Oropharyngeal microbiome profiled at admission is predictive of the need for respiratory support among COVID-19 patients

  1. Evan S. Bradley
  2. Abigail L. Zeamer
  3. Vanni Bucci
  4. Lindsey Cincotta
  5. Marie-Claire Salive
  6. Protiva Dutta
  7. Shafik Mutaawe
  8. Otuwe Anya
  9. Christopher Tocci
  10. Ann Moormann
  11. Doyle V. Ward
  12. Beth A. McCormick
  13. John P. Haran

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Abstract

The oropharyngeal microbiome, the collective genomes of the community of microorganisms that colonizes the upper respiratory tract, is thought to influence the clinical course of infection by respiratory viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Infectious Disease 2019 (COVID-19). In this study, we examined the oropharyngeal microbiome of suspected COVID-19 patients presenting to the Emergency Department and an inpatient COVID-19 unit with symptoms of acute COVID-19. Of 115 initially enrolled patients, 50 had positive molecular testing for COVID-19+ and had symptom duration of 14 days or less. These patients were analyzed further as progression of disease could most likely be attributed to acute COVID-19 and less likely a secondary process. Of these, 38 (76%) went on to require some form of supplemental oxygen support. To identify functional patterns associated with respiratory illness requiring respiratory support, we applied an interpretable random forest classification machine learning pipeline to shotgun metagenomic sequencing data and select clinical covariates. When combined with clinical factors, both species and metabolic pathways abundance-based models were found to be highly predictive of the need for respiratory support (F1-score 0.857 for microbes and 0.821 for functional pathways). To determine biologically meaningful and highly predictive signals in the microbiome, we applied the Stable and Interpretable RUle Set to the output of the models. This analysis revealed that low abundance of two commensal organisms, Prevotella salivae or Veillonella infantium (< 4.2 and 1.7% respectively), and a low abundance of a pathway associated with LPS biosynthesis (< 0.1%) were highly predictive of developing the need for acute respiratory support (82 and 91.4% respectively). These findings suggest that the composition of the oropharyngeal microbiome in COVID-19 patients may play a role in determining who will suffer from severe disease manifestations.

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  1. Version published to 10.3389/fmicb.2022.1009440
  2. ScreenIT

    SciScore for 10.1101/2022.02.28.22271627: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The Institutional Review Board at the University of Massachusetts Medical School approved this study (protocol # H00020145).
    Field Sample Permit: Sample Collection and Processing: Oropharyngeal samples were collected using OMNIgene•ORAL collection kits (OMR-120, DNA Genotek).
    Sex as a biological variablenot detected.
    RandomizationFor each subset of data, the pipeline was run six times from six different random seeds and statistics for the model’s classification performance and variables contribution to class discrimination were calculated for each seed.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Sequence Processing and Analysis: Shotgun metagenomic reads were first trimmed and quality filtered to remove sequencing adapters and host contamination using Trimmomatic39 and Bowtie240, respectively, as part of the KneadData pipeline version 0.7.2 (https://huttenhower.sph.harvard.edu/kneaddata/).
    KneadData
    suggested: None
    Plots were generated in R using the ggplot2 package45 and color palettes from the calecopal package (https://github.com/an-bui/calecopal).
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Strengths and Limitations: Our strengths include our enrollment of patients within the Emergency Department during acute presentation of the disease, prospective data collection, use of metagenomic sequencing, and use of two independent analysis techniques to verify our results. The enrollment and collection of samples within the Emergency Department has allowed us to sample the microbiome of patients early in disease course before medical intervention. We excluded any patients with self-reported symptoms longer than 14 days at time of collection to focus our analysis on the acute phase of the COVID-19. Our characterization of the oropharyngeal microbiome shows us features that can be predictive of disease course and potentially a target for therapeutics. In addition, the use of metagenomic sequencing for microbiome characterization has enabled us to determine what bacterial metabolic pathways could potentially affect disease course as opposed to just genus-level information provided by 16S rRNA sequencing. Although some microbiome features were also associated with age by MaAsLin2, these represent independent associations and would have been corrected for when determining associations with the need for respiratory support. Weaknesses of this study include a single time-point in microbiome sampling from a single center and enrollment of a limiting number of patients presenting with acute COVID-19 early in the disease course. Single time-point sampling does not allow observati...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  3. Version published to 10.1101/2022.02.28.22271627 on medRxiv