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Open Access 01-12-2023 | SARS-CoV-2 | Research

Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study

Authors: Florian Voit, J. Erber, M. Feuerherd, H. Fries, N. Bitterlich, E. Diehl-Wiesenecker, S. Gladis, J. Lieb, U. Protzer, J. Schneider, F. Geisler, R. Somasundaram, R. M. Schmid, W. Bauer, C. D. Spinner

Published in: European Journal of Medical Research | Issue 1/2023

Abstract

Background

An effective testing strategy is essential for pandemic control of the novel Coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Breath gas analysis can expand the available toolbox for diagnostic tests by using a rapid, cost-beneficial, high-throughput point-of-care test. We conducted a bi-center clinical pilot study in Germany to evaluate breath gas analysis using multi-capillary column ion mobility spectrometry (MCC-IMS) to detect SARS-CoV-2 infection.

Methods

Between September 23, 2020, and June 11, 2021, breath gas measurements were performed on 380 patients (SARS-CoV-2 real-time polymerase chain reaction (PCR) positive: 186; PCR negative: 194) presenting to the emergency department (ED) with respiratory symptoms.

Results

Breath gas analysis using MCC-IMS identified 110 peaks; 54 showed statistically significant differences in peak intensity between the SARS-CoV-2 PCR-negative and PCR-positive groups. A decision tree analysis classification resulted in a sensitivity of 83% and specificity of 86%, but limited robustness to dataset changes. Modest values for the sensitivity (74%) and specificity (52%) were obtained using linear discriminant analysis. A systematic search for peaks led to a sensitivity of 77% and specificity of 67%; however, validation by transferability to other data is questionable.

Conclusions

Despite identifying several peaks by MCC-IMS with significant differences in peak intensity between PCR-negative and PCR-positive samples, finding a classification system that allows reliable differentiation between the two groups proved to be difficult. However, with some modifications to the setup, breath gas analysis using MCC-IMS may be a useful diagnostic toolbox for SARS-CoV-2 infection.

Trial registration: This study was registered at ClinicalTrials.gov on September 21, 2020 (NCT04556318; Study-ID: HC-N-H-2004).

Available only for authorised users

Johns Hopkins Coronavirus Resource Center. https://coronavirus.jhu.edu/. Accessed 15 Jan 2023.

Forni G, Mantovani A, COVID-19 Commission of Accademia Nazionale dei Lincei R. COVID-19 vaccines: where we stand and challenges ahead. Cell Death Differ. 2021;28:626–39. https://doi.org/10.1038/s41418-020-00720-9.CrossRefPubMedPubMedCentral

Fernandes Q, Inchakalody VP, Merhi M, Mestiri S, Taib N, Moustafa Abo El-Ella D, et al. Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis, therapeutics and vaccines. Ann Med. 2022. https://doi.org/10.1080/07853890.2022.2031274.CrossRefPubMedPubMedCentral

Rickman HM, Rampling T, Shaw K, Martinez-Garcia G, Hail L, Coen P, et al. Nosocomial transmission of coronavirus disease 2019: a retrospective study of 66 hospital-acquired cases in a London teaching hospital. Clin Infect Dis. 2020. https://doi.org/10.1093/cid/ciaa816.CrossRef

Abbas M, Robalo Nunes T, Martischang R, Zingg W, Iten A, Pittet D, et al. Nosocomial transmission and outbreaks of coronavirus disease 2019: the need to protect both patients and healthcare workers. Antimicrob Resist Infect Control. 2021. https://doi.org/10.1186/s13756-020-00875-7.CrossRefPubMedPubMedCentral

Crotty MP, Meyers S, Hampton N, Bledsoe S, Ritchie DJ, Buller RS, et al. Impact of antibacterials on subsequent resistance and clinical outcomes in adult patients with viral pneumonia: an opportunity for stewardship. Crit Care. 2015. https://doi.org/10.1186/s13054-015-1120-5.CrossRefPubMedPubMedCentral

Barlam TF, Cosgrove SE, Abbo LM, Macdougall C, Schuetz AN, Septimus EJ, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016. https://doi.org/10.1093/cid/ciw118.CrossRefPubMedPubMedCentral

Dinnes J, Deeks JJ, Adriano A, Berhane S, Davenport C, Dittrich S, et al. Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev. 2020. https://doi.org/10.1002/14651858.CD013705.CrossRefPubMedPubMedCentral

Vandenberg O, Martiny D, Rochas O, van Belkum A, Kozlakidis Z. Considerations for diagnostic COVID-19 tests. Nat Rev Microbiol. 2021. https://doi.org/10.1038/s41579-020-00461-z.CrossRefPubMed

10.

Diel R, Nienhaus A. Point-of-care COVID-19 antigen testing in German emergency rooms—a cost-benefit analysis. Pulmonology. 2022;28:164–72. https://doi.org/10.1016/j.pulmoe.2021.06.009.CrossRefPubMed

11.

Osterman A, Baldauf H-M, Eletreby M, Wettengel JM, Afridi SQ, Fuchs T, et al. Evaluation of two rapid antigen tests to detect SARS-CoV-2 in a hospital setting. Med Microbiol Immunol. 2021. https://doi.org/10.1007/s00430-020-00698-8.CrossRefPubMedPubMedCentral

12.

World Health Organization (WHO). Antigen-detection in the diagnosis of SARS-CoV-2 infection using rapid immunoassays. Interim Guid. 2020. p. 9. https://www.who.int/publications/i/item/antigen-detection-in-the-diagnosis-of-sars-cov-2infection-using-rapid-immunoassays. Accessed 20 Nov 2020.

13.

Paul-Ehrlich-Institut. Minimum criteria for rapid SARS-CoV-2 antigen tests pursuant to section 1 para 1 sentence 1 TestVO (statutory test regulation): rapid antigen tests (a) performance indicators. Paul-Ehrlich-Institut. 2021;2–4.

14.

Del Vecchio C, Cracknell Daniels B, Brancaccio G, Brazzale AR, Lavezzo E, Ciavarella C, et al. Impact of antigen test target failure and testing strategies on the transmission of SARS-CoV-2 variants. Nat Commun. 2022;13:5870. https://doi.org/10.1038/s41467-022-33460-0.CrossRefPubMedPubMedCentral

15.

Möckel M, Corman VM, Stegemann MS, Hofmann J, Stein A, Jones TC, et al. SARS-CoV-2 antigen rapid immunoassay for diagnosis of COVID-19 in the emergency department. Biomarkers. 2021;26:213–20. https://doi.org/10.1080/1354750X.2021.1876769.CrossRefPubMed

16.

Yang SM, Lv S, Zhang W, Cui Y. Microfluidic point-of-care (POC) devices in early diagnosis: a review of opportunities and challenges. Sensors. 2022. https://doi.org/10.3390/s22041620.CrossRefPubMedPubMedCentral

17.

Yin B, Wan X, Sohan ASMMF, Lin X. Microfluidics-based POCT for SARS-CoV-2 diagnostics. Micromachines. 2022. https://doi.org/10.3390/mi13081238.CrossRefPubMedPubMedCentral

18.

Walker HJ, Burrell MM. Could breath analysis by MS could be a solution to rapid, non-invasive testing for COVID-19? Bioanalysis. 2020. https://doi.org/10.4155/bio-2020-0125.CrossRefPubMed

19.

Cumeras R, Figueras E, Davis CE, Baumbach JI, Gràcia I. Review on ion mobility spectrometry. Part 1: current instrumentation. Analyst. 2015. https://doi.org/10.1039/c4an01100g.CrossRefPubMedPubMedCentral

20.

Cumeras R, Figueras E, Davis CE, Baumbach JI, Gràcia I. Review on ion mobility spectrometry. Part 2: hyphenated methods and effects of experimental parameters. Analyst. 2015. https://doi.org/10.1039/c4an01101e.CrossRefPubMedPubMedCentral

21.

