Creutzfeldt-Jakob Disease:

August 1, 2001

Creutzfeldt-Jakob Disease:
Risks and Prevention of Nosocomial Acquisition

By: William A. Rutala, Ph.D., MPH, and David J. Weber,
MD, MPH

Objectives

  1. To understand the epidemiology of spongiform encephalopathies (e.g.,
    Creutzfeldt-Jakob disease) including risks of iatrogenic transmission.
  2. To review the susceptibility of prions to disinfecting agents and
    methods of sterilization.
  3. To develop scientifically-based infection control recommendations
    regarding the disinfection and sterilization of equipment potentially
    contaminated with prions.

Creutzfeldt-Jakob Disease (CJD) is a degenerative neurologic
disorder of humans that affects approximately one person per million population
per year both in the US1,2 and worldwide.3 CJD is
transmitted by a proteinaceous infectious agent or prion.4 It has
been estimated that the incubation period can vary from months to decades, but
once symptoms develop, the disorder is usually fatal within one year. At
present, there are no effective vaccines, completely reliable and validated
laboratory tests for detecting infection in presymptomatic persons, or specific
therapy available for prion diseases.

CJD is classified as a human transmissible spongiform encephalopathy (TSE);
other human TSEs include kuru, Gertsmann-Straussler-Sheinker, and fatal familial
insomnia syndrome (Table 1). In recent years, a new variant form of CJD (vCJD)
has been recognized.5-7 This variant of CJD differs from CJD in many
respects to include epidemiology, pathology, and geographic distribution
(primarily in the United Kingdom [UK]). In addition to these four human prion
diseases, six prion diseases in animals have been described: scrapie in sheep
and goats, transmissible mink encephalopathy, exotic ungulate encephalopathy,
chronic wasting disease of mule deer and elk, feline spongiform encephalopathy,
and bovine spongiform encephalopathy (BSE or "mad cow disease"). The
major mode of transmission in animals appears to be the consumption of prion-infected
feeds. Prion diseases do not elicit an immune response and all result in a
noninflammatory pathologic process confined to the central nervous system.3
CJD and other transmissible spongiform encephalopathies exhibit an unusual
resistance to conventional chemical and physical decontamination methods.8-10
Since CJD is not readily inactivated by conventional disinfection and
sterilization procedures and because of the invariably fatal outcome of CJD, the
procedures for disinfection and sterilization of the CJD prion have been both
conservative and controversial for many years. The purpose of this article is to
update a recent article that critiqued the literature and developed an
evidence-based guideline to prevent cross-transmission of infection from CJD-contaminated
medical devices.10

Prions are a unique class of pathogens because an agent-specific nucleic acid
(DNA or RNA) has not been detected. The infection is associated with the
abnormal isoform of a host cellular protein called prion protein (PrPc).3
In humans, the PrP gene resides on chromosome 20; mutations in this gene may
trigger the transformation of the PrP protein into the pathologic isoform. This
conversion of the normal cellular protein into the abnormal disease-causing
isoform (PrPsc) involves a conformational change whereby the (*helical content
diminishes and the amount of (ßpleated sheet increases, resulting in profound
changes in properties. Thus, the PrPc is susceptible to proteases and the PrPsc
is partially resistant. No prion-specific nucleic acid is known to be required
for transmission of disease.3,11,12 The pathogenic prions accumulate
in neural cells, disrupting function and leading to vacuolization and cell
death. Korth has described a monoclonal antibody that distinguishes between the
normal and disease form of PrP.13

Epidemiology of CJD

CJD is the most prevalent form of the transmissible spongiform
encephalopathies (TSE) in humans (Table 1). CJD is manifested clinically as a
rapidly progressive dementia (cognitive imbalance) that includes psychiatric and
behavioral abnormalities, coordination deficits, myoclonus and a distinct
electroencephalogram. Approximately 80% of sporadic CJD cases are diagnosed
between 50 and 70 years of age Definitive diagnosis of CJD requires a histologic
examination of the affected brain tissue. 3,11,12

CJD occurs as both a sporadic and familial disease. Approximately 10% of CJD
cases are inherited and caused by mutations in the PrP gene located on the short
arm of chromosome 20. Less than 1% of CJD cases result from person-to-person
transmission, primarily as a result of iatrogenic exposure. About 90% of CJD
cases are classified as sporadic because there is no family history and no known
source of transmission. There is no seasonal distribution, no evidence of
changing incidence, and no convincing geographic aggregation of cases.3,
11-14
Ninety percent of the deaths in the US are among persons older than
55 years of age and both genders are affected equally. Death usually occurs
within six months (median age at death 68 years).1,2 CJD is not
transmitted by direct contact, droplet, or airborne spread. Latrogenic
transmission of CJD from person-to-person has resulted from the direct
inoculation, implantation, or transplantation of infectious materials either
intracerebrally or peripherally. CJD can be transmitted from samples obtained
from patients to nonhuman primates.3 Transmission can occur by
peripheral routes of inoculation, but larger doses are required than
intracerebral inoculation. Oral transmission has been demonstrated with even
larger doses3, 15. The incubation period depends on the dose of
prions and the route of exposure. Studies have shown that prions (i.e.,
scrapie) are not inactivated by three years of environmental exposure.16

Variant CJD

BSE was first identified in 1986 in the UK and by April 2001 approximately
180,000 cattle had been infected.17 The number of cases peaked in
1992 and has been declining since with 1537 cases reported in 2000. BSE has been
reported from native cattle in Belgium, Denmark, France, Germany, the Republic
of Ireland, Liechtenstein, Luxembourg, Netherlands, Portugal, Spain, and
Switzerland.17 BSE appeared to have resulted from the exposure of
cattle to meat and bone meal that was produced by a new rendering process in
which the temperature was reduced and the hydrocarbon solvent extraction step
was omitted. The protein supplement was made from the remains of sheep and beef
contaminated with scrapie and BSE.18 The World Health Organization
(WHO) has published a guideline designed to control the transmission of BSE and
other similar diseases in animals.19 In 1996, an advisory committee
to the UK government announced its conclusion that the BSE agent might have
spread to humans, based on the recognition of the vCJD in 10 persons during 1994
to 1995. A total of 105 human cases have been diagnosed (101 in the United
Kingdom, 3 in France, 1 in Ireland) by early June 2001.17

The epidemiology, clinical and pathologic profile differ from sporadic CJD.
The mean age on onset is 29 years (range 16-48 years) compared with 65 years for
sCJD. The duration of illness is 14 months for vCJD and 4.5 months for sCJD.
Patients with vCJD frequently present with sensory and psychiatric symptoms that
are uncommon with sCJD.12 All patients with vCJD were potentially
exposed to contaminated bovine during the 1980s, before measures to control
human exposure were taken.

Both epidemiologic and molecular biologic evidence support a casual link
between BSE and vCJD.7, 20,21 For example, intracerebral inoculation
of cynomolgus macaque monkeys with brain tissue obtained from cattle with BSE
resulted in all the monkeys developing a neuropathological phenotype similar to
that described with vCJD but which differed from macaques inoculated with
sporadic CJD.22 More recently, Lasmezas and colleagues have
demonstrated primate-to-primate transmission of the BSE agent via intracerebral
or intravenous challenge of infected brain tissue.23 Neither BSE nor
variant CJD has been reported in the United States.

Infectivity of tissue

To date all known cases of iatrogenic CJD have resulted from exposure to
infectious brain, dura mater, pituitary, or eye tissue. This is likely due to
the high levels of abnormal prions in the central nervous system. It has been
well established that the infectious agent may be present in many body tissues
from tissue infectivity studies in experimental animals and epidemiological
studies in humans. However, in other tissues prions are present in lower numbers
than the brain and therefore transmission less likely (Table 2). Consistent
experimental transmission of infectivity has been possible with homogenates of
brain, spinal cord, and eye tissue. Transmission occurs in less than 20% of the
attempts with low-risk tissues such as liver, kidney, spleen, lymph node, and
cerebrospinal fluid, except lung tissue for which transmission is 50%.
Transmission to primates has never been documented with any body fluid other
than cerebrospinal fluid.24,25 Prions have been isolated from the
blood of infected guinea pigs, mice and patients with CJD.26,27 There
are no known cases of CJD attributable to the reuse of devices contaminated with
blood or via transfusion of blood products. So while transmission of CJD from
human blood to laboratory animals through intracerebral inoculation have been
reported27 attempts to transmit CJD from CJD-infected patients into
primates via whole blood or serum have failed.24

Iatrogenic CJD

Iatrogenic CJD has been described in humans in three circumstances: after use
of contaminated medical equipment (2 confirmed cases); after the use of
extracted pituitary hormones (>130 cases), or gonadotrophin (4 cases); and
after implant of contaminated grafts from humans (cornea-3 cases, dura mater
>110 cases).8,28 Transmission via stereotactic electrodes is the
only convincing example of transmission via a medical device. The electrodes had
been implanted in a patient with known CJD disease and then cleaned with benzene
and "sterilized" with 70% alcohol and formaldehyde vapor.29
Two years later, these electrodes were retrieved and implanted into a chimpanzee
in which the disease developed. The method used to "sterilize" these
electrodes would not currently be considered an adequate method for sterilizing
medical devices. The infrequent transmission of CJD via contaminated medical
devices probably reflects the inefficiency of transmission unless dealing with
neural tissue and the effectiveness of conventional cleaning and current
disinfection and sterilization procedures. Retrospective studies suggest five
other cases may have resulted from use of contaminated instruments in
neurosurgical operations.28

Johnson and Gibbs3 and more recently Brown30 have
reviewed the risks associated with blood products and concluded that CJD had not
been transmitted by transfusion of human blood products. Evidence supporting
this conclusion has included the following: case-control studies have not linked
a history of transfusions to an increased risk of CJD,31 the disease
has not been reported in patients with hemophilia;32, 33 intravenous
drug use does not increase the risk;3 investigating recipients of
blood components from known CJD donors has not revealed transmission of CJD;34
and transfusion with full units of blood from CJD patients to chimpanzees failed
to induce CJD.35 Although there have been no proven cases of CJD
transmission via blood transfusions these epidemiologic studies could miss very
rare events. While no case of transfusion-transmitted vCJD have ever been
detected, the US and Canada currently defer donors at higher risk of vCJD.36,37
Although a single case of transmission of BSE by blood transfusion in sheep has
been reported in a preliminary paper,38 alteration of blood
transfusion practices beyond recently introduced changes (e.g.,
leukodepletion in the UK) does not appear warranted.30

There is no evidence of occupational transmission of CJD to health-care
workers. Although cases of CJD have been reported in approximately 24 healthcare
workers, this incidence does not exceed what would be expected by chance alone.12
In the context of occupational exposure, the highest potential risk is from
exposure to high infectivity tissue through needlestick injuries with
inoculation.8 Exposure by splashing of the mucous membranes (notably
the conjunctiva) or unintentional ingestion may be considered a hypothetical
risk.8 For these reasons, all healthcare personnel who work with
patients with known or suspected prion diseases should use standard precautions.

Control Measures

We believe that infection control measures should be based on epidemiologic
evidence linking specific body tissues or fluids to transmission of CJD and/or
infectivity assays demonstrating that body tissues or fluids are contaminated
with infectious prions. The Centers for Disease Control and Prevention (CDC)39,40
has used these principles plus inactivation data to develop draft guidelines for
reprocessing CJD-contaminated medical devices. Guidelines are also available
from the WHO8 and health care professionals. 41,42 Other
CJD recommendations have been based primarily on inactivation studies42-44).
Our recommendations are also based on epidemiological data, infectivity data,
cleaning data using standard biological indicators, inactivation data of prions,
the risk of disease transmission associated with the use of the instrument or
device, and a review of other recommendations (8,39-44 (Appendix).

Healthcare workers should use standard precautions when caring for patients
with CJD. Added personal protective equipment (PPE) such as gowns or masks are
unnecessary in view of the lack of communicability to healthcare workers.

To minimize the possibility of use of potentially contaminated neurosurgical
instruments from patients later diagnosed with CJD, hospitals should consider
using the sterilization guidelines below for neurosurgical instruments used on
patients undergoing brain biopsy when a specific lesion has not been
demonstrated (e.g., magnetic resonance imaging, computer tomography
scans).10,40 Alternatively, neurosurgical instruments used in such
cases could be disposable. Failure to implement protocols to identify patients
with possible CJD and ensure proper disinfection or sterilization of potentially
contaminated instruments has led to adverse publicity and governmental
investigation.45

Disinfection and sterilization

Numerous studies have been conducted on the inactivation of prions by
germicides and sterilization processes but these studies do not reflect current
reprocessing procedures in a clinical setting. First, these studies have not
incorporated a cleaning procedure that normally reduces microbial contamination
by 4-logs.44 Second, the prion studies have been done with tissue
homogenates and the protective effect of tissue may explain, in part, why the
TSE agents are difficult to inactivate.46 Brain homogenates have been
found to confer thermal stability to small subpopulations of the scrapie agent
and some viruses. This subpopulation may be due to the protective effect of
aggregation or population heterogeneity.46

Favero has explained that the draft CDC guidelines are based on a risk
assessment that considers cleaning and prion bioburden from contact with
infectious tissues.39 In addition, one must consider the risk of
infection associated with the use of the medical device. The three categories of
medical devices are critical, semicritical, and noncritical. Items assigned to
the critical category present a high risk of infection if contaminated with CJD
as it enters a sterile tissue or the vascular system. This category includes
surgical instruments and implants. Semicritical items (e.g., endoscopes,
respiratory therapy equipment) are devices that come in contact with mucous
membranes or skin that is not intact. In general, these items should be free of
all microorganisms with the exception of small numbers of bacterial spores.
Transmission of CJD via contact with mucous membranes or non-intact skin has not
been described. Noncritical items (e.g., floors, walls, blood pressure
cuffs, patient furniture) come in contact with intact skin but not mucous
membranes. Intact skin should act as an effective barrier to microorganisms and
prions. Thus, a critical or semicritical device that has contact with high-risk
tissue (e.g., brain) from a high-risk patient (e.g., suspected or
known CJD) must be reprocessed in a manner to ensure prion elimination. The
combined contribution of cleaning and an effective physical or chemical
reprocessing procedure should eliminate the risk of CJD transmission. Critical
or semicritical instruments or medical devices that have contact with low or no
risk tissue can be treated using conventional methods, as the devices have not
resulted in transmission of CJD (Appendix).

To assess the effectiveness of disinfection or sterilization procedures one
must consider the inactivation/removal factor47-49); that is, the
reduction of infectious units during the disinfection or sterilization process.
Thus, the probability of an instrument remaining capable of transmitting disease
depends on the initial degree of contamination and the effectiveness of the
decontamination procedures. An instrument contaminated with 50 mg of CJD brain
with a titer of 5.0 LD50 intracerebral units/g24 would
have 5 x103 infectious units. It has been suggested a titer loss of
104 prions should be regarded as indicating appropriate disinfection
of CJD.49 However, the effectiveness of a disinfection or
sterilization procedure should be considered in conjunction with the
effectiveness of cleaning. Studies with microbial agents demonstrate that
cleaning by conventional methods used in healthcare results in a 104
reduction of microbes. Thus, cleaning followed by disinfection would result in a
titer loss of 107 (4-log reduction with cleaning plus >3-log
reduction with an effective disinfection process) while tissues with high prion
infectivity (e.g., brain) would be contaminated with 105 prion/gram.
Cleaning followed by a disinfection or sterilization procedure should destroy
infectivity and provide a significant safety margin.

Disinfection

Results of chemical inactivation studies of prions have been inconsistent due
to the use of differing methodologies including: strain of prion (e.g.,
prions may vary in thermostability but differential susceptibility to
disinfectants has not been described), prion concentration in brain tissue, test
tissues (intact brain tissue, brain homogenates, partially purified
preparations), test animals, duration of follow-up of inoculated test animals,
exposure container, log decrease calculated from incubation period assays not
endpoint titrations, concentration of disinfectant at the beginning and end of
an experiment (e.g., chlorine), exposure conditions, and cycle parameters
of the sterilizer.42 Despite these limitations, there is some
consistency in the results. An important limitation of current disinfection
research is that currently prion assays are slow, laborious, and costly. Studies
evaluating the efficacy of combined cleaning and disinfection have not been
published.

It has been established that most disinfectants are inadequate for
eliminating prion infectivity. There are four chemicals that have been
demonstrated to reduce prion titers by >4-logs: chlorine, a phenolic,
guanidine thiocyanate, and sodium hydroxide (Table 3). 47-55 Of these
four chemical compounds the disinfectant that is available and provides the most
consistent prion inactivation results is chlorine but even chlorine has had
unexplainable reduced activity (e.g., reduction of 3.3-logs of CJD in 60
min by 2.5% hypochlorite).52 The corrosive nature of chlorine would
make it unsuitable for semicritical devices such as endoscopes. Several
investigators have found that 1N NaOH51,56,57 incompletely
inactivates CJD. Other antimicrobials that have been shown to be ineffective
(less than 3 log reduction in 1 hour) against CJD or other TSEs are listed in
Table 3.47-49,52,55,58-61 Studies have also shown that aldehydes such
as formaldehyde enhance the resistance of prions and pretreatment of scrapie-infected
brain with formaldehyde abolished the inactivating affect of autoclaving.62
A formalin-formic acid procedure is required for inactivating prion infectivity
in tissue samples from patients with CJD63.

Both flexible and rigid endoscopes have been used in neurosurgery.64,65
If such scopes come into contact with high-risk tissue in a patient with known
or suspected CJD, either they should undergo sterilization (if possible, see
below) or single-use devices should be used. Endoscopes coming into contact with
other tissues (e.g., gastrointestinal tract, respiratory tract, joints,
abdomen) can be disinfected using conventional methods.

Sterilization

Prions exhibit an unusual resistance to conventional chemical and physical
decontamination methods. These include both gaseous (i.e., ethylene oxide
and formaldehyde) and physical processes (e.g., dry heat, glass bead
sterilization, boiling, and autoclaving at conventional exposure conditions [e.g.,
121oC for 15 min]).42,48,52,55 Rohwer's data suggest that
the majority of scrapie infectivity is inactivated by brief exposure to
temperatures of 100oC or greater. For example, when scrapie strain
263K was exposed to 121oC, 99.9999% of the infectivity was destroyed
during the minute required to bring the sample to temperature. At 100oC,
97% was destroyed within 2 minutes of exposure at temperature. Thus, only a
fraction of the infectious activity is extremely resistant.46

Standard gravity displacement steam sterilization at 121oC has
been studied using different strains of CJD, BSE and scrapie and has been shown
to be only partially effective even after exposure times of 120 min. As the
temperature and exposure time increases, greater inactivation of the prion
agents was achieved (Table 4). While there is some disagreement of the ideal
time and temperature cycle,41 the recommendation for 121-132oC
for 60 min (gravity) and 134oC for >18 min (prevacuum) are
reasonable based on the scientific literature. These methods should result in a
decrease of >5-logs and cleaning should result in a 4-log reduction providing
a significant margin of safety (brain tissue concentration 105 prion/gram.24
Other steam sterilization cycles such as 132oC for 15 min (gravity)
have been shown to be only partially effective.52

Several investigators have found that combining sodium hydroxide (e.g.,
0.09N for 2 hr) with steam sterilization for 1 hour at 121oC results
in complete inactivation of infectivity (>7.4-logs).54 However,
the combination of sodium hydroxide and steam sterilization may be deleterious
to surgical instruments.42

Conclusion

Prion diseases are rare and hence do not constitute a major infection control
risk. Nevertheless, prions represent an exception to conventional disinfection
and sterilization practices. These guidelines for CJD disinfection and
sterilization are based on consideration of epidemiological data, infectivity
data, and cleaning and inactivation studies. Guidelines for management of CJD
infected patients and patient equipment should be modified as scientific
information becomes available. Importantly, studies assessing the susceptibility
of vCJD to disinfectants and sterilants should be undertaken. In addition,
studies consistent with actual clinical practices (e.g., operation in
infected animals followed by cleaning with enzymatic detergents and disinfection
or sterilization) should be undertaken.

William A. Rutala, PhD, MPH, is a professor in the Department of Medicine,
School of Medicine, University of North Carolina at Chapel Hill. He serves as
director of the departments of Hospital Epidemiology (Infection Control),
Occupational Health, and Safety Program for the University of North Carolina
Health Care System. In addition, Dr. Rutala is the director of the North
Carolina Statewide Program in Infection Control and Epidemiology. Dr. Rutala has
published approximately 300 papers in the field of infection control,
disinfection and sterilization.

David J. Weber, MD, MPH, is a professor in the departments of Medicine and
Pediatrics, School of Medicine and a professor in the Department of Epidemiology,
School of Public Health, University of North Carolina at Chapel Hill. He serves
as medical director of the Departments of Hospital Epidemiology (Infection
Control), Occupational Health, and Safety Program for the University of North
Carolina Health Care System. Dr. Weber has published more than 250 papers in the
field
of infection control.

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Test Questions: True or False

  1. Transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob
    disease) are common diseases.
  2. Creutzfeldt-Jakob disease occurs with a frequency of approximately 1 per
    million population.
  3. Transmissible spongiform encephalopathies are caused by prions, an
    abnormal protein that accumulates in the central nervous system.
  4. Prions demonstrate an unusual resistance to standard methods of
    disinfection and sterilization.
  5. The same agent that causes bovine spongiform encephalopathy causes variant
    Creutzfeldt-Jakob disease.
  6. Variant Creutzfeldt-Jakob disease has rarely been reported in the United
    States.
  7. Iatrogenic Creutzfeldt-Jakob disease has occurred via transplanted
    contaminated tissues (e.g., dura mater grafts) or use of contaminated
    human biologics (e.g., pituitary hormones).
  8. Iatrogenic Creutzfeldt-Jakob disease has occurred due to use of medical
    instruments contaminated with central nervous tissue
  9. Iatrogenic Creutzfeldt-Jakob disease has occurred due via blood
    transfusions from infected persons.

Answers

1. F
2. T
3. T
4. T
5. T
6. F
7. T
8. T
9. F

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