Severe dysbiosis and specific Haemophilus and Neisseria signatures as hallmarks of the oropharyngeal microbiome in critically ill COVID-19 patients

Juliana de Castilhos; Eli Zamir; Theresa Hippchen; Roman Rohrbach; Sabine Schmidt; Silvana Hengler; Hanna Schumacher; Melanie Neubauer; Sabrina Kunz; Tonia Müller-Esch; Andreas Hiergeist; André Gessner; Dina Khalid; Rogier Gaiser; Nyssa Cullin; Stamatia M Papagiannarou; Bettina Beuthien-Baumann; Alwin Krämer; Ralf Bartenschlager; Dirk Jäger; Michael Müller; Felix Herth; Daniel Duerschmied; Jochen Schneider; Roland M Schmid; Johann F Eberhardt; Yascha Khodamoradi; Maria J G T Vehreschild; Andreas Teufel; Matthias P Ebert; Peter Hau; Bernd Salzberger; Paul Schnitzler; Hendrik Poeck; Eran Elinav; Uta Merle; Christoph K Stein-Thoeringer

doi:10.1093/cid/ciab902

. 2021 Oct 25:ciab902. doi: 10.1093/cid/ciab902

Severe dysbiosis and specific Haemophilus and Neisseria signatures as hallmarks of the oropharyngeal microbiome in critically ill COVID-19 patients

Juliana de Castilhos ^1,^22,^#, Eli Zamir ^1,^#, Theresa Hippchen ^2,^#, Roman Rohrbach ^1,^#, Sabine Schmidt ¹, Silvana Hengler ¹, Hanna Schumacher ¹, Melanie Neubauer ³, Sabrina Kunz ⁴, Tonia Müller-Esch ⁴, Andreas Hiergeist ⁵, André Gessner ⁵, Dina Khalid ⁶, Rogier Gaiser ¹, Nyssa Cullin ¹, Stamatia M Papagiannarou ¹, Bettina Beuthien-Baumann ⁷, Alwin Krämer ⁸, Ralf Bartenschlager ^9,¹⁰, Dirk Jäger ¹¹, Michael Müller ¹², Felix Herth ¹², Daniel Duerschmied ¹³, Jochen Schneider ¹⁴, Roland M Schmid ¹⁴, Johann F Eberhardt ¹⁵, Yascha Khodamoradi ¹⁵, Maria J G T Vehreschild ^15,¹⁶, Andreas Teufel ¹⁷, Matthias P Ebert ¹⁷, Peter Hau ¹⁸, Bernd Salzberger ¹⁹, Paul Schnitzler ⁶, Hendrik Poeck ^4,²⁰, Eran Elinav ^1,^21,^#, Uta Merle ^2,^#, Christoph K Stein-Thoeringer ^1,^11,^#,^✉

¹German Cancer Research Center (DKFZ), Research Division Microbiome and Cancer, Heidelberg, Germany

²Department of Gastroenterology and Infectious Diseases, University Clinic Heidelberg, Heidelberg, Germany

³Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

⁴Department of Internal Medicine III, University Clinic Regensburg, Regensburg, Germany

⁵Institute of Clinical Microbiology and Hygiene, University Clinic Regensburg, Regensburg, Germany

⁶Department of Virology, University Clinic Heidelberg, Heidelberg, Germany

⁷German Cancer Research Center (DKFZ), Research Division Radiology, Heidelberg, Germany

⁸German Cancer Research Center (DKFZ), Research Division Molecular Hematology/Oncology, Heidelberg, Germany

⁹Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany

¹⁰German Cancer Research Center (DKFZ), Research Division Virus-associated Carcinogenesis, Heidelberg

¹¹National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany

¹²Thoraxklinik and Translational Lung Research Center, Heidelberg University, Heidelberg, Germany

¹³Department of Internal Medicine III, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

¹⁴Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

¹⁵Department of Internal Medicine, Infectious Diseases, University Hospital Frankfurt, Frankfurt, Germany

¹⁶German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany

¹⁷Department of Medicine II, Section of Hepatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, and Center for Preventive Medicine and Digital Health Baden-Württemberg, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

¹⁸Wilhelm Sander-NeuroOncology Unit and Department of Neurology, University Clinic Regensburg, Regensburg, Germany

¹⁹Department of Infectious Disease, University Clinic Regensburg, Regensburg, Germany

²⁰National Center for Tumor Diseases (NCT) WERA

²¹Weizmann Institute of Science, Rehovot, Israel

²²Vale do Rio dos Sinos University (UNISINOS), Sao Leopoldo, Brazil

contributed equally

^✉

Corresponding author: Christoph K. Stein-Thoeringer, MD, Microbiome and Cancer Research Division, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany, Email: c.stein-thoeringer@dkfz.de

PMCID: PMC8586732 PMID: 34694375

Abstract

Background

At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with Coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict COVID-19 illness. However, the results are not conclusive, as critical illness can drastically alter a patient’s microbiome through multiple confounders.

Methods

To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 (n=322 participants).

Results

In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features.

Conclusion

In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.

Keywords: SARS-CoV-2, COVID-19, microbiome, dysbiosis, intensive medical care, machine learning

Supplementary Material

ciab902_suppl_Supplementary_Materials_1

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ciab902_suppl_Supplementary_Materials_1

Click here for additional data file.^{(1.8MB, docx)}

PERMALINK

Severe dysbiosis and specific Haemophilus and Neisseria signatures as hallmarks of the oropharyngeal microbiome in critically ill COVID-19 patients

Juliana de Castilhos, PhD

Eli Zamir, PhD

Theresa Hippchen, MD

Roman Rohrbach

Sabine Schmidt

Silvana Hengler

Hanna Schumacher

Melanie Neubauer

Sabrina Kunz

Tonia Müller-Esch

Andreas Hiergeist, PhD

André Gessner, MD PhD

Dina Khalid, MD

Rogier Gaiser, PhD

Nyssa Cullin, PhD

Stamatia M Papagiannarou

Bettina Beuthien-Baumann, MD

Alwin Krämer, MD

Ralf Bartenschlager, PhD

Dirk Jäger, MD

Michael Müller, MD

Felix Herth, MD

Daniel Duerschmied, MD

Jochen Schneider, MD

Roland M Schmid, MD

Johann F Eberhardt

Yascha Khodamoradi, MD

Maria J G T Vehreschild, MD

Andreas Teufel, MD

Matthias P Ebert, MD

Peter Hau, MD

Bernd Salzberger, MD

Paul Schnitzler, PhD

Hendrik Poeck, MD

Eran Elinav, MD PhD

Uta Merle, MD

Christoph K Stein-Thoeringer, MD

Abstract

Background

Methods

Results

Conclusion

Supplementary Material

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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