Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis

M. R. Wilson, H. A. Sample, K. C. Zorn, S. Arevalo, G. Yu, J. Neuhaus, S. Federman, D. Stryke, B. Briggs, C. Langelier, A. Berger, V. Douglas, S. A. Josephson, F. C. Chow, B. D. Fulton, J. L. DeRisi, J. M. Gelfand, S. N. Naccache, J. Bender, J. Dien Bard & 23 others J. Murkey, M. Carlson, P. M. Vespa, T. Vijayan, P. R. Allyn, S. Campeau, R. M. Humphries, J. D. Klausner, C. D. Ganzon, F. Memar, N. A. Ocampo, Lara Zimmermann, Stuart H Cohen, Christopher R Polage, R. L. DeBiasi, B. Haller, R. Dallas, G. Maron, R. Hayden, K. Messacar, S. R. Dominguez, S. Miller, C. Y. Chiu

Research output: Contribution to journalArticle

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Abstract

BACKGROUND Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases.

Original languageEnglish (US)
Pages (from-to)2327-2340
Number of pages14
JournalNew England Journal of Medicine
Volume380
Issue number24
DOIs
StatePublished - Jun 13 2019

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Metagenomics
Encephalitis
Meningitis
Cerebrospinal Fluid
Infection
Nervous System
Telecommunications
Multicenter Studies
Intensive Care Units
Prospective Studies
Pediatrics
Physicians
Mortality

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wilson, M. R., Sample, H. A., Zorn, K. C., Arevalo, S., Yu, G., Neuhaus, J., ... Chiu, C. Y. (2019). Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. New England Journal of Medicine, 380(24), 2327-2340. https://doi.org/10.1056/NEJMoa1803396

Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. / Wilson, M. R.; Sample, H. A.; Zorn, K. C.; Arevalo, S.; Yu, G.; Neuhaus, J.; Federman, S.; Stryke, D.; Briggs, B.; Langelier, C.; Berger, A.; Douglas, V.; Josephson, S. A.; Chow, F. C.; Fulton, B. D.; DeRisi, J. L.; Gelfand, J. M.; Naccache, S. N.; Bender, J.; Dien Bard, J.; Murkey, J.; Carlson, M.; Vespa, P. M.; Vijayan, T.; Allyn, P. R.; Campeau, S.; Humphries, R. M.; Klausner, J. D.; Ganzon, C. D.; Memar, F.; Ocampo, N. A.; Zimmermann, Lara; Cohen, Stuart H; Polage, Christopher R; DeBiasi, R. L.; Haller, B.; Dallas, R.; Maron, G.; Hayden, R.; Messacar, K.; Dominguez, S. R.; Miller, S.; Chiu, C. Y.

In: New England Journal of Medicine, Vol. 380, No. 24, 13.06.2019, p. 2327-2340.

