Integrating genetic and immune factors to uncover pathogenetic mechanisms of viral-associated pulmonary aspergillosis

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ABSTRACT

Invasive pulmonary aspergillosis is a severe fungal infection primarily affecting immunocompromised patients. Individuals with severe viral infections have recently been identified as vulnerable to developing invasive fungal infections. Both influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are linked to high mortality rates, emphasizing the urgent need for an improved understanding of disease pathogenesis to unveil new molecular targets with diagnostic and therapeutic potential. The recent establishment of animal models replicating the co-infection context has offered crucial insights into the mechanisms that underlie susceptibility to disease. However, the development and progression of human viral-fungal co-infections exhibit a significant degree of interindividual variability, even among patients with similar clinical conditions. This observation implies a significant role for host genetics, but information regarding the genetic basis for viral-fungal co-infections is currently limited. In this review, we discuss how genetic factors known to affect either antiviral or antifungal immunity could potentially reveal pathogenetic mechanisms that predispose to IAPA or CAPA and influence the overall disease course. These insights are anticipated to foster further research in both pre-clinical models and human patients, aiming to elucidate the complex pathophysiology of viral-associated pulmonary aspergillosis and contributing to the identification of new diagnostic and therapeutic targets to improve the management of these co-infections.

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Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Mark Peters (2021)

Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)

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Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

(2021)

Abstract Background The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. Methods We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support–free days, on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both. Results Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 (interquartile range, −1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, −1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists. Conclusions In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.)

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Proteomic and Metabolomic Characterization of COVID-19 Patient Sera

Bo Shen, Xiao Yi, Yaoting Sun … (2020)

Summary Early detection and effective treatment of severe COVID-19 patients remain major challenges. Here, we performed proteomic and metabolomic profiling of sera from 46 COVID-19 and 53 control individuals. We then trained a machine learning model using proteomic and metabolomic measurements from a training cohort of 18 non-severe and 13 severe patients. The model was validated using ten independent patients, seven of which were correctly classified. Targeted proteomics and metabolomics assays were employed to further validate this molecular classifier in a second test cohort of 19 new COVID-19 patients, leading to 16 correct assignments. We identified molecular changes in the sera of COVID-19 patients compared to other groups implicating dysregulation of macrophage, platelet degranulation and complement system pathways, and massive metabolic suppression. This study revealed characteristic protein and metabolite changes in the sera of severe COVID-19 patients, which might be used in selection of potential blood biomarkers for severity evaluation.

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Author and article information

Contributors

Agostinho Carvalho:

ORCID: https://orcid.org/0000-0001-8935-8030

Marcio Rodrigues: Role: Editor

Journal

Journal ID (nlm-ta): mBio

Journal ID (iso-abbrev): mBio

Journal ID (publisher-id): mbio

Title: mBio

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2150-7511

Publication date (Electronic, collection): June 2024

Publication date (Electronic, pub): 23 April 2024

Publication date PMC-release: 23 April 2024

Volume: 15

Issue: 6

Electronic Location Identifier: e01982-23

Affiliations

[1 ]Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho; , Braga, Portugal

[2 ]ICVS/3B’s-PT Government Associate Laboratory; , Guimarães/Braga, Portugal

[3 ]Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven; , Leuven, Belgium

[4 ]Department of Microbiology, Immunology and Transplantation, KU Leuven; , Leuven, Belgium

[5 ]Laboratory of Clinical Microbiology and Microbial Pathogenesis, School of Medicine, University of Crete; , Heraklion, Crete, Greece

[6 ]Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology; , Heraklion, Crete, Greece

[7 ]Division of Infectious Diseases, ECMM Excellence Center for Medical Mycology, Department of Internal Medicine, Medical University of Graz; , Graz, Austria

[8 ]BioTechMed; , Graz, Austria

[9 ]Department of Internal Medicine, Radboud University Nijmegen Medical Centre; , Nijmegen, the Netherlands

[10 ]Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre; , Nijmegen, the Netherlands

Instituto Carlos Chagas; , Curitiba, Brazil

Author notes

Address correspondence to Agostinho Carvalho, agostinhocarvalho@ 123456med.uminho.pt

Samuel M. Gonçalves and Inês Pereira contributed equally to this article. Author order was determined in order of decreasing time committed to writing the article.

S.F. received travel grants for conference attendance from Pfizer and Gilead and a speaker fee from The Healthbook Company. M.H. received grants and research funding from Astellas, Gilead, MSD, Pfizer, Euroimmun, F2G, Pulmocide, AiCuris, Partners, IMMY, Melinta, Mundipharma, Shionogi, and Scynexis. J.W. received an institutional research fund from Pfizer, investigator-initiated grants from Pfizer, Gilead, and MSD, and speaker and travel fees from Pfizer, Gilead, and MSD. J.W. also declares participation in advisory boards of Pfizer and Gilead and receipt of study drugs from MSD. A.C. received a speaker fee from Gilead.

Author information

Georgios Chamilos https://orcid.org/0000-0002-7987-4055

Agostinho Carvalho https://orcid.org/0000-0001-8935-8030

Article

Publisher ID: 01982-23 Publisher ID: mbio.01982-23

DOI: 10.1128/mbio.01982-23

PMC ID: 11237550

PubMed ID: 38651925

SO-VID: 5894946c-843e-490c-ab13-8d7ed7c17a27

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.