{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T10:49:59Z","timestamp":1768906199845,"version":"3.49.0"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Schmidt Futures","award":["NCT04556149"],"award-info":[{"award-number":["NCT04556149"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background: In just twenty years, three dangerous human coronaviruses\u2014SARS-CoV, MERS-CoV, and SARS-CoV-2 have exposed critical gaps in early detection of emerging viral threats. Current diagnostics remain pathogen-focused, often missing the earliest phase of infection. A virus-agnostic, host-based diagnostic capable of detecting responses to viral intrusion is urgently needed. Methods: We hypothesized that the lungs act as biomechanical instruments, with infection altering tissue tension, wave propagation, and flow dynamics in ways detectable through subaudible vibroacoustic signals. In a matched case\u2013control study, we enrolled 19 RT-PCR-confirmed COVID-19 inpatients and 16 matched controls across two Johns Hopkins hospitals. Multimodal data were collected, including passive vibroacoustic auscultation, lung ultrasound, peak expiratory flow, and laboratory markers. Machine learning models were trained to identify host-response biosignatures from anterior chest recordings. Results: 19 COVID-19 inpatients and 16 matched controls (mean BMI 32.4 kg\/m2, mean age 48.6 years) were successfully enrolled to the study. The top-performing, unoptimized, vibroacoustic-only model achieved an AUC of 0.84 (95% CI: 0.67\u20130.92). The host-covariate optimized model achieved an AUC of 1.0 (95% CI: 0.94\u20131.0), with 100% sensitivity (95% CI: 82\u2013100%) and 99.6% specificity (95% CI: 85\u2013100%). Vibroacoustic data from the anterior chest alone reliably distinguished COVID-19 cases from controls. Conclusions: This proof-of-concept study demonstrates that passive, noninvasive vibroacoustic biosignatures can detect host response to viral infection in a hospitalized population and supports further testing of this modality in broader populations. These findings support the development of scalable, host-based diagnostics to enable early, agnostic detection of future pandemic threats (ClinicalTrials.gov number: NCT04556149).<\/jats:p>","DOI":"10.3390\/v17070943","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T04:35:52Z","timestamp":1751517352000},"page":"943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evidence Generation for a Host-Response Biosignature of Respiratory Disease"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-5256","authenticated-orcid":false,"given":"Kelly E.","family":"Dooley","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Level 42 AI, Inc., Mountain View, CA 94041, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Kaszuba","sequence":"additional","affiliation":[{"name":"Hylomorph Solutions, Ltd., Glasgow G2 4JR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Krasne","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6407-1874","authenticated-orcid":false,"given":"Gigi","family":"Liu","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-5788","authenticated-orcid":false,"given":"Peter","family":"Rexelius","sequence":"additional","affiliation":[{"name":"Level 42 AI, Inc., Mountain View, CA 94041, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1944-7147","authenticated-orcid":false,"given":"Jerry","family":"Swan","sequence":"additional","affiliation":[{"name":"Hylomorph Solutions, Ltd., Glasgow G2 4JR, UK"},{"name":"School of Computer Science, University of York, York YO10 5DD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5439-3231","authenticated-orcid":false,"given":"Krzysztof","family":"Krawiec","sequence":"additional","affiliation":[{"name":"Hylomorph Solutions, Ltd., Glasgow G2 4JR, UK"},{"name":"Institute of Computing Science, Poznan University of Technology, 60-965 Pozna\u0144, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Hammond","sequence":"additional","affiliation":[{"name":"Hylomorph Solutions, Ltd., Glasgow G2 4JR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1051-7260","authenticated-orcid":false,"given":"Stuart C.","family":"Ray","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5516-8367","authenticated-orcid":false,"given":"Ryan","family":"Hafen","sequence":"additional","affiliation":[{"name":"Level 42 AI, Inc., Mountain View, CA 94041, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Schuh","sequence":"additional","affiliation":[{"name":"Level 42 AI, Inc., Mountain View, CA 94041, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2111-857X","authenticated-orcid":false,"given":"Nelson