Creutzfeldt-Jakob Disease:

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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