Investigation of a Researcher's Death Due to Septicemic Plague — NEJM

Investigation of a Researcher's Death Due to Septicemic Plague
N Engl J Med 2011; 364:2563-2564June 30, 2011

Article
To the Editor:
Infection with virulent Yersinia pestis is associated with rapid dissemination and a high risk of death. Attenuated vaccine strains exist that lack a chromosomal fragment comprising the high-pathogenicity island involved in iron uptake and the pigmentation segment associated with the microbe's heme-staining phenotype and its survival in arthropods.1 Attenuated strains, such as Y. pestis KIM D27, are routinely manipulated in many laboratories with the use of biosafety level 2 precautions; to our knowledge plague infection caused by a nonpigmented Y. pestis strain has not been reported in the United States.2

We report a case of lethal septicemic plague caused by an attenuated, nonpigmented Y. pestis isolate (designated UC91309). A 60-year-old researcher with a history of insulin-dependent diabetes, hypertension, and hyperlipidemia presented to the emergency department with a 1-week history of worsening shortness of breath and associated dry cough, fevers, chills, and weakness. His condition rapidly deteriorated, and despite resuscitation efforts the patient died after 13 hours.

Blood cultures grew Y. pestis, and an autopsy revealed abnormally high levels of iron deposition in the noncirrhotic liver (Figure 1AFigure 1
Histologic Studies of Tissues Obtained at Autopsy.). Testing of antemortem serum samples revealed markedly elevated levels of ferritin, iron, total iron-binding capacity, and iron saturation. The iron level in the liver tissue was consistent with hereditary hemochromatosis,3 and genetic testing confirmed the presence of a C282Y mutation. Analysis of the UC91309 genome sequence revealed the insertion of an antibiotic-resistance cassette that had been engineered by the patient as a research activity, indicating that the patient isolate was the laboratory-manipulated strain and not a naturally occurring U.S. strain.

The route of entry of the organism was not determined despite a thorough autopsy and an investigation by the university and by local, regional, and national public health departments. It is possible that inadvertent exposure to a subcutaneous or mucous membrane had occurred. Previous work showed that vaccine strains are attenuated for virulence but can cause lethal plague infections in animals pretreated with iron salts.4 Studies in mice showed that UC91309 is attenuated and does not display a significant difference in virulence from the parent strain. Preloading animals with iron dextran enabled increased growth and dissemination of the UC91309 strain. In this case, clinically unrecognized hemochromatosis appears to have been a risk factor for severe infection with this attenuated, nonpigmented Y. pestis strain.

This report emphasizes the need for strict attention to protocols for laboratory safety. When illness does occur, all potential sources of microbial exposure should be considered and the nature of the ill person's employment determined. A plan for early, rapid assessment and treatment should be in place. Given the probable role of undiagnosed hemochromatosis in this fatal case, researchers working with yersinia species may choose to determine whether or not they have the hemochromatosis mutation.

Karen M. Frank, M.D., Ph.D.
Olaf Schneewind, M.D., Ph.D.
University of Chicago, Chicago, IL
kfrank@uchicago.edu

Wun-Ju Shieh, M.D., Ph.D.
Centers for Disease Control and Prevention, Atlanta, GA


Supported by the University of Chicago and the Great Lakes Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Consortium through an award from the National Institutes of Health (1-U54-AI057153).

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

4 References
1
Buchrieser C, Rusniok C, Frangeul L, et al. The 102-kilobase pgm locus of Yersinia pestis: sequence analysis and comparison of selected regions among different Yersinia pestis and Yersinia pseudotuberculosis strains. Infect Immun 1999;67:4851-4861
Web of Science | Medline
.2
Brubaker RR. Mutation rate to nonpigmentation in Pasteurella pestis. J Bacteriol 1969;98:1404-1406
Web of Science | Medline
.3
Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408
CrossRef | Web of Science | Medline
.4
Hallett AF, Isaacson M, Meyer KF. Pathogenicity and immunogenic efficacy of a live attenuated plaque vaccine in vervet monkeys. Infect Immun 1973;8:876-881
Web of Science | Medline

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.Investigation of a Researcher's Death Due to Septicemic Plague — NEJM