Vautz W, Nolte J, Fobbe R, Baumbach JI. Breath analysis—Performance and potential of ion mobility spectrometry. J Breath Res. 2009. https://doi.org/10.1088/1752-7155/3/3/036004.CrossRefPubMed

22.

Amann A, Miekisch W, Schubert J, Buszewski B, Ligor T, Jezierski T, et al. Analysis of exhaled breath for disease detection. Annu Rev Anal Chem. 2014. https://doi.org/10.1146/annurev-anchem-071213-020043.CrossRef

23.

Schivo M, Aksenov AA, Linderholm AL, McCartney MM, Simmons J, Harper RW, et al. Volatile emanations from in vitro airway cells infected with human rhinovirus. J Breath Res. 2014. https://doi.org/10.1088/1752-7155/8/3/037110.CrossRefPubMedPubMedCentral

24.

Aksenov AA, Sandrock CE, Zhao W, Sankaran S, Schivo M, Harper R, et al. Cellular scent of influenza virus infection. ChemBioChem. 2014;15:1040–8. https://doi.org/10.1002/cbic.201300695.CrossRefPubMedPubMedCentral

25.

Purcaro G, Rees CA, Wieland-Alter WF, Schneider MJ, Wang X, Stefanuto PH, et al. Volatile fingerprinting of human respiratory viruses from cell culture. J Breath Res. 2018. https://doi.org/10.1088/1752-7163/aa9eef.CrossRefPubMedPubMedCentral

26.

Bos LDJ, Sterk PJ, Schultz MJ. Volatile metabolites of pathogens: a systematic review. PLoS Pathog. 2013. https://doi.org/10.1371/journal.ppat.1003311.CrossRefPubMedPubMedCentral

27.

Gould O, Ratcliffe N, Król E, De Lacy Costello B. Breath analysis for detection of viral infection, the current position of the field. J Breath Res. 2020. https://doi.org/10.1088/1752-7163/ab9c32.CrossRefPubMed

28.

Feuerherd M, Sippel AK, Erber J, Baumbach JI, Schmid RM, Protzer U, et al. A proof of concept study for the differentiation of SARS-CoV-2, hCoV-NL63, and IAV-H1N1 in vitro cultures using ion mobility spectrometry. Sci Rep. 2021. https://doi.org/10.1038/s41598-021-99742-7.CrossRefPubMedPubMedCentral

29.

Chen H, Qi X, Ma J, Zhang C, Feng H, Yao M. Breath-borne VOC biomarkers for COVID-19. medRxiv. 2020. https://doi.org/10.1101/2020.06.21.20136523.CrossRefPubMedPubMedCentral

30.

Ruszkiewicz DM, Sanders D, O’Brien R, Hempel F, Reed MJ, Riepe AC, et al. Diagnosis of COVID-19 by analysis of breath with gas chromatography-ion mobility spectrometry—a feasibility study. EClinicalMedicine. 2020. https://doi.org/10.1016/j.eclinm.2020.100609.CrossRefPubMed

31.

Steppert C, Steppert I, Sterlacci W, Bollinger T. Rapid detection of SARS-CoV-2 infection by multicapillary column coupled ion mobility spectrometry (MCC-IMS) of breath. A proof of concept study. J Breath Res. 2021. https://doi.org/10.1088/1752-7163/abe5ca.CrossRefPubMed

32.

Ibrahim W, Cordell RL, Wilde MJ, Richardson M, Carr L, Sundari Devi Dasi A, et al. Diagnosis of COVID-19 by exhaled breath analysis using gas chromatography–mass spectrometry. ERJ Open Res. 2021. https://doi.org/10.1183/23120541.00139-2021.CrossRefPubMedPubMedCentral

33.

Grassin-Delyle S, Roquencourt C, Moine P, Saffroy G, Carn S, Heming N, et al. Metabolomics of exhaled breath in critically ill COVID-19 patients: a pilot study. EBioMedicine. 2021. https://doi.org/10.1016/j.ebiom.2020.103154.CrossRefPubMed

34.