L. Shasha","family":"Jumbe","sequence":"additional","affiliation":[{"name":"Level 42 AI, Inc., Mountain View, CA 94041, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/5584_2020_549","article-title":"Immune Responses to SARS-CoV, MERS-CoV and SARS-CoV-2","volume":"1288","author":"Akkoc","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20220062","DOI":"10.1098\/rsif.2022.0062","article-title":"Computational lung modelling in respiratory medicine","volume":"19","author":"Neelakantan","year":"2022","journal-title":"J. R. Soc. Interface"},{"key":"ref_3","unstructured":"Azarnoosh, J., Sreenivas, K., Arabshahi, A., and Newman, J.C. (2016). Computational Fluid Dynamics Simulation of the Airflow Through the Human Respiratory Tract. [Master\u2019s Thesis, University of Tennessee at Chattanooga]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5157","DOI":"10.1002\/j.2040-4603.2023.tb00284.x","article-title":"Mechanosensitive Channels in Lung Health and Disease","volume":"13","author":"Migulina","year":"2023","journal-title":"Compr. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"R445","DOI":"10.1016\/j.cub.2018.02.003","article-title":"Tensile Forces and Mechanotransduction at Cell\u2013Cell Junctions","volume":"28","author":"Charras","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1136\/archdischild-2013-304604","article-title":"Whistles and Wheezes: Don\u2019t Miss Diseases","volume":"100","author":"Cyriac","year":"2015","journal-title":"Arch. Dis. Child. Educ. Pract. Ed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.ccm.2021.08.007","article-title":"Pneumothorax: Classification and Etiology","volume":"42","author":"Huan","year":"2021","journal-title":"Clin. Chest Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0272-5231(21)01018-2","article-title":"Wheezing and stridor","volume":"8","author":"Hollingsworth","year":"1987","journal-title":"Clin. Chest Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.chest.2021.03.049","article-title":"Peak Inspiratory Flow as a Predictive Therapeutic Biomarker in COPD","volume":"160","author":"Mahler","year":"2021","journal-title":"Chest"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1136\/thx.26.3.288","article-title":"Breath sounds","volume":"26","author":"Forgacs","year":"1971","journal-title":"Thorax"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1111\/crj.13466","article-title":"Idiopathic pulmonary fibrosis: Current and future treatment","volume":"16","author":"Glass","year":"2022","journal-title":"Clin. Respir. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1007\/s00134-020-06048-9","article-title":"What\u2019s new in lung ultrasound during the COVID-19 pandemic","volume":"46","author":"Volpicelli","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e369","DOI":"10.7717\/peerj-cs.369","article-title":"Deep learning based respiratory sound analysis for detection of chronic obstructive pulmonary disease","volume":"7","author":"Srivastava","year":"2021","journal-title":"PeerJ Comput. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bbe.2022.08.005","article-title":"Explainable COVID-19 detection using fractal dimension and vision transformer with Grad-CAM on cough sounds","volume":"42","author":"Sobahi","year":"2022","journal-title":"Biocybern. Biomed. Eng."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cui, Y., Zhang, C., Qiao, K., Wang, L., Yan, B., and Tong, L. (2020). Study on Representation Invariances of CNNs and Human Visual Information Processing Based on Data Augmentation. Brain Sci., 10.","DOI":"10.3390\/brainsci10090602"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1053\/j.ro.2021.10.005","article-title":"Imaging Patterns of Pneumonia","volume":"57","author":"Cook","year":"2022","journal-title":"Semin. Roentgenol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1097\/CCM.0000000000005303","article-title":"Extended Lung Ultrasound to Differentiate Between Pneumonia and Atelectasis in Critically Ill Patients: A Diagnostic Accuracy Study","volume":"50","author":"Haaksma","year":"2022","journal-title":"Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.medengphy.2017.09.003","article-title":"Non-contact and through-clothing measurement of the heart rate using ultrasound vibrocardiography","volume":"50","author":"Gateau","year":"2017","journal-title":"Med. Eng. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/0002-8703(63)90078-4","article-title":"Fundamentals in vibrocardiography. Precordial accelerography and acceleration ballistocardiography","volume":"66","author":"Lohr","year":"1963","journal-title":"Am. Heart J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Will, C., Shi, K., Schellenberger, S., Steigleder, T., Michler, F., Fuchs, J., Weigel, R., Ostgathe, C., and Koelpin, A. (2018). Radar-Based Heart Sound Detection. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-29984-5"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Abbas, A.K., and Bassam, R. (2009). Phonocardiography Signal Processing, Springer International Publishing.","DOI":"10.1007\/978-3-031-01637-0"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Jaros, R., Koutny, J., Ladrova, M., and Martinek, R. (2023). Novel phonocardiography system for heartbeat detection from various locations. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-41102-8"},{"key":"ref_23","first-page":"1050","article-title":"Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency","volume":"11","author":"Agarwal","year":"2013","journal-title":"Clin. Gastroenterol. Hepatol. Off. Clin. Pract. J. Am. Gastroenterol. Assoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s11605-015-2956-3","article-title":"Postoperative Gastrointestinal Telemetry with an Acoustic Biosensor Predicts Ileus vs. Uneventful GI Recovery","volume":"20","author":"Kaneshiro","year":"2016","journal-title":"J. Gastrointest. Surg. Off. J. Soc. Surg. Aliment. Tract"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"73","DOI":"10.4236\/eng.2013.55B015","article-title":"Acoustic and Intraluminal Ultrasonic Technologies in the Diagnosis of Diseases in Gastrointestinal Tract: A Review","volume":"5","author":"Lu","year":"2013","journal-title":"Engineering"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"i969","DOI":"10.1136\/bmj.i969","article-title":"Analysis of matched case-control studies","volume":"352","author":"Pearce","year":"2016","journal-title":"Br. Med. J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Rose, S., and van der Laan, M.J. (2009). Why match? Investigating matched case-control study designs with causal effect estimation. Int. J. Biostat., 5.","DOI":"10.2202\/1557-4679.1127"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Sousa, A.I.A.D., and Duarte, E.C. (2023). Case-control and case-cohort study designs: Methodological considerations. SciELO Prepr.","DOI":"10.1590\/SciELOPreprints.7327"},{"key":"ref_29","first-page":"CD013705","article-title":"Rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection","volume":"7","author":"Dinnes","year":"2022","journal-title":"Cochrane Database Syst Rev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Arshadi, M., Fardsanei, F., Deihim, B., Farshadzadeh, Z., Nikkhahi, F., Khalili, F., Sotgiu, G., Shahidi, B.A.H., Centis, R., and Migliori, G.B. (2022). Diagnostic Accuracy of Rapid Antigen Tests for COVID-19 Detection: A Systematic Review with Meta-analysis. Front. Med., 9.","DOI":"10.3389\/fmed.2022.870738"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e51614","DOI":"10.2196\/51614","article-title":"Detecting Algorithmic Errors and Patient Harms for AI-Enabled Medical Devices in Randomized Controlled Trials: Protocol for a Systematic Review","volume":"13","author":"Kale","year":"2024","journal-title":"JMIR Res. Protoc."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kaszuba, P., Turner, A., Mikulski, B., Jumbe, N.L.S., Schuh, A., Morimoto, M., Rexelius, P., Hafen, R., Deiotte, R., and Hammond, K. (2023, January 15\u201319). Synthesizing Effective Diagnostic Models from Small Samples using Structural Machine Learning: A Case Study in Automating COVID-19 Diagnosis. Proceedings of the GECCO\u201923 Companion: Companion Conference on Genetic and Evolutionary Computation, Lisbon, Portugal.","DOI":"10.1145\/3583133.3590598"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Schuh, A., Morimoto, M., Kaszuba, P., Hammond, K., Swan, J., Krawiec, K., and Jumbe, N.L.S. (2023, January 15\u201318). Host-directed vibroacoustic biosignature of viral respiratory infection. Proceedings of the 2023 IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI), Pittsburgh, PA, USA. Sponsored by the IEEE Engineering in Medicine and Biology Society (IEEEEMBS).","DOI":"10.1109\/BHI58575.2023.10313464"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/7\/943\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:03:17Z","timestamp":1760032997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/7\/943"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,2]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["v17070943"],"URL":"https:\/\/doi.org\/10.3390\/v17070943","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,2]]}}}