Research output: Contribution to journalArticle

Wilson, MR, Sample, HA, Zorn, KC, Arevalo, S, Yu, G, Neuhaus, J, Federman, S, Stryke, D, Briggs, B, Langelier, C, Berger, A, Douglas, V, Josephson, SA, Chow, FC, Fulton, BD, DeRisi, JL, Gelfand, JM, Naccache, SN, Bender, J, Dien Bard, J, Murkey, J, Carlson, M, Vespa, PM, Vijayan, T, Allyn, PR, Campeau, S, Humphries, RM, Klausner, JD, Ganzon, CD, Memar, F, Ocampo, NA, Zimmermann, L, Cohen, SH, Polage, CR, DeBiasi, RL, Haller, B, Dallas, R, Maron, G, Hayden, R, Messacar, K, Dominguez, SR, Miller, S & Chiu, CY 2019, 'Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis', New England Journal of Medicine, vol. 380, no. 24, pp. 2327-2340. https://doi.org/10.1056/NEJMoa1803396
Wilson MR, Sample HA, Zorn KC, Arevalo S, Yu G, Neuhaus J et al. Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. New England Journal of Medicine. 2019 Jun 13;380(24):2327-2340. https://doi.org/10.1056/NEJMoa1803396
Wilson, M. R. ; Sample, H. A. ; Zorn, K. C. ; Arevalo, S. ; Yu, G. ; Neuhaus, J. ; Federman, S. ; Stryke, D. ; Briggs, B. ; Langelier, C. ; Berger, A. ; Douglas, V. ; Josephson, S. A. ; Chow, F. C. ; Fulton, B. D. ; DeRisi, J. L. ; Gelfand, J. M. ; Naccache, S. N. ; Bender, J. ; Dien Bard, J. ; Murkey, J. ; Carlson, M. ; Vespa, P. M. ; Vijayan, T. ; Allyn, P. R. ; Campeau, S. ; Humphries, R. M. ; Klausner, J. D. ; Ganzon, C. D. ; Memar, F. ; Ocampo, N. A. ; Zimmermann, Lara ; Cohen, Stuart H ; Polage, Christopher R ; DeBiasi, R. L. ; Haller, B. ; Dallas, R. ; Maron, G. ; Hayden, R. ; Messacar, K. ; Dominguez, S. R. ; Miller, S. ; Chiu, C. Y. / Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. In: New England Journal of Medicine. 2019 ; Vol. 380, No. 24. pp. 2327-2340.
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abstract = "BACKGROUND Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5{\%} had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3{\%}. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9{\%}). Among these 58 infections, metagenomic NGS identified 13 (22{\%}) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78{\%}), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases.",
author = "Wilson, {M. R.} and Sample, {H. A.} and Zorn, {K. C.} and S. Arevalo and G. Yu and J. Neuhaus and S. Federman and D. Stryke and B. Briggs and C. Langelier and A. Berger and V. Douglas and Josephson, {S. A.} and Chow, {F. C.} and Fulton, {B. D.} and DeRisi, {J. L.} and Gelfand, {J. M.} and Naccache, {S. N.} and J. Bender and {Dien Bard}, J. and J. Murkey and M. Carlson and Vespa, {P. M.} and T. Vijayan and Allyn, {P. R.} and S. Campeau and Humphries, {R. M.} and Klausner, {J. D.} and Ganzon, {C. D.} and F. Memar and Ocampo, {N. A.} and Lara Zimmermann and Cohen, {Stuart H} and Polage, {Christopher R} and DeBiasi, {R. L.} and B. Haller and R. Dallas and G. Maron and R. Hayden and K. Messacar and Dominguez, {S. R.} and S. Miller and Chiu, {C. Y.}",
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TY - JOUR

T1 - Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis

AU - Wilson, M. R.

AU - Sample, H. A.

AU - Zorn, K. C.

AU - Arevalo, S.

AU - Yu, G.

AU - Neuhaus, J.

AU - Federman, S.

AU - Stryke, D.

AU - Briggs, B.

AU - Langelier, C.

AU - Berger, A.

AU - Douglas, V.

AU - Josephson, S. A.

AU - Chow, F. C.

AU - Fulton, B. D.

AU - DeRisi, J. L.

AU - Gelfand, J. M.

AU - Naccache, S. N.

AU - Bender, J.

AU - Dien Bard, J.

AU - Murkey, J.

AU - Carlson, M.

AU - Vespa, P. M.

AU - Vijayan, T.

AU - Allyn, P. R.

AU - Campeau, S.

AU - Humphries, R. M.

AU - Klausner, J. D.

AU - Ganzon, C. D.

AU - Memar, F.

AU - Ocampo, N. A.

AU - Zimmermann, Lara

AU - Cohen, Stuart H

AU - Polage, Christopher R

AU - DeBiasi, R. L.

AU - Haller, B.

AU - Dallas, R.

AU - Maron, G.

AU - Hayden, R.

AU - Messacar, K.

AU - Dominguez, S. R.

AU - Miller, S.

AU - Chiu, C. Y.

PY - 2019/6/13

Y1 - 2019/6/13

N2 - BACKGROUND Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases.

AB - BACKGROUND Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases.

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U2 - 10.1056/NEJMoa1803396

DO - 10.1056/NEJMoa1803396

M3 - Article

VL - 380

SP - 2327

EP - 2340

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 24

ER -