A Test for Creutzfeldt–Jakob Disease Using Nasal Brushings
Christina D. Orrú, Ph.D., Matilde Bongianni, Ph.D., Giovanni Tonoli, M.D.,
Sergio Ferrari, M.D., Andrew G. Hughson, M.S., Bradley R. Groveman, Ph.D.,
Michele Fiorini, Ph.D., Maurizio Pocchiari, M.D., Salvatore Monaco, M.D., Byron
Caughey, Ph.D., and Gianluigi Zanusso, M.D., Ph.D.
N Engl J Med 2014; 371:519-529August 7, 2014DOI:
Share: Background Definite diagnosis of sporadic Creutzfeldt–Jakob disease
in living patients remains a challenge. A test that detects the specific marker
for Creutzfeldt–Jakob disease, the prion protein (PrPCJD), by means of real-time
quaking-induced conversion (RT-QuIC) testing of cerebrospinal fluid has a
sensitivity of 80 to 90% for the diagnosis of sporadic Creutzfeldt–Jakob
disease. We have assessed the accuracy of RT-QuIC analysis of nasal brushings
from olfactory epithelium in diagnosing sporadic Creutzfeldt–Jakob disease in
Methods We collected olfactory epithelium brushings and cerebrospinal fluid
samples from patients with and patients without sporadic Creutzfeldt–Jakob
disease and tested them using RT-QuIC, an ultrasensitive, multiwell plate–based
fluorescence assay involving PrPCJD-seeded polymerization of recombinant PrP
into amyloid fibrils.
Results The RT-QuIC assays seeded with nasal brushings were positive in 30
of 31 patients with Creutzfeldt–Jakob disease (15 of 15 with definite sporadic
Creutzfeldt–Jakob disease, 13 of 14 with probable sporadic Creutzfeldt–Jakob
disease, and 2 of 2 with inherited Creutzfeldt–Jakob disease) but were negative
in 43 of 43 patients without Creutzfeldt–Jakob disease, indicating a sensitivity
of 97% (95% confidence interval [CI], 82 to 100) and specificity of 100% (95%
CI, 90 to 100) for the detection of Creutzfeldt–Jakob disease. By comparison,
testing of cerebrospinal fluid samples from the same group of patients had a
sensitivity of 77% (95% CI, 57 to 89) and a specificity of 100% (95% CI, 90 to
100). Nasal brushings elicited stronger and faster RT-QuIC responses than
cerebrospinal fluid (P<0 .001="" 105="" 107="" approximately="" at="" between-group="" brushings="" cerebrospinal="" comparison="" concentrations="" contained="" fluid.="" for="" greater="" in="" individual="" logs10="" of="" p="" prion="" response="" seeds="" several="" strength="" than="" the="" to="">
Conclusions In this preliminary study, RT-QuIC testing of olfactory
epithelium samples obtained from nasal brushings was accurate in diagnosing
Creutzfeldt–Jakob disease and indicated substantial prion seeding activity
lining the nasal vault. (Funded by the Intramural Research Program of the
National Institute of Allergy and Infectious Diseases and others.)
Supported by the Intramural Research Program of the National Institute of
Allergy and Infectious Diseases (NIAID), by a grant from Fondazione Cariverona
(Disabilità cognitiva e comportamentale nelle demenze e nelle psicosi, to Dr.
Monaco), by a grant from the Italian Ministry of Health (RF2009-1474758, to Drs.
Zanusso and Pocchiari), by a grant from the Creutzfeldt–Jakob Disease Foundation
(to Dr. Orrú), by a fellowship from Programma Master and Back–Percorsi di
rientro (PRR-MAB-A2011-19199, to Dr. Orrú), and by donations to the NIAID Gift
Fund from Mary Hilderman Smith, Zoë Smith Jaye, and Jenny Smith Unruh, in memory
of Jeffrey Smith.
Disclosure forms provided by the authors are available with the full text
of this article at NEJM.org.
Drs. Orrú and Bongianni contributed equally to this article.
We thank our many colleagues (see Acknowledgments in the Supplementary
Appendix) for their support of this project and for assistance with the
preparation of earlier versions of the manuscript.
Source Information From the Laboratory of Persistent Viral Diseases, Rocky
Mountain Laboratories, National Institute of Allergy and Infectious Diseases
(NIAID), National Institutes of Health, Hamilton, MT (C.D.O., M.B., A.G.H.,
B.R.G., B.C.); and the Department of Biomedical Sciences, University of
Cagliari, Cagliari (C.D.O.), the Department of Neurologic and Movement Sciences,
University of Verona, Verona (M.B., S.F., M.F., S.M., G.Z.), Clinica
Otorinolaringoiatrica, Policlinico G.B. Rossi, Azienda Ospedaliera Universitaria
Integrata, Verona (G.T.), and the Department of Cell Biology and Neurosciences,
Istituto Superiore di Sanità, Rome (M.P.) — all in Italy.
Address reprint requests to Dr. Caughey at Rocky Mountain Laboratories,
NIAID, 903 S. 4th St., Hamilton, MT 59840, or at email@example.com; or to Dr.
Zanusso at Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134 Verona, Italy,
or at firstname.lastname@example.org.
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