Assessing the entire landscape of antifungal immune response to COVID-19-associated pulmonary aspergillosis
Authors: Florian Reizine, Jean-Marc Tadié, Murielle Grégoire, Karin Tarte, Jean-Pierre Gangneux
Journal: The Lancet Microbe (2024)

Susceptibility to invasive pulmonary aspergillosis has been linked to myeloid cell dysfunction, and patients with neutropenia are particularly at risk for these infections. Recently, Simon Feys and colleagues showed in an Article published in The Lancet Microbe that the innate immune response to Aspergillus fumigatus is essential to fight against COVID-19-associated pulmonary aspergillosis (CAPA),1Feys S Vanmassenhove S Kraisin S et al.Lower respiratory tract single-cell RNA sequencing and neutrophil extracellular trap profiling of COVID-19-associated pulmonary aspergillosis: a single centre, retrospective, observational study.Lancet Microbe. 2024; 5: e247-e260Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar highlighting local quantitative and qualitative impairments in neutrophil functions.See Online for appendix See Online for appendix However, other approaches for CAPA treatment should be considered because anti-Aspergillus immune response is now considered a continuum from innate to adaptive immune response. Besides the classically described myeloid response, other immune responses including NK cell-derived IFN-γ production and cytotoxic activity have been reported to be important against fungal infections.2Bouzani M Ok M McCormick A et al.Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-γ release.J Immunol. 2011; 187: 1369-1376Crossref PubMed Scopus (0) Google Scholar Furthermore, the crosstalk between IgG-producing B1a cells and neutrophils is essential, with an antibody-dependent neutrophil-mediated host defence against A fumigatus being profoundly affected by corticosteroid treatment.3Sarden N Sinha S Potts KG et al.A B1a-natural IgG-neutrophil axis is impaired in viral- and steroid-associated aspergillosis.Sci Transl Med. 2022; 14eabq6682Crossref PubMed Scopus (15) Google Scholar In addition, alterations of adaptive immune compartments, in particular T-cell exhaustion, are associated with severe fungal infections. PD-1 blockade in a murine model of post-sepsis aspergillosis has been shown to reinvigorate T cells and attenuate secondary aspergillosis.4Vu CTB Thammahong A Yagita H et al.Blockade of PD-1 attenuated postsepsis aspergillosis via the activation of IFN-γ and the dampening of IL-10.Shock. 2020; 53: 514-524Crossref PubMed Scopus (0) Google Scholar Altogether, these data suggest that abnormalities of the lymphoid compartments might considerably affect anti-Aspergillus response, which were not explored by Feys and colleagues. As part of a larger study of patients with COVID-19 with acute respiratory distress syndrome (ARDS) devoid of any immunosuppressive therapy (including corticosteroids),5Reizine F Lesouhaitier M Gregoire M et al.SARS-CoV-2-induced ARDS associates with MDSC expansion, lymphocyte dysfunction, and arginine shortage.J Clin Immunol. 2021; 41: 515-525Crossref PubMed Scopus (86) Google Scholar we performed a longitudinal flow cytometry phenotypic analysis of peripheral blood cell subsets from five individuals with severe CAPA and eight with severe COVID-19 without aspergillosis, with 13 healthy volunteers as controls. In this limited but homogeneous cohort, patients with CAPA were characterised by a more profound lymphopenia (appendix p 1), together with stronger quantitative and qualitative alterations of lymphoid subsets compared with those without CAPA and healthy volunteers. Moreover, at days 1 and 4 after ARDS onset, T-cell counts were lower, and the expression of PD-1 exhaustion marker on these T cells was increased (appendix p 1). NK cell counts were not differentially affected in patients with COVID-19 with or without CAPA. Nonetheless, NK cell activation, as assessed by HLA-DR expression, was lower in patients with CAPA at day 7 after diagnosis of ARDS than in patients without CAPA and healthy volunteers (appendix p 1). We believe that lymphocyte counts (NK cells and T cells) and markers of dysfunction of these cells are easy to measure in the blood. Thus, these markers should be considered for identifying critically ill COVID-19 individuals and those infected with influenza virus susceptible to Aspergillus infection. The study was funded by grants from the University Hospital of Rennes (CFTR2). JPG received Payment or honoraria for lectures, presentations from Gilead, MundiPharma, Pfizer, and Shionoghi. All other authors declare no competing interests. FR, JMT, KT, and JPG conceived, designed, coordinated the data collection and supervised the study. FR, JMT, MG, KP, KT, and JPG collected and interpreted the data. FR performed the statistical analysis. FR and JPG wrote the first draft of the Correspondence. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Download .pdf (.16 MB) Help with pdf files Supplementary appendix