in 3 out of 4 adult patients with illness duration of <2 weeks, but in none of the 23 adult patients with an illness duration of >2 weeks. A remarkable result was the detection of viral protein, gRNA and sgRNA in the lung cells of the pediatric patient after 95 days of illness. Additional pulmonary infections included: 9 acute bronchopneumonia, 2 aspergillosis, 2 cytomegalovirus, and 1 BK virus infection. These results suggest that in severe COVID-19, SARS-CoV-2 could persist for longer periods than expected, especially in immunocompromised populations, contributing to the persistence of chronic lung lesions. Additional infections contribute to the fatal course of the disease.

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Section: Discussionmentioning

confidence: 56%

RNA SARS-CoV-2 Persistence in the Lung of Severe COVID-19 Patients: A Case Series of Autopsies

et al. 2022

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“…The significant lower number of alveolar macrophages in non-treated mice could point to a potential immune dysregulation through which influenza predisposes to a fungal superinfection. It is known that type I IFN induced by influenza can inhibit the production of the chemokine CCL2, which is important for macrophage recruitment [31,32]. Besides an effect on recruitment, influenza virus infection can result in depletion of alveolar macrophages and can impair the macrophage phago-cytic activity important for fungal clearance [31][32][33].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that type I IFN induced by influenza can inhibit the production of the chemokine CCL2, which is important for macrophage recruitment [31,32]. Besides an effect on recruitment, influenza virus infection can result in depletion of alveolar macrophages and can impair the macrophage phago-cytic activity important for fungal clearance [31][32][33]. However, further comprehensive immunological studies are needed to identify the immunological mechanism behind IAPA.…”

Section: Discussionmentioning

confidence: 99%

Overcome Double Trouble: Baloxavir Marboxil Suppresses Influenza Thereby Mitigating Secondary Invasive Pulmonary Aspergillosis

Seldeslachts

Jacobs

Tielemans

et al. 2021

JoF

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Influenza-associated pulmonary aspergillosis (IAPA) is a global recognized superinfection in critically ill influenza patients. Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is a newly approved anti-influenza therapeutic. Although the benefits as a treatment for influenza are clear, its efficacy against an influenza-A. fumigatus co-infection has yet to be determined. We investigated the therapeutic effect of baloxavir marboxil in a murine model for IAPA. Immunocompetent mice received intranasal instillation of influenza A followed by orotracheal inoculation with Aspergillus fumigatus 4 days later. Administration of baloxavir marboxil or sham was started at day 0, day 2 or day 4. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (µCT) and fungal burden with bioluminescence imaging (BLI). In vivo imaging was supplemented with virological, mycological and biochemical endpoint investigations. We observed an improved body weight, survival and viral clearance in baloxavir marboxil treated mice. µCT showed less pulmonary lesions and bronchial dilation after influenza and after Aspergillus co-infection in a treatment-dependent pattern. Furthermore, baloxavir marboxil was associated with effective inhibition of fungal invasion. Hence, our results provide evidence that baloxavir marboxil mitigates severe influenza thereby decreasing the susceptibility to a lethal invasive Aspergillus superinfection.

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“…Importantly, the incidence of CAPA varies considerably among countries and units and is likely underdiagnosed, further contributing to the poor outcomes observed [ 9 , 10 , 11 , 12 ]. While this is a new entity, it is important to recognise a similar presentation is well described in post influenza patients [ 13 ]. Both of these entities are associated with increased mortality, morbidity, duration of hospital stay and mechanical ventilation duration [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Associated Immune Dysregulation and COVID-Associated Pulmonary Aspergilliosis (CAPA): A Cautionary Tale

Worku

2022

IJMS

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As the global SARS-CoV-2 pandemic continues to plague healthcare systems, it has become clear that opportunistic pathogens cause a considerable proportion of SARS-CoV-2-associated mortality and morbidity cases. Of these, Covid-Associated Pulmonary Aspergilliosis (CAPA) is a major concern with evidence that it occurs in the absence of traditional risk factors such as neutropenia and is diagnostically challenging for the attending physician. In this review, we focus on the immunopathology of SARS-CoV-2 and how this potentiates CAPA through dysregulation of local and systemic immunity as well as the unintended consequences of approved COVID treatments including corticosteroids and IL-6 inhibitors. Finally, we will consider how knowledge of the above may aid in the diagnosis of CAPA using current diagnostics and what treatment should be instituted in probable and confirmed cases.

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Pathogenesis of Respiratory Viral and Fungal Coinfections

Abstract: Individuals suffering from severe viral respiratory tract infections have recently emerged as “at risk” groups for developing invasive fungal infections. Influenza virus is one of the most common causes of acute lower respiratory tract infections worldwide.

Cited by 89 publications

References 575 publications

RNA SARS-CoV-2 Persistence in the Lung of Severe COVID-19 Patients: A Case Series of Autopsies

RNA SARS-CoV-2 Persistence in the Lung of Severe COVID-19 Patients: A Case Series of Autopsies

Overcome Double Trouble: Baloxavir Marboxil Suppresses Influenza Thereby Mitigating Secondary Invasive Pulmonary Aspergillosis

SARS-CoV-2 Associated Immune Dysregulation and COVID-Associated Pulmonary Aspergilliosis (CAPA): A Cautionary Tale

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