Review 1: "A 5-transcript Signature for Discriminating Viral and Bacterial Etiology in Pediatric Pneumonia"

Matt Zinter

doi:doi:10.1162/2e3983f5.796bd3e9

A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia

by Sandra Viz-Lasheras, Alberto Gómez-Carballa, Jacobo Pardo-Seco, Xabier Bello, Irene Rivero-Calle, Ana Isabel Dacosta, Myrsini Kaforou, Dominic Coote, Aubrey J. Cunnington, Marieke Emonts, Jethro A. Herberg, Victoria J. Wright, Enitan D. Carrol, Stephane C. Paulus, Werner Zenz, Daniela S. Kohlfürst, Michiel Van der Flier, Ronald de Groot, Luregn J. Schlapbach, Philipp Agyeman, Andrew J. Pollard, Colin Fink, Taco T. Kuijpers, Suzanne Anderson, Cristina Calvo, María del Carmen Martínez-Padilla, Ana Pérez-Aragón, Esteban Gómez-Sánchez, Juan Valencia-Ramos, Francisco Giménez-Sánchez, Paula Alonso-Quintela, Laura Moreno-Galarraga, Ulrich von Both, Marko Pokorn, Dace Zavadska, María Tsolia, Clementien L. Vermont, Henriëtte A. Moll, Michael Levin, Federico Martinón-Torres, and Antonio Salas

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Published on Nov 05, 2024
www.medrxiv.org

Description

Abstract Pneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A, BAG3, TDRD9, MXRA7 and KLF14) that effectively distinguishes bacterial from viral pneumonia (AUC: 0.95 [0.88–1.00]) Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77–0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83–1]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments, and potentially transforming clinical practice.

RR\ID Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: In this manuscript, Viz-Lasheras and Gomez-Carballa et al describe peripheral blood transcriptomics of 192 children and identified a transcriptomic signature that differentiates pneumonia vs healthy as well as bacterial pneumonia (n=40) vs viral pneumonia (n=9). The methods are very robust and the inclusion of validation cohorts is a strength. Although the overall sample size is good, the number of patients with DV is low. The rationale is clear. My major comment is that the cohort characteristics and definitions of DB, PB, DV, PV (and how these diagnoses were made) are included in the methods at the end of the text and/or with reference to other papers but could be included upfront in the text for ease of reading. Overall this is a strong paper.

Introduction:

Comprehensive, well described

Results:

I understand the detailed cohort description is listed in the methods but please include at least some detail at the beginning of the results section, otherwise I can't really understand the context for what I am reading. Also can you comment if patients had any underlying medical comorbidity or were they all healthy?
p7, the sentence "the majority of bacterial pneumonias were caused by ... between others (35%)." What does "between others" mean? This sentence also doesn't describe how these etiologies were diagnosed -- was it by blood culture? Endotracheal aspirate? etc What about the many patients without a definite etiology?
p7, define DB, PB, DV, PV here
p9, what is severe CAP?

Discussion:

Nicely written

Methods:

p28, please define DB and DV vs PB and PV, not adequate to only cite a different paper. Please describe how co-infection was dealt with
I am familiar with all the RNAseq methods and they are done very well!

Review 1: "A 5-transcript Signature for Discriminating Viral and Bacterial Etiology in Pediatric Pneumonia"

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