Chronic Wasting Disease and Potential Transmission to Humans

Ermias D. Belay; Ryan A. Maddox; Elizabeth S. Williams; Michael W. Miller; Pierluigi Gambetti; Lawrence B. Schonberger


Emerging Infectious Diseases. 2004;10(6) 

In This Article

Risk for Transmission to Humans

The increasing detection of CWD in a wider geographic area and the presumed foodborne transmission of BSE to humans, resulting in cases of vCJD, have raised concerns about the possible zoonotic transmission of CWD.[32] In the late 1990s, such concerns were heightened by the occurrence of CJD among three patients 30 years of age who were deer hunters or ate deer and elk meat harvested by family members ( Table 2 ). However, epidemiologic and laboratory investigations of these case-patients indicated no strong evidence for a causal link between CWD and their CJD illness.[33] None of the patients were reported to have hunted deer or eaten deer meat harvested in the CWD-endemic areas of Colorado and Wyoming. Such a history in unusually young CJD patients, if present, would have supported a causal link with CWD. Moreover, the testing of brain tissues from >1,000 deer and elk harvested from areas where the patients hunted or their venison originated did not show any evidence of CWD.[33] In addition, the lack of homogeneity in the clinicopathologic manifestation and codon 129 of the prion protein gene among the three patients suggested that their illnesses could not be explained by exposure to the same prion strain. In vCJD, homogeneity of the genotype at codon 129 and the clinical and pathologic phenotype were attributed to the patients' exposure to the same prion strain, the agent of BSE.

In 2001, the case of a 25-year-old man who reportedly died of a prion disease after an illness lasting ≈22 months was investigated ( Table 2 ). Although this man had hunted deer only rarely, his grandfather hunted deer and elk throughout much of the 1980s and 1990s and regularly shared the venison with the case-patient's family. The grandfather primarily hunted in southeastern Wyoming, around the known CWD-endemic area. The case-patient's illness began with a seizure and progressed to fatigue, poor concentration, and depression. Memory loss, ataxia, speech abnormalities, combative behavior, and recurrent seizures also developed. Histopathologic, immunohistochemical, and Western blot testing of brain autopsy samples confirmed a prion disease diagnosis. Analysis of the prion protein gene indicated a P102L mutation coupled with valine at the polymorphic codon 129 in the mutant allele, confirming a diagnosis of Gerstmann-Sträussler-Scheinker syndrome (GSS). This case-patient was unusually young even for a person with a GSS P102L mutation. It remains unknown whether the possible exposure of the case-patient to CWD-infected venison potentially contributed to the early onset of his prion disease.

In 2001, two additional CJD patients 26 and 28 years of age were reported from a single state ( Table 2 ).[34] The patients grew up in adjacent counties and had illness onset within several months of each other. As a result of this fact and their unusually young age, a possible environmental source of infection, including exposure to CWD-infected venison, was considered. One of the patients died after an illness lasting 5–6 months that was characterized by progressive aphasia, memory loss, social withdrawal, vision disturbances, and seizure activity leading to status epilepticus and induced coma. Histopathologic, immunohistochemical, and Western blot testing of brain biopsy and autopsy samples confirmed a CJD diagnosis. The patient's disease phenotype corresponded to the MM2 sporadic CJD subtype reported by Parchi et al.[35] This patient did not hunt, and family members provided no history of regularly eating venison. The patient may have occasionally eaten venison originating from the Upper Peninsula of Michigan while away from home during his college years. However, ongoing surveillance has not detected CWD in Michigan deer.[36]

The second patient died from an illness lasting ≈16 months. The patient's illness began with behavioral changes, including unusual outbursts of anger and depression. Confusion, memory loss, gait disturbances, incontinence, headaches, and photophobia also developed. Western blot analysis of frozen brain biopsy tissue confirmed a prion disease diagnosis. Immunohistochemical analysis of brain tissue obtained after the patient's death showed prion deposition consistent with GSS. A prion protein gene analysis could not be performed because appropriate samples were lacking. However, prion protein gene analysis of a blood sample from one of the patient's parents indicated a GSS P102L mutation. The patient did not hunt but may have eaten venison from Michigan once when he was 1–2 years old. The GSS diagnosis greatly reduced the likelihood that the two patients reported from adjacent counties had disease with a common origin.

Recently, rare neurologic disorders resulting in the deaths of three men who participated in "wild game feasts" in a cabin owned by one of the decedents created concern about the possible relationship of their illnesses with CWD ( Table 2 ).[37] Two of the patients reportedly died of CJD, and the third died from Pick's disease. More than 50 persons were identified as possibly participating in these feasts; the three patients were the only participants reported to have died of a degenerative neurologic disorder. Reanalysis of autopsy brain tissues from the three patients at the National Prion Disease Pathology Surveillance Center indicated that two of them had no evidence of a prion disease by immunohistochemical analysis. CJD was confirmed in the third patient, who had clinicopathologic, codon 129, and prion characteristics similar to the most common sporadic CJD subtype (MM1/MV1).[35] This patient participated in the feasts only once, perhaps in the mid-1980s. In addition, the investigation found no evidence that the deer and elk meat served during the feasts originated from the known CWD-endemic areas of Colorado and Wyoming.

