Interventions to reduce the risk of surgically transmitted Creutzfeldt Jakob disease: a cost-effective modelling review

Cost-effectiveness searches

A literature search was undertaken to identify evidence relevant to the cost-effectiveness model such as relevant economic evaluations in CJD.

Four electronic databases were searched on 7 June 2017 from 2004 to present:

• MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations – via Ovid, 1946 to 2017

• EMBASE – via Ovid, 1974 to 2017

• The Cochrane Library (Wiley Online Library) Cochrane Database of Systematic Reviews, 1996 to 2017; Health Technology Assessment Database, 1995 to 2016; NHS Economic Evaluation Database, 1995 to 2015

• Science Citation Index and Conference Proceedings Citation Index – Web of Science, 1990 to 2017.

The search strategy comprised Medical Subject Headings or Emtree thesaurus terms and free-text synonyms for ‘CJD’. Searches were translated across databases and were not limited by language. The search strategies are presented in Appendix 2. Search filters designed to identify economic evaluations were used on MEDLINE and EMBASE.

Study selection

Results from the electronic bibliographic searches were imported into reference management software, EndNote Version 8 [Clarivate Analytics (formerly Thomson Reuters), Philadelphia, PA, USA], and duplicates were removed. Titles and abstracts of retrieved records were examined by one reviewer (LU) and irrelevant citations were excluded. A proportion (10%) of randomly selected excluded citations were double-checked by a second reviewer (CC) and any disagreements were resolved by discussion between the reviewers. Consultation with the third designated team member (MS) was not required for any citation. At the full-paper stage, all citations excluded from a particular review question by the reviewer were double-checked by the second reviewer. Lists of these citations, with the principal reason for exclusion, are reported for each review in Appendix 3. Data identified from countries outside the UK were incorporated if deemed relevant.

Literature identified within the cost-effectiveness review was processed in a similar manner. Titles and abstracts of retrieved records were examined by one reviewer (MS) and irrelevant citations were excluded. A proportion (10%) of randomly selected excluded citations were double-checked by a second reviewer (LU). All full-text articles were independently assessed for inclusion by two reviewers (MS, and LU). No disagreements were required to be resolved through discussion or with involvement of the third designated team member (CC).

Data extraction

Bespoke data extraction forms were developed for each review question in Microsoft Excel^® (Microsoft Corporation, Redmond, WA, USA) to record relevant outcome data for the review question in hand. All data were extracted by one systematic reviewer (LU for reviews 1, 2 and 4; CC for reviews 3, 5, 6, 7 and 8) and independently checked by a second reviewer (LU for reviews 3, 5, 6, 7 and 8; CC for reviews 1, 2 and 4). Any disagreements were resolved by discussion and consensus or by consulting with a third member of the project team (MS).

Quality assessment

Formal quality assessment using standard checklists, such as the Cochrane risk-of-bias tool, was considered for these systematic reviews. The value of conducting quality assessment is to assess how a study has been conducted in order to balance the numerical findings (or the statistical strength of effects) against the methodological quality. There are a range of quality assessment tools available depending on the study type included; quality assessment is not only amenable to a review of RCTs. However, none of the review questions sought data that were estimating treatment effects; therefore, the typical domains of quality assessment, such as randomisation, performance bias, detection bias and attrition bias, are less relevant. Furthermore, in many cases, the included ‘studies’ in this review were not amenable to quality assessment because (1) they are surveillance reports, thereby not constituting the traditional definition of a study or (2) they are laboratory studies using highly specific scientific methods that are not amenable to the quality assessment for clinical trials. As these included studies were mainly observational in nature, the data of interest were less vulnerable to author conflicts of interest or systematic bias. Assessment of study heterogeneity is most important when performing formal synthesis to estimate treatment effects, which is not the objective of this review. Indeed, limitations to review inclusion criteria based on study design, scientific discipline, setting or context would potentially have restricted the external validity of the review. Therefore, no formal quality assessment has been undertaken and the protocol for the systematic review, registered on the PROSPERO database (CRD42017071807), was updated accordingly. 21 The purpose of the reviews was primarily to describe the relevant literature rather than to aggregate data or rank individual studies.