Shan B, Broza YY, Li W, Wang Y, Wu S, Liu Z, et al. Multiplexed nanomaterial-based sensor array for detection of COVID-19 in exhaled breath. ACS Nano. 2020;14:12125–32. https://doi.org/10.1021/acsnano.0c05657.CrossRefPubMed

35.

Wintjens AGWE, Hintzen KFH, Engelen SME, Lubbers T, Savelkoul PHM, Wesseling G, et al. Applying the electronic nose for pre-operative SARS-CoV-2 screening. Surg Endosc. 2020. https://doi.org/10.1007/s00464-020-08169-0.CrossRefPubMedPubMedCentral

36.

de Vries R, Vigeveno RM, Mulder S, Farzan N, Vintges DR, Goeman JJ, et al. Ruling out SARS-CoV-2 infeciton using exhaled breath analysis by electronic nose in a public health setting. medRxiv. 2021. https://doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a3768.CrossRef

37.

Baizyldayeva UB, Uskenbayeva RK, Amanzholova ST. Decision making procedure: applications of IBM SPSS cluster analysis and decision tree. World Appl Sci J. 2013;21:1207–12. https://doi.org/10.5829/idosi.wasj.2013.21.8.2913.CrossRef

38.

Public Health England. Understanding cycle threshold (Ct) in SARS-CoV-2 RT-PCR: a guide for health protection teams. Public Heal Engl; 2020. p. 1–12.

39.

RKI—Coronavirus SARS-CoV-2—Empfehlungen zu Isolierung und Quarantäne bei SARS-CoV-2-Infektion und -Exposition, Stand 2.5.2022. https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Quarantaene/Absonderung.html;jsessionid=1FC86EBE9E72AA0888DD33D7C7E5F806.internet082?nn=13490888. Accessed 26 May 2022.

40.

Subali AD, Wiyono L, Yusuf M, Zaky MFA. The potential of volatile organic compounds-based breath analysis for COVID-19 screening: a systematic review & meta-analysis. Diagn Microbiol Infect Dis. 2022. https://doi.org/10.1016/j.diagmicrobio.2021.115589.CrossRefPubMed

41.

Nurputra DK, Kusumaatmaja A, Hakim MS, Hidayat SN, Julian T, Sumanto B, et al. Fast and noninvasive electronic nose for sniffing out COVID-19 based on exhaled breath-print recognition. NPJ Digit Med. 2022;5:1–17. https://doi.org/10.1038/s41746-022-00661-2.CrossRef

42.

Lee Y, Min P, Lee S, Kim SW. Prevalence and duration of acute loss of smell or taste in COVID-19 patients. J Korean Med Sci. 2020. https://doi.org/10.3346/JKMS.2020.35.E174.CrossRefPubMedPubMedCentral

43.

Hosny A, Parmar C, Quackenbush J, Schwartz LH, Aerts HJWL. Artificial intelligence in radiology. Nat Rev Cancer. 2018. https://doi.org/10.1038/s41568-018-0016-5.CrossRefPubMedPubMedCentral

44.

Kaissis G, Ziller A, Passerat-Palmbach J, Ryffel T, Usynin D, Trask A, et al. End-to-end privacy preserving deep learning on multi-institutional medical imaging. Nat Mach Intell. 2021;3:473–84. https://doi.org/10.1038/s42256-021-00337-8.CrossRef

45.

Robert Koch Institut. Bericht zu Virusvarianten von SARS-CoV-2 in Deutschland. Robert Koch Inst. 2021;2:1–19.

Title: Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study
Authors: Florian Voit
J. Erber
M. Feuerherd
H. Fries
N. Bitterlich
E. Diehl-Wiesenecker
S. Gladis
J. Lieb
U. Protzer
J. Schneider
F. Geisler
R. Somasundaram
R. M. Schmid
W. Bauer
C. D. Spinner
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: SARS-CoV-2
Polymerase Chain Reaction
COVID-19
Care
Published in: European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI: https://doi.org/10.1186/s40001-023-01284-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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