In 2003, CJD in two deer and elk hunters (54 and 66 years of age) was reported.[38] The report implied that the patients had striking neuropathologic similarities and that their illness may represent a new entity in the spectrum of prion diseases. A third patient (63 years of age), who was also purported to have been a big game hunter, was subsequently reported from the same area. However, none of the three patients were reported to have eaten venison from the CWD-endemic areas of the western United States. The 66-year-old patient hunted most of his life in Washington State. Although information about the 54-year-old patient was limited, there was no evidence that he hunted in CWD-endemic areas. The third patient was not a hunter but ate venison harvested from Pennsylvania and Washington. The neuropathologic changes, Western blot profile, and genotype at codon 129 of the three patients each fit the MM1, VV1, or VV2 sporadic CJD subtype, indicating absence of phenotypic similarity among the cases or atypical neuropathologic features.[35]

To date, only two nonfamilial CJD cases with a positive history of exposure to venison obtained from the known CWD-endemic areas have been reported. One of the patients was a 61-year-old woman who grew up in an area where this disease is known to be endemic, and she ate venison harvested locally. She died in 2000, and analysis of autopsy brain specimens confirmed that the patient's CJD phenotype fit the MM1 subtype, with no atypical neuropathologic features. The second patient was a 66-year-old man who was reported to have eaten venison from two deer harvested in a CWD-endemic area. Both deer tested negative for CWD, and the patient's illness was consistent with the MM1 CJD phenotype.

Despite the decades-long endemicity of CWD in Colorado and Wyoming, the incidence of CJD and the age distribution of CJD case-patients in these two states are similar to those seen in other parts of the United States. From 1979 to 2000, 67 CJD cases from Colorado and 7 from Wyoming were reported to the national multiple cause-of-death database. The average annual age-adjusted CJD death rate was 1.2 per million persons in Colorado and 0.8 in Wyoming. The proportion of CJD patients who died before age 55 in Colorado (13.4%) was similar to that of the national (10.2%). The only CJD case-patient <30 years of age in Colorado had iatrogenic CJD linked to receipt of human growth hormone injections. CJD was not reported in persons <55 years of age in Wyoming during the 22-year surveillance period.

The possible interspecies transmission of prions can be assessed with laboratory methods. In BSE and vCJD, several laboratory studies provided crucial evidence that helped establish a causal link between the two diseases.[39–41] These studies characterized the molecular similarities of the agents causing BSE and vCJD and determined the lesion profile and incubation period patterns of different panels of mice inoculated by the two agents. Limited laboratory studies have been performed to molecularly characterize CWD-associated prions and to compare them with prions from human case-patients and other species. Strain typing studies involving wild-type inbred mice indicated that the CWD agent from a mule deer produced incubation-period and brain-lesion profiles different from those produced by the agents causing BSE and scrapie.[39,42] These same strain-typing techniques had identified the similarities of the etiologic agents of BSE and vCJD, providing strong laboratory evidence for a link between the two diseases.

In human prion diseases, two major types of the proteinase-K–resistant prion protein fragment have been identified on the basis of their molecular size by one-dimensional immunoblot analysis: type 1 migrating at 21 kDa and type 2 at 19 kDa.[35] N-terminal protein sequencing indicated that the cleavage site of the type 1 fragment is generally at residue 82 and that of type 2 is at residue 97.[43] Prion strain diversity is believed to be encoded in the three-dimensional conformation of the protein, which determines the cleavage site and molecular size of proteinase-K–treated prion fragment, indicating that the difference in molecular size may correlate with strain differences. However, one-dimensional immunoblot analysis may not identify more subtle differences that may influence the conformation of different prion strains. Analysis of the glycoform ratios of prion fragments and application of a two-dimensional immunoblot may help further identify these subtle differences. On one-dimensional immunoblot analysis, the prion fragment from several CWD-infected deer and elk migrated to 21 kDa, corresponding to the type 1 pattern. This specific type has been identified in most cases of sporadic CJD in the United States. However, the deer and elk prion fragment differs from that in sporadic CJD cases in the glycoform ratio. In the CWD-associated prion fragment, the diglycosylated form was predominant, but in the CJD-associated prions, the monoglycosylated form was predominant. Preliminary analysis using two-dimensional immunoblot indicated that the CWD-associated prion fragment exhibited patterns different from that of the CJD-associated prion fragment from a human patient with the type 1 pattern (S. Chen, pers. comm.). Although analysis of more samples from cervids and humans is needed before meaningful conclusions can be made, these molecular techniques could potentially be used to study the similarities or differences in prion strains from cervids and humans with possible exposure to CWD.

The likelihood of successful interspecies transmission of prion diseases is influenced by the degree of homology of the infecting prion with that of the host endogenous prion protein. Such observations have given rise to the concept of a "species barrier," which would need to be overcome before an infecting prion strain caused disease in a recipient host. In vitro cell-free conversion reaction experiments have been developed to assess the degree of molecular compatibility of disease-associated prions from one species with normal prion protein obtained from a different species.[44,45] Such experiments specifically assess the likelihood that an infecting prion would potentially initiate the formation and propagation of pathogenic prions if it came in contact with normal prion protein. A cell-free conversion experiment indicated that CWD-associated prions can convert human prion protein into its abnormal conformer, albeit at a very low rate.[44] The efficiency of this conversion was >14-fold weaker than the homologous conversion of cervid prion protein and >5-fold weaker than the homologous conversion induced by CJD-associated prions. A similar low efficiency conversion of human prion protein by bovine- and scrapie-associated prions was also reported.[44,45] Although a high level of compatibility of prions in in vitro conversion reactions is believed to correlate with in vivo transmissibility of the agents, the threshold of compatibility efficiency below which no natural transmission should be anticipated is unknown. A low level of compatibility of infecting prions and host prion protein does not necessarily rule in or out natural interspecies transmission of prion diseases. However, the comparably low-level in vitro conversion of bovine prion protein by CWD-associated prions is consistent with the relative in vivo resistance of cattle to CWD under all but the most extreme experimental challenges. In addition, several other factors may determine the in vivo transmission of disease-associated prions, including dose, strain of the agent, route of infection, stability of the agent inside and outside the host, and the efficiency of agent delivery to the nervous system.[44,46]