Data analysis/synthesis

Data were tabulated, synthesised and discussed narratively for each review question. Meta-analyses were planned to be conducted by an experienced statistician using appropriate software, and heterogeneity was to be explored using meta-regression where comparable data were available. However, no suitable data were identified for formal aggregation using meta-analysis.

Meta-biases and assessment of external validity

Owing to the complex nature of the clinical topic, the number of review questions and the diverse information required to inform the economic model, the systematic reviews were methodologically challenging. To obtain high-quality, trustworthy data and to maintain the external validity of the reviews, the inclusion criteria were kept broad until full text retrieval. After discussion within the project team and with the NICE committee experts, a decision was made to take a broad approach during the assessment of study relevance, rather than applying stringent inclusion criteria.

The risk of this approach was that the evidence generated from the reviews was less amenable to replication. However, the purpose the clinical reviews was to inform commissioners about potential risks of CJD transmission via surgery rather than estimating treatment effect. Therefore, a more inclusive methodological approach by the evidence review group in this complex clinical topic was deemed justifiable.

Increase in the UK sporadic Creutzfeldt–Jakob disease incidence over time

Between 1990 and 2017, the NCJDRSU recorded figures of iCJD [from receipt of human gonadotrophin (hGN), human-derived growth hormone or dura mater) and vCJD, which were relatively low compared with sCJD. Figure 2 plots the number of deaths in the UK that have been attributed to definite or probable CJD between 1996 and 2017 (as of 2 May 2018) as reported by the NCJDRSU. An increase in sCJD cases is noted over the 27-year period, whereas iatrogenic, genetic and variant forms remain rare.

FIGURE 2.

Deaths attributed to definite or probable CJD in the UK, using data from the NCJDRSU, between 1996 and 2017. 30

Possible reasons for the increase in the detection of sCJD cases in the UK are speculated to include:

• improved case ascertainment because of clinician awareness and/or improvements in diagnostic testing

• population increases

• an ageing population

• changes to the sporadic case definition to include cerebrospinal fluid and magnetic resonance imaging (MRI) diagnostic tests.

An upwards trajectory of CJD cases may be attributable to the way that data are collected for the surveillance of CJD. Case ascertainment is likely to improve in areas where CJD surveillance is strong, where there is greater awareness among health-care professionals of CJD and where there are more neurologists who are able to diagnose CJD. As the national surveillance programme for CJD has been operating since May 1990, and is a prospective surveillance programme, there are likely to be improvements over time with respect to how this rare condition is detected, referred, investigated and reported when compared with retrospective surveillance studies. Moreover, owing to the potential for iatrogenic transmission, there has been a focused collaborative effort to examine the evidence of transmission through different exposures by examining the links to confirmed CJD cases through retrospective ‘lookback’ studies. 31

The gradual increase in sCJD but not gCJD, adds support to the ‘ageing population’ theory over merely population increase and improved case ascertainment.

Increase in sporadic Creutzfeldt–Jakob disease incidence globally

Reports of increased rates of sCJD were noted from other countries. In Finland, an increased incidence of sCJD was noted between 1974 and 1989 of 0.6 per million to 1.36–1.44 per million in 2007–13, as reported in an abstract by Isotalo et al. 32 An abstract by Chen33 reports that sCJD incidence rates in Taiwan doubled between 2008 and 2015. They also report that age at onset became younger. Chen33 speculates that the reasons for the increase in CJD cases include physician’s sensitivity in recognising CJD; improved reporting systems; concerns around vCJD, and high media coverage. A published study34 from Belgium noted a relevant trend of significantly increased age-specific incidence of sCJD patients between the age of 70 and 90 years in the period 2002–04 compared with 1998–2001, using retrospectively obtained data (1990–1997; p < 0.01). The authors conducted a clinical and biochemical analysis to investigate this increase, but could not identify any reason other than an increased vigilance for the diagnosis. Similarly, in Japan, Ae et al. 35 report in a study abstract that the annual incidence of human prion diseases has increased since 1999, particularly so in older patients (aged ≥ 70 years), with cases of rapidly developing dementia increasingly being identified by domestic physicians.

