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.

The authors have declared no competing interest.

This work was supported by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS project (Grant Agreement number 279185) and the European Union's Horizon 2020 research and innovation programme under Grant Agreement Nos. 668303 (PERFORM) and 848196 (DIAMONDS). This study also received support by i) ISCIII: TRINEO: PI22/00162; DIAVIR: DTS19/00049; Resvi-Omics: PI19/01039 (to A.S.), ReSVinext: PI16/01569, Enterogen: PI19/01090, OMI-COVI-VAC: PI22/00406 (to F.M.-T.), cofinanciados FEDER, ii) GAIN: IN607B 2020/08 and IN607A 2023/02 (to A.S.), GEN-COVID (IN845D 2020/23 (to F.M.-T.), IIN607A2021/05 (to F.M.-T.); iii) ACIS: BI-BACVIR (PRIS-3, to A.S.), CovidPhy (SA 304 C, to A.S.); iv) Spanish Ministry of Science and Innovation (MCIN)/Spanish Research Agency (AEI) (PID2022-142156OB-I00, to AG-C); and v) consorcio Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CB21/06/00103; to A.S. and F.M.-T.). AGC is supported by the Miguel Servet programme (CP23/00080) contract, funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Written, informed consent was obtained from parents or guardians at all sites using locally approved permissions (St Mary's Research Ethics Committee (REC 09/H0712/58); Ethical Committee of Clinical Investigation of Galicia (CEIC ref 2010/015); Amsterdam, the Netherlands (NL41023.018.12 and NL34230.018.10); the University of California San Diego (Human Research Protection Program 140220); The Gambia Government/MRC Joint Ethics (Committee reference L2013.07V2); Cape Town, South Africa (HREC No 389/2017 linked to No 045/2008); Cantonal Ethics Committee Bern (KEK-029); also refer to study protocol DIAMONDS: register ISRCTN12394803. https://doi.org/10.1186/ISRCTN12394803; study protocol EUCLIDS: see DOI: 10.1016/S2352-4642(18)30113-5; study protocol PERFORM: see DOI: 10.1093/cid/ciad615.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors