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

Creutzfeldt-Jakob Disease (CJD) is a degenerative neurologicdisorder of humans that affects approximately one person per million populationper year both in the US1,2 and worldwide.3 CJD istransmitted by a proteinaceous infectious agent or prion.4 It hasbeen estimated that the incubation period can vary from months to decades, butonce symptoms develop, the disorder is usually fatal within one year. Atpresent, there are no effective vaccines, completely reliable and validatedlaboratory tests for detecting infection in presymptomatic persons, or specifictherapy available for prion diseases.

CJD is classified as a human transmissible spongiform encephalopathy (TSE);other human TSEs include kuru, Gertsmann-Straussler-Sheinker, and fatal familialinsomnia 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 manyrespects to include epidemiology, pathology, and geographic distribution(primarily in the United Kingdom [UK]). In addition to these four human priondiseases, six prion diseases in animals have been described: scrapie in sheepand 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"). Themajor mode of transmission in animals appears to be the consumption of prion-infectedfeeds. Prion diseases do not elicit an immune response and all result in anoninflammatory pathologic process confined to the central nervous system.3CJD and other transmissible spongiform encephalopathies exhibit an unusualresistance to conventional chemical and physical decontamination methods.8-10Since CJD is not readily inactivated by conventional disinfection andsterilization procedures and because of the invariably fatal outcome of CJD, theprocedures for disinfection and sterilization of the CJD prion have been bothconservative and controversial for many years. The purpose of this article is toupdate a recent article that critiqued the literature and developed anevidence-based guideline to prevent cross-transmission of infection from CJD-contaminatedmedical 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 theabnormal isoform of a host cellular protein called prion protein (PrPc).3In humans, the PrP gene resides on chromosome 20; mutations in this gene maytrigger the transformation of the PrP protein into the pathologic isoform. Thisconversion of the normal cellular protein into the abnormal disease-causingisoform (PrPsc) involves a conformational change whereby the (*helical contentdiminishes and the amount of (ßpleated sheet increases, resulting in profoundchanges in properties. Thus, the PrPc is susceptible to proteases and the PrPscis partially resistant. No prion-specific nucleic acid is known to be requiredfor transmission of disease.3,11,12 The pathogenic prions accumulatein neural cells, disrupting function and leading to vacuolization and celldeath. Korth has described a monoclonal antibody that distinguishes between thenormal and disease form of PrP.13

Epidemiology of CJD

CJD is the most prevalent form of the transmissible spongiformencephalopathies (TSE) in humans (Table 1). CJD is manifested clinically as arapidly progressive dementia (cognitive imbalance) that includes psychiatric andbehavioral abnormalities, coordination deficits, myoclonus and a distinctelectroencephalogram. Approximately 80% of sporadic CJD cases are diagnosedbetween 50 and 70 years of age Definitive diagnosis of CJD requires a histologicexamination of the affected brain tissue. 3,11,12

CJD occurs as both a sporadic and familial disease. Approximately 10% of CJDcases are inherited and caused by mutations in the PrP gene located on the shortarm of chromosome 20. Less than 1% of CJD cases result from person-to-persontransmission, primarily as a result of iatrogenic exposure. About 90% of CJDcases are classified as sporadic because there is no family history and no knownsource of transmission. There is no seasonal distribution, no evidence ofchanging incidence, and no convincing geographic aggregation of cases.3,11-14 Ninety percent of the deaths in the US are among persons older than55 years of age and both genders are affected equally. Death usually occurswithin six months (median age at death 68 years).1,2 CJD is nottransmitted by direct contact, droplet, or airborne spread. Latrogenictransmission of CJD from person-to-person has resulted from the directinoculation, implantation, or transplantation of infectious materials eitherintracerebrally or peripherally. CJD can be transmitted from samples obtainedfrom patients to nonhuman primates.3 Transmission can occur byperipheral routes of inoculation, but larger doses are required thanintracerebral inoculation. Oral transmission has been demonstrated with evenlarger doses3, 15. The incubation period depends on the dose ofprions 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 approximately180,000 cattle had been infected.17 The number of cases peaked in1992 and has been declining since with 1537 cases reported in 2000. BSE has beenreported from native cattle in Belgium, Denmark, France, Germany, the Republicof Ireland, Liechtenstein, Luxembourg, Netherlands, Portugal, Spain, andSwitzerland.17 BSE appeared to have resulted from the exposure ofcattle to meat and bone meal that was produced by a new rendering process inwhich the temperature was reduced and the hydrocarbon solvent extraction stepwas omitted. The protein supplement was made from the remains of sheep and beefcontaminated with scrapie and BSE.18 The World Health Organization(WHO) has published a guideline designed to control the transmission of BSE andother similar diseases in animals.19 In 1996, an advisory committeeto the UK government announced its conclusion that the BSE agent might havespread to humans, based on the recognition of the vCJD in 10 persons during 1994to 1995. A total of 105 human cases have been diagnosed (101 in the UnitedKingdom, 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 forsCJD. 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 thatare uncommon with sCJD.12 All patients with vCJD were potentiallyexposed to contaminated bovine during the 1980s, before measures to controlhuman exposure were taken.

Both epidemiologic and molecular biologic evidence support a casual linkbetween BSE and vCJD.7, 20,21 For example, intracerebral inoculationof cynomolgus macaque monkeys with brain tissue obtained from cattle with BSEresulted in all the monkeys developing a neuropathological phenotype similar tothat described with vCJD but which differed from macaques inoculated withsporadic CJD.22 More recently, Lasmezas and colleagues havedemonstrated primate-to-primate transmission of the BSE agent via intracerebralor intravenous challenge of infected brain tissue.23 Neither BSE norvariant CJD has been reported in the United States.

Infectivity of tissue

To date all known cases of iatrogenic CJD have resulted from exposure toinfectious brain, dura mater, pituitary, or eye tissue. This is likely due tothe high levels of abnormal prions in the central nervous system. It has beenwell established that the infectious agent may be present in many body tissuesfrom tissue infectivity studies in experimental animals and epidemiologicalstudies in humans. However, in other tissues prions are present in lower numbersthan the brain and therefore transmission less likely (Table 2). Consistentexperimental transmission of infectivity has been possible with homogenates ofbrain, spinal cord, and eye tissue. Transmission occurs in less than 20% of theattempts with low-risk tissues such as liver, kidney, spleen, lymph node, andcerebrospinal fluid, except lung tissue for which transmission is 50%.Transmission to primates has never been documented with any body fluid otherthan cerebrospinal fluid.24,25 Prions have been isolated from theblood of infected guinea pigs, mice and patients with CJD.26,27 Thereare no known cases of CJD attributable to the reuse of devices contaminated withblood or via transfusion of blood products. So while transmission of CJD fromhuman blood to laboratory animals through intracerebral inoculation have beenreported27 attempts to transmit CJD from CJD-infected patients intoprimates via whole blood or serum have failed.24

Iatrogenic CJD

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

Johnson and Gibbs3 and more recently Brown30 havereviewed the risks associated with blood products and concluded that CJD had notbeen transmitted by transfusion of human blood products. Evidence supportingthis conclusion has included the following: case-control studies have not linkeda history of transfusions to an increased risk of CJD,31 the diseasehas not been reported in patients with hemophilia;32, 33 intravenousdrug use does not increase the risk;3 investigating recipients ofblood components from known CJD donors has not revealed transmission of CJD;34and transfusion with full units of blood from CJD patients to chimpanzees failedto induce CJD.35 Although there have been no proven cases of CJDtransmission via blood transfusions these epidemiologic studies could miss veryrare events. While no case of transfusion-transmitted vCJD have ever beendetected, the US and Canada currently defer donors at higher risk of vCJD.36,37Although a single case of transmission of BSE by blood transfusion in sheep hasbeen reported in a preliminary paper,38 alteration of bloodtransfusion 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-careworkers. Although cases of CJD have been reported in approximately 24 healthcareworkers, this incidence does not exceed what would be expected by chance alone.12In the context of occupational exposure, the highest potential risk is fromexposure to high infectivity tissue through needlestick injuries withinoculation.8 Exposure by splashing of the mucous membranes (notablythe conjunctiva) or unintentional ingestion may be considered a hypotheticalrisk.8 For these reasons, all healthcare personnel who work withpatients with known or suspected prion diseases should use standard precautions.

Control Measures

We believe that infection control measures should be based on epidemiologicevidence linking specific body tissues or fluids to transmission of CJD and/orinfectivity assays demonstrating that body tissues or fluids are contaminatedwith infectious prions. The Centers for Disease Control and Prevention (CDC)39,40has used these principles plus inactivation data to develop draft guidelines forreprocessing CJD-contaminated medical devices. Guidelines are also availablefrom the WHO8 and health care professionals. 41,42 OtherCJD 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 ordevice, and a review of other recommendations (8,39-44 (Appendix).

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

To minimize the possibility of use of potentially contaminated neurosurgicalinstruments from patients later diagnosed with CJD, hospitals should considerusing the sterilization guidelines below for neurosurgical instruments used onpatients undergoing brain biopsy when a specific lesion has not beendemonstrated (e.g., magnetic resonance imaging, computer tomographyscans).10,40 Alternatively, neurosurgical instruments used in suchcases could be disposable. Failure to implement protocols to identify patientswith possible CJD and ensure proper disinfection or sterilization of potentiallycontaminated instruments has led to adverse publicity and governmentalinvestigation.45

Disinfection and sterilization

Numerous studies have been conducted on the inactivation of prions bygermicides and sterilization processes but these studies do not reflect currentreprocessing procedures in a clinical setting. First, these studies have notincorporated a cleaning procedure that normally reduces microbial contaminationby 4-logs.44 Second, the prion studies have been done with tissuehomogenates and the protective effect of tissue may explain, in part, why theTSE agents are difficult to inactivate.46 Brain homogenates have beenfound to confer thermal stability to small subpopulations of the scrapie agentand some viruses. This subpopulation may be due to the protective effect ofaggregation or population heterogeneity.46

Favero has explained that the draft CDC guidelines are based on a riskassessment that considers cleaning and prion bioburden from contact withinfectious tissues.39 In addition, one must consider the risk ofinfection associated with the use of the medical device. The three categories ofmedical devices are critical, semicritical, and noncritical. Items assigned tothe critical category present a high risk of infection if contaminated with CJDas it enters a sterile tissue or the vascular system. This category includessurgical instruments and implants. Semicritical items (e.g., endoscopes,respiratory therapy equipment) are devices that come in contact with mucousmembranes or skin that is not intact. In general, these items should be free ofall microorganisms with the exception of small numbers of bacterial spores.Transmission of CJD via contact with mucous membranes or non-intact skin has notbeen described. Noncritical items (e.g., floors, walls, blood pressurecuffs, patient furniture) come in contact with intact skin but not mucousmembranes. Intact skin should act as an effective barrier to microorganisms andprions. Thus, a critical or semicritical device that has contact with high-risktissue (e.g., brain) from a high-risk patient (e.g., suspected orknown CJD) must be reprocessed in a manner to ensure prion elimination. Thecombined contribution of cleaning and an effective physical or chemicalreprocessing procedure should eliminate the risk of CJD transmission. Criticalor semicritical instruments or medical devices that have contact with low or norisk tissue can be treated using conventional methods, as the devices have notresulted in transmission of CJD (Appendix).

To assess the effectiveness of disinfection or sterilization procedures onemust consider the inactivation/removal factor47-49); that is, thereduction of infectious units during the disinfection or sterilization process.Thus, the probability of an instrument remaining capable of transmitting diseasedepends on the initial degree of contamination and the effectiveness of thedecontamination procedures. An instrument contaminated with 50 mg of CJD brainwith a titer of 5.0 LD50 intracerebral units/g24 wouldhave 5 x103 infectious units. It has been suggested a titer loss of104 prions should be regarded as indicating appropriate disinfectionof CJD.49 However, the effectiveness of a disinfection orsterilization procedure should be considered in conjunction with theeffectiveness of cleaning. Studies with microbial agents demonstrate thatcleaning by conventional methods used in healthcare results in a 104reduction of microbes. Thus, cleaning followed by disinfection would result in atiter loss of 107 (4-log reduction with cleaning plus >3-logreduction with an effective disinfection process) while tissues with high prioninfectivity (e.g., brain) would be contaminated with 105 prion/gram.Cleaning followed by a disinfection or sterilization procedure should destroyinfectivity and provide a significant safety margin.

Disinfection

Results of chemical inactivation studies of prions have been inconsistent dueto the use of differing methodologies including: strain of prion (e.g.,prions may vary in thermostability but differential susceptibility todisinfectants has not been described), prion concentration in brain tissue, testtissues (intact brain tissue, brain homogenates, partially purifiedpreparations), test animals, duration of follow-up of inoculated test animals,exposure container, log decrease calculated from incubation period assays notendpoint titrations, concentration of disinfectant at the beginning and end ofan experiment (e.g., chlorine), exposure conditions, and cycle parametersof the sterilizer.42 Despite these limitations, there is someconsistency in the results. An important limitation of current disinfectionresearch is that currently prion assays are slow, laborious, and costly. Studiesevaluating the efficacy of combined cleaning and disinfection have not beenpublished.

It has been established that most disinfectants are inadequate foreliminating prion infectivity. There are four chemicals that have beendemonstrated to reduce prion titers by >4-logs: chlorine, a phenolic,guanidine thiocyanate, and sodium hydroxide (Table 3). 47-55 Of thesefour chemical compounds the disinfectant that is available and provides the mostconsistent prion inactivation results is chlorine but even chlorine has hadunexplainable reduced activity (e.g., reduction of 3.3-logs of CJD in 60min by 2.5% hypochlorite).52 The corrosive nature of chlorine wouldmake it unsuitable for semicritical devices such as endoscopes. Severalinvestigators have found that 1N NaOH51,56,57 incompletelyinactivates 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 inTable 3.47-49,52,55,58-61 Studies have also shown that aldehydes suchas formaldehyde enhance the resistance of prions and pretreatment of scrapie-infectedbrain with formaldehyde abolished the inactivating affect of autoclaving.62A formalin-formic acid procedure is required for inactivating prion infectivityin tissue samples from patients with CJD63.

Both flexible and rigid endoscopes have been used in neurosurgery.64,65If such scopes come into contact with high-risk tissue in a patient with knownor suspected CJD, either they should undergo sterilization (if possible, seebelow) or single-use devices should be used. Endoscopes coming into contact withother 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 physicaldecontamination methods. These include both gaseous (i.e., ethylene oxideand formaldehyde) and physical processes (e.g., dry heat, glass beadsterilization, boiling, and autoclaving at conventional exposure conditions [e.g.,121oC for 15 min]).42,48,52,55 Rohwer's data suggest thatthe majority of scrapie infectivity is inactivated by brief exposure totemperatures of 100oC or greater. For example, when scrapie strain263K was exposed to 121oC, 99.9999% of the infectivity was destroyedduring the minute required to bring the sample to temperature. At 100oC,97% was destroyed within 2 minutes of exposure at temperature. Thus, only afraction of the infectious activity is extremely resistant.46

Standard gravity displacement steam sterilization at 121oC hasbeen studied using different strains of CJD, BSE and scrapie and has been shownto be only partially effective even after exposure times of 120 min. As thetemperature and exposure time increases, greater inactivation of the prionagents was achieved (Table 4). While there is some disagreement of the idealtime and temperature cycle,41 the recommendation for 121-132oCfor 60 min (gravity) and 134oC for >18 min (prevacuum) arereasonable based on the scientific literature. These methods should result in adecrease of >5-logs and cleaning should result in a 4-log reduction providinga significant margin of safety (brain tissue concentration 105 prion/gram.24Other 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 resultsin complete inactivation of infectivity (>7.4-logs).54 However,the combination of sodium hydroxide and steam sterilization may be deleteriousto surgical instruments.42

Conclusion

Prion diseases are rare and hence do not constitute a major infection controlrisk. Nevertheless, prions represent an exception to conventional disinfectionand sterilization practices. These guidelines for CJD disinfection andsterilization are based on consideration of epidemiological data, infectivitydata, and cleaning and inactivation studies. Guidelines for management of CJDinfected patients and patient equipment should be modified as scientificinformation becomes available. Importantly, studies assessing the susceptibilityof vCJD to disinfectants and sterilants should be undertaken. In addition,studies consistent with actual clinical practices (e.g., operation ininfected animals followed by cleaning with enzymatic detergents and disinfectionor 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 asdirector of the departments of Hospital Epidemiology (Infection Control),Occupational Health, and Safety Program for the University of North CarolinaHealth Care System. In addition, Dr. Rutala is the director of the NorthCarolina Statewide Program in Infection Control and Epidemiology. Dr. Rutala haspublished 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 andPediatrics, School of Medicine and a professor in the Department of Epidemiology,School of Public Health, University of North Carolina at Chapel Hill. He servesas medical director of the Departments of Hospital Epidemiology (InfectionControl), Occupational Health, and Safety Program for the University of NorthCarolina Health Care System. Dr. Weber has published more than 250 papers in thefield of infection control.

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Test Questions: True or False

  • Transmissible spongiform encephalopathies (e.g., Creutzfeldt-Jakob disease) are common diseases.

  • Creutzfeldt-Jakob disease occurs with a frequency of approximately 1 per million population.

  • Transmissible spongiform encephalopathies are caused by prions, an abnormal protein that accumulates in the central nervous system.

  • Prions demonstrate an unusual resistance to standard methods of disinfection and sterilization.

  • The same agent that causes bovine spongiform encephalopathy causes variant Creutzfeldt-Jakob disease.

  • Variant Creutzfeldt-Jakob disease has rarely been reported in the United States.

  • 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).

  • Iatrogenic Creutzfeldt-Jakob disease has occurred due to use of medical instruments contaminated with central nervous tissue

  • 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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