One study from Slovenia reported an apparent fluctuation of sCJD cases in 2015, with seven definite and two probable sCJD cases resulting in an incidence of 4.36 per million for the country that year. 36

Autopsy and biopsy in Creutzfeldt–Jakob disease

In the UK, confirmation of CJD from neuropathological (via autopsy or brain biopsy), immunocytochemical or biochemical examination is required for obtaining a definitive sCJD diagnosis. For vCJD, confirmation must be from neuropathology. 1 Despite the observed increase in sCJD cases over the last twenty years, autopsy is not performed routinely on sCJD cases. In the UK, almost 50% of all cases referred to the NCJDRSU undergo autopsy. 2 The most recent case of vCJD appeared in its clinical presentation and neuroimaging to be sCJD, but as the age of the patient was atypically young (aged 36 years), a pathological examination after death in February 2016 confirmed it to be vCJD despite the absence of clinical epidemiologic diagnostic criteria for probable or possible vCJD. 37 On the basis of this recent vCJD case, pathological examination of every sCJD case would be required to know the true figures of autopsy-proven sCJD and vCJD. Given this, an alternative explanation for the increasing number of sCJD cases over the last 20 years could be attributable to an altered incubation and clinical presentation of acquired CJD (variant or iatrogenic CJD) that mimics sCJD or another neurological condition. Indeed, surgery has been posited as a risk factor the transmission of sCJD by a number of epidemiological studies; a retrospective study by Urwin et al. ,38 described as ongoing, is seeking to investigate this risk factor further by reviewing UK sCJD cases.

Cursory analysis of published literature from studies on CJD around the world generates potential reasons for why autopsy is not always routinely completed in sCJD patients. Brain biopsy and autopsy of suspected CJD cases carry the risk of iatrogenic transmission to medical or pathology staff, meaning that there is an extra burden of duty to ensure that stringent infection control protocols are followed. Protocols for instrument decontamination are required for brain biopsy. For example, Shi et al. 39 state that although an intracranial biopsy procedure is invasive and carries risk of cerebral infection or hematoma, it is generally a safe and well-tolerated procedure; however, special precautions to prevent the spread of prions must be taken. Medical instruments and equipment supplies must be either destroyed by incineration or autoclaved and sterilised. Similarly, Baig and Phillips. 40 state that getting a biopsy in a timely manner is often not possible given the costly and aggressive nature of the diagnostic test and that the rigorous decontamination and sterilisation techniques for handling tissue at biopsy may make it impractical in a community setting.

Ethnic and geographical differences

Variations in CJD incidence according to ethnicity by Maddox et al. 41 and Holman et al. 42 were noted in the literature. In the USA, the age-adjusted CJD incidence for white people was reported as being 2.7 times higher than that for black people (1.04 and 0.40 per million, respectively). Similarly, the estimated incidence of CJD (0.7 per million) among Asians and Pacific Islanders in the USA between 2003 and 2009 was reported by Maddox et al. 43 as being significantly lower than that for white people (p < 0.001).

Nakatani et al. 44 noted that the occurrence of sCJD appeared to have regional variations in Japan, suggesting that the existence of genetic or region-specific factors may affect the incidence of the disease, such as hereditary background or other local factors. In this study, geographical clusters of sCJD were scattered in the western half of Japan. However, no direct evidence to support theories about the causative factors underlying this trend are presented and, therefore, this particular phenomenon remains to be explored. Klug et al. 45 conducted a spatial and epidemiological analysis of sCJD case-clusters in Australia. The authors concluded that the observed increase of sCJD cases in a geographic area is more likely to be related to better awareness of the disease by local neurologists rather than to an increase in risk factors.

Genetic forms of CJD are most often associated with a mutation at codon 200. 46 Mitrova et al. 47 report that although gCJD represents approximately 10–15% of all CJD patients in the majority of countries, in Slovakia the rate of gCJD has been higher than 65% since 1975 owing to an accumulation of gCJD incidence in two clusters in central Slovakia. The authors state that all but one of the 202 patients who had gCJD in Slovakia carried the mutation form E200K and highlight that asymptomatic carriers of this gene could contribute to iatrogenic transmission of CJD. A voluntary genetic testing study conducted by the authors showed positivity for the E200K mutation in 9 out of 2662 subjects who were unrelated to the gCJD cases both inside and outside the focal cluster. This finding indicates an unusual phenomenon of an increased prevalence of the E200K mutation linked to gCJD in the Slovak region. A study by Ladogana et al. 48 reported similar prevalence of sCJD across the UK, France, Germany, Italy, the Netherlands and Slovakia, but also reported an excess of genetic cases in Italy and Slovakia.

Geographical differences in CJD incidence are likely to be influenced by ascertainment bias in countries where access to health care is free and, moreover, when active national CJD surveillance is in place.

Diagnosis of Creutzfeldt–Jakob disease

Global differences in the culture of pursuing autopsy to confirm CJD diagnosis and subtype are likely to exist depending on national CJD surveillance protocols. For example, Tuskan–Mohar et al. 49 report that post-mortem examination was not performed in any of the five cases of CJD occurring in Croatia between 2001 and 2011 owing to patient families’ refusal of the procedure. More generally, Kosier50 state anecdotally in a US case report that the diagnosis of CJD is often delayed because of clinician bias towards more obvious possible medical or psychiatric causes. Litzroth et al. 51 highlight that in Belgium, between 1998 and 2012, on average 60% of hospitalised patients who died with suspected CJD were captured by the surveillance system. The authors also report that 11% of surveyed neurologists would not refer suspect vCJD cases for autopsy, nor contact a reference centre for diagnostic support and that 61% of surveyed neurologists were not familiar with the surveillance system.

Two studies from Ireland describe a relatively sensitive surveillance system for CJD detection but less accuracy in obtaining a final confirmatory CJD diagnosis. From a review of 21 referrals to the National CJD Centre in Ireland, Brett et al. 52 found that only five referrals were positive for CJD, with 12 being referred as part of their differential diagnosis. Brett et al. 52 cautioned that, more often than not, the clinical suspicion of CJD was not borne from the final neuropathological diagnosis and that failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel. Loftus et al. 53 also raised the issue that the terms ‘probable CJD’ and ‘definite CJD’ might be used indiscriminately. They highlight from an analysis of 100 cases of CJD in Ireland, that approximately half of cases (50/96 referrals) were confirmed as definite CJD via tissue samples through biopsy or autopsy. 53 The authors proposed an algorithm for CJD referrals to reduce infection control and diagnostic difficulties encountered in CJD surveillance.

Despite the fact that sCJD is a condition known to affect older people, its detection may have improved in the last 6 years. Figure 3 is taken from the 25th Annual Report of the NCJDRSU2 and shows a steep increase in the detection of CJD mortality in the UK,2 particularly in the age category of 65–69 years. However, incidence using age-adjusted data of CJD-related deaths per million will be influenced by the assumed population in each band. The mortality rates for 1995–2004 use the same census data as those for 2005–9. However, if there are proportionately more older people in the more recent age band, the incidence will be inflated.

FIGURE 3.

Age-specific mortality rates from sCJD in the UK 1970–2016: reproduced from NCJDRSU Annual Report 2016. 2 1970–1984 mortality rates calculated using mid-1981 England and Wales population estimates based on the 1981 Census. 1985–1994 mortality rates calculated using mid-1991 UK population estimates based on the 1991 Census. 1995–2004 mortality rates calculated using mid-2001 UK population estimates based on the 2001 Census. 2005–2009 mortality rates calculated using mid-2001 UK population estimates based on the 2001 Census. 2010–2016 mortality rates calculated using mid-2011 UK population estimates based on the 2011 Census. Reproduced with permission from the National CJD Research & Surveillance Unit, University of Edinburgh. 2

Reproduced with permission from the National CJD Research & Surveillance Unit, University of Edinburgh.

Owing to the median age at onset of sCJD symptoms, it is possible that CJD and prion disease cases may be concealed among cases of more commonly encountered but similarly rapidly deteriorating neurological conditions affecting older people, such as Alzheimer’s disease. In the published literature, there are numerous reports of CJD mimicking other conditions including stroke,54,55 acute neuropathy,56 hyperparathyroidism,57 dementia,51,58–61 Lewy body dementia,51 encephalitis,51 aphasia,62 Alzheimer’s disease,51,60 psychiatric decompensation50 and movement disorder. 63 The potential for CJD cases to be misdiagnosed was first demonstrated in a study in 1995 which found from an analysis of dementia autopsies that only about 60% of prion disease cases with pathologically typical spongiform encephalopathy were identified clinically during life. 64 Therefore, the observed rates of any type of CJD could still be an underestimate of the actual rate of CJD deaths in the absence of definitive pathological examination of all cases. It is also plausible that numerous cases of CJD that occur later in life, particularly where access to clinicians with experience of diagnosing CJD is limited, may result in some cases of misclassification of CJD, despite potentially improved detection. However, given the rarity of CJD presentation worldwide and consequent clinical expertise, a degree of caution should be exercised in the interpretation of the limited available data.

Disease duration

Disease duration is regarded as the time between the onset of clinical CJD symptoms and death. sCJD is commonly reported to have a disease duration of 4–7 months;2,22,65–67 however, Nagoshi et al. 68 report that duration of disease was longer for sCJD in Japan than in Western countries. The authors state that sCJD, which represented 77.0% of cases of prion disease in their surveillance network between 1999 and 2008, had a mean disease duration of 15.7 months. This longer disease duration in Japan is more akin to the median observed in the UK for vCJD, which is 14 months from the onset of symptoms to death (NCJDRSU’s 2016 annual report2) or indeed iCJD via human growth hormone (hGH), the median of which is reported as 16 months (mean 14 months) for 22 iCJD patients. 69 Nagoshi et al. 68 also report that disease duration was longer in females (19.7 months) than males (14.5 months) for sCJD and that this tendency was also true for dura mater iCJD and types of gCJD including human GSS syndrome and FFI. Nagoshi et al. 68 also report that younger onset of disease was associated with longer disease duration for all types of CJD.

Genotype: codon 129

Methionine homozygosity at codon 129 (MM) is considered the most susceptible genotype for CJD, with sCJD and vCJD occurring mostly in individuals with the MM genotype. Both methionine (MM) and valine (VV) homozygotes at codon 129 of PRNP are at an increased risk of sCJD. 70 In the north of Europe, the MM genotype represents 38% of the general population, whereas 11% of the population have the VV genotype and 51% are heterozygotes (methionine/valine; MV) at codon 129 of PRNP. 71 An epidemiological study by Giaccone et al. 72 of the PRNP genotype of 402 consecutive sCJD cases in Italy revealed that 70.4% (n = 283) had the MM genotype, 15.4% (n = 62) were MV and 14.2% (n = 57) were VV. 72 Although the numbers of MV and VV sCJD cases appear comparable in this study, the fact that over half of the population in Europe are MV indicates that the relative incidence of sCJD in heterozygotes at codon 129 is low.

In 2006, Ironside et al. 73 re-analysed three of the appendixes identified (from the 12,674 appendix and tonsil samples analysed by Hilton et al. 7) as positive for disease-associated PrP; two of the three were found to be VV genotype, which provided the first indication that the valine homozygotes are also susceptible to vCJD infection. 73 The authors suggested that people infected with vCJD who are VV may have a prolonged incubation period with subclinical infection that could cause secondary infection via blood transfusion or surgery. Additionally, detection of subclinical prion accumulation in peripheral tissue by Gill et al. 74 from 16 positive appendix samples found that eight were MM, four were MV, and four were VV at codon 129 of PRNP, indicating that genetic susceptibility for subclinical CJD was more equally distributed in the population.

Heterozygosity at codon 129 of PRNP was generally believed to confer complete resistance to both sporadic and acquired prion diseases. 75 However, the most recent case of clinical vCJD in 2016 was heterozygous37 and an additional possible vCJD case reported by Kaski et al. 76 in 2008 was also heterozygous, but this possible vCJD case was not confirmed by autopsy. Two case reports indicate that the MV genotype is susceptible to iCJD, but the cases were subclinical. First, the case of a heterozygous 73-year-old male with haemophilia whose spleen at autopsy gave a strong positive result on repeated testing for protease-resistant prion protein (PrP^res) by western blot analysis, as reported by Peden et al. 77 This patient had received over 9000 units of factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor. Second, a case in 2004 of subclinical vCJD from blood transfusion, who was heterozygous at codon 129, and died from a cause unrelated to CJD78 highlights the possibility of potential transmission to this genotype. A study using mice supports the notion that transmission efficiency of vCJD is greatest in MM but indicates that all genotypes are susceptible, with the MV and VV genotypes benefiting from apparent reduced transmission efficiency and longer asymptomatic incubation periods. 79

Disease duration and genotype

Prion protein–gene data from 378 of the Japanese patients diagnosed with sCJD, reported by Nagoshi et al. ,68 showed that 364 cases (96.3%) had the MM genotype but that disease duration was longest for the 11 patients (2.9%) who were MV (mean, 32.2 months for MV vs. 16.6 months for MM and 13.2 months for VV). 68 Begué et al. 26 report data for the disease duration of sCJD from 59 definite cases in Argentina. Genotype analysis indicated that the MV genotype was associated with the longest disease duration (10.9 months), followed by the VV (5.6 months) and the MM genotypes (3.6 months). 26 Data from Rudge et al. 69 relating to CJD transmission via hGH in the UK also found that MM patients had the shortest disease duration; MM patients had a mean disease duration of 7.8 months, the VV patients 17 months and MV patients had a mean disease duration of 18.6 months (range 10–32 months). In addition, the duration of disease from first symptom was significantly longer in the MV patients (p = 0.02, two-tailed t-test). Although there were only four patients who were MM, three of these had the most rapid disease progression (p = 0.04, Mann–Whitney U-test). Yamada et al. 24 state that the majority of the general Japanese population (93%) carry the MM genotype. Considering that a large share of patients in the Argentinian sample also contained the MM genotype (n = 37, 66%), genotype data at codon 129 alone cannot account for the substantial difference in disease duration for sCJD reported between Japan and other countries.

Data from Japan,68 Argentina,26 and the UK69 therefore indicate that the MV genotype is associated with the longest disease duration compared with homozygotes. Pennington and Knight80 also reported disease duration to be significantly longer in codon 129 heterozygotes for gCJD.

Variant Creutzfeldt–Jakob disease

The annual number of confirmed cases of clinical vCJD has declined since 2005. As of 2016, the NCJDRSU recorded 178 cases of vCJD in the UK. 1 The most recent vCJD case occurred in an individual who was heterozygous at codon 129. 37 A further 52 cases have been reported from other countries around the world, which brings the global total of clinical vCJD cases to 231. 81 Between 2005 and 2014, 68 vCJD cases were reported from 11 countries including the UK (n = 29), France (n = 19), Spain (n = 5), Ireland (n = 3), the USA (n = 3), Holland (n = 3), Portugal (n = 2), Italy (n = 1), Canada (n = 1), Saudi Arabia (n = 1) and Taiwan (n = 1). 22 A total of 3 out of the 178 cases in the UK that occurred up to 2016 are considered to have occurred through blood transfusion. 2 A fourth case of vCJD transmission through blood transfusion was identified in the spleen of an individual (heterozygous at codon 129) who died of a non-CJD related cause. This is considered to be preclinical vCJD. 78 Three further potential, but unconfirmed, cases of CJD transmission through blood transfusion are described by Chohan et al. 82 and Davidson et al. 83 A retrospective study by Molesworth et al.,84 which was performed to identify situations where the transplantation of organs or tissues might have occurred in any of the 177 UK vCJD cases, found no evidence of transplant-associated vCJD in the UK. 84 The remaining 175 clinical