Human Prion Disease Surveillance in Washington State, 2006-2017

Key Points Question What are the results of human prion disease surveillance in Washington state? Findings In this cross-sectional study using state surveillance data from 2006 to 2017, 143 human prion disease cases were detected, with an average annual age-adjusted incidence consistent with national reports. The majority of cases (94%) were sporadic, and no cases met criteria for a variant Creutzfeldt-Jakob disease diagnosis. Meaning These findings indicate that prion disease surveillance in Washington state is beneficial for monitoring epidemiological trends, facilitating accurate diagnoses, and detecting variant Creutzfeldt-Jakob disease or other emerging human prion diseases should they occur.


Introduction
Prion diseases, also called transmissible spongiform encephalopathies, are a group of rare, fatal, neurodegenerative diseases that occur in animals and humans. These diseases are characterized by the conversion of normal prion proteins into abnormal, pathogenic agents known as prions. [1][2][3] This conversion process can be sporadic, related to a genetic mutation, or induced by the uptake of the pathogenic prions. 3,4 The accumulation of prions is associated with neuronal injury leading to spongiform changes in the central nervous system. 5 The most common human prion disease (HPD) is Creutzfeldt-Jakob disease (CJD), with an age-adjusted incidence of 1.2 cases per million population per year in the United States, similar to the incidence reported in other countries. 6,7 Sporadic CJD accounts for approximately 85% of CJD cases and familial CJD for 10% to 15%. 3 Other less common prion diseases include fatal familial insomnia, sporadic fatal insomnia, Gerstmann-Straüssler-Scheinker disease, variably protease-sensitive prionopathy, and acquired prion disease.
In 1996, a new, acquired HPD, termed variant CJD (vCJD), was described in the United Kingdom. 8 It was linked to the consumption of prion-contaminated beef or beef products from cattle afflicted with bovine spongiform encephalopathy (BSE). 9 Later, several patients with vCJD were determined to have contracted their illness through receipt of blood from donors who subsequently developed vCJD. 10,11 As of January 2020, 232 cases of vCJD have been described around the world. 12 This number includes 4 patients who were diagnosed in the United States but were likely exposed to the infectious agent outside the country. 13 Variant and iatrogenic (ie, health care-acquired) CJD accounts for less than 1% of the total number of HPD cases.
In December 2003, a dairy cow imported from Canada into the state of Washington was diagnosed with BSE. Beef from the slaughtered cow had been processed for human consumption, and a recall of all beef from cattle slaughtered the same day at the involved slaughter plant was requested. 14 In response to this incident, the Washington State Department of Health (WA DOH) established an enhanced HPD surveillance system the following year and has maintained a centralized database of all suspected cases in the state since that time. Human prion disease has been a distinct notifiable condition in Washington (Washington Administrative Code 246-101-101) since February 2011. Once clinically diagnosed, cases are to be reported within 3 business days to public health authorities (ie, local health jurisdictions). 15 Before 2011, HPD was notifiable under the category of "other rare diseases of public health significance." The objectives of surveillance activities in Washington are (1) to establish background incidence rates and monitor trends in the epidemiology of HPD in the state, (2) to detect the possible emergence of vCJD or a possible new HPD, (3) to detect and help prevent potential iatrogenic CJD, and (4) to facilitate accurate HPD diagnoses. To aid in accomplishing these objectives, and in collaboration with the US Centers for Disease Control and Prevention (CDC), WA DOH personnel work closely with the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University, which is supported by the CDC and sponsored by the American Association of Neuropathologists. A major purpose of the NPDPSC is to provide state-of-the-art diagnostic testing for clinically suspected HPD cases. 16 This article describes the current HPD surveillance system in place in Washington and the epidemiological and clinical results of surveillance activities during the years 2006 through 2017.

Methods
This cross-sectional study was conducted using data obtained through the HPD surveillance system

Case Finding
The WA DOH receives prion disease reports from 3 main sources: the NPDPSC, death certificate data, and health care professionals, including physicians and infection control professionals. On rare occasions, notifications from the general public have also been received.
The NPDPSC provides a WA DOH prion epidemiologist (including L.S.-G. or L.L.) with a copy of the results of brain autopsies and tests performed at the center for Washington residents or those ordered by Washington health care professionals. Among the possible tests are cerebrospinal fluid (CSF) Tau protein, CSF 14-3-3 protein, second-generation real-time quaking-induced conversion (RT-QuIC), brain biopsy, and blood PRNP genotyping. For some cases, the center may arrange for expert reviews of available magnetic resonance imaging results. The prion epidemiologist combines these NPDPSC data with available WA DOH information from case reports and investigations.

Case Investigation
Data on demographics, clinical presentation and course, and infection prevention and control are collected. Race and ethnicity are obtained from the demographics section of available medical records, if noted, with options being defined by the hospitals and medical institutions; otherwise, these data are obtained from the death certificate. These characteristics were assessed because previous studies have shown differences in prion disease incidence by race. 6,17 After notification of a suspected case, the prion epidemiologist obtains and reviews medical records and tests results. Facilities where the patient had been hospitalized are contacted, and interviews with clinicians, infection control professionals, and/or families are pursued to collect information on clinical presentation and risk factors for acquired prion disease, such as previous neurosurgery or receipt of a cadaver-derived pituitary hormone. Information regarding prion diseases and infection control measures are shared with infection control professionals.
The prion epidemiologist encourages health care professionals to discuss the possibility of autopsy with the patient's caregivers when appropriate to obtain neuropathological confirmation of the diagnosis. Information regarding the NPDPSC's autopsy service is given to the health care professional; information regarding other services available at the NPDPSC (eg, genetic testing for familial prion disease) and support services (eg, CJD Foundation) is given to families.
Cases of CJD are classified as sporadic (definite, probable, or possible), familial, or iatrogenic according to the current CDC Diagnostic Criteria. 18 Cases lacking histopathological confirmation, genetic testing, and information indicating an iatrogenic source of infection or familial disease are classified as sporadic by default. Cases with insufficient information available for designation as definite, probable, or possible CJD are classified as physician-diagnosed CJD, provided CJD is listed as a cause of death on the death certificate and a prion disease diagnosis cannot be ruled out. Cases are followed until a prion disease diagnosis is excluded or confirmed or the patient dies. If biopsy or autopsy is performed, the follow-up continues until final results of brain tissue tests are received, a type of prion disease is established, and the case is closed. Cases in which the patient is younger than 55 years or those with unusual clinical presentation or diagnostic results, concerning exposures, or any other special characteristics are discussed with the CDC and the NPDPSC in order to determine the need for further testing or public health measures. second-generation RT-QuIC in CSF were available for 10 of the probable CJD cases, 9 of which were positive, indicating likely true prion disease given the test's very high specificity. 19 Four of the 42 cases (9.5%) met criteria for possible CJD, and the remaining 2 cases lacked sufficient information for classification and were designated as physician-diagnosed cases; both of these patients were older than 60 years, making a vCJD diagnosis unlikely.

Data Collection and Statistical Analysis
Of the 8 familial prion disease cases, 7 were familial CJD, and 1 was Gerstmann-Straüssler-Scheinker disease. All familial cases were classified as definite, including 2 that lacked neuropathologic testing but met clinical criteria and had a genetic mutation and/or positive family history. Three of the familial CJD cases had the E200K mutation; the remaining 4 cases had T183A, T188R, or D178N mutations, or a 5 octapeptide insert. The Gerstmann-Straüssler-Scheinker case had a 9 octapeptide insert.
The iatrogenic CJD case was associated with cadaver-derived human growth hormone administration during childhood and is part of an ongoing US outbreak of human growth hormoneassociated CJD. 20 It also had the unusual, distinct pathological phenotype reported as likely specific for iatrogenic CJD. [20][21][22] Cases Case-defining symptoms and signs reported for sporadic prion disease patients are summarized in Table 3. All patients presented with rapidly progressive dementia. Cerebellar abnormalities were

Discussion
Since the identification of a BSE-positive dairy cow in the state in 2003, WA DOH, in collaboration with the CDC and the NPDPSC, has been conducting HPD surveillance. During the 12-year period evaluated in this cross-sectional study, the vast majority of HPD cases identified were classified as sporadic CJD, and no vCJD cases were detected. The average annual age-adjusted incidence, 1.5 cases per million population, was stable during this period with no apparent geographical clustering.
Higher incidence rates were reported among decedents who were male, White, and aged 55 years or older, congruous with national findings. 6 The finding of an average annual age-adjusted incidence slightly higher than the national rate, 1.2 per million, may be at least partially explained by the enhanced prion disease surveillance conducted in Washington, which has led to improved case detection. Efforts have been made in the state to increase awareness among neurologists and other medical providers regarding prion disease and the services available at the NPDPSC for diagnosis and confirmation purposes. Recently, concerns about the potential for chronic wasting disease (CWD), a prion disease of deer, elk, and moose, to transmit to humans have also been raised. 27

Limitations
A limitation of this study is that only partial medical records were available for some patients, and the complete clinical presentation of the disease, including initial signs and symptoms, was sometimes difficult to ascertain. This limitation could potentially influence case classification, because some actual criteria and findings may not have been considered. In addition, the highly specific secondgeneration RT-QuIC CSF test was not regularly used by NPDPSC until 2015. Most cases, however, had neuropathologic confirmation. Collaboration with the NPDPSC, which performs the majority of premortem tests, enables a timely notification to WA DOH of suspected cases in the state and thus contributes to the number of subsequent autopsies performed.

Conclusions
In this cross-sectional study of Washington state's HPD surveillance system, findings suggest that the demographic characteristics of patients with prion disease between 2006 and 2017 were consistent with national findings. Despite a statewide prion disease surveillance program being in place since 2004, neither vCJD nor another new prion disease has been detected in the state. Given the long incubation periods associated with prion diseases, ongoing vigilance and collaboration with surveillance partners continue to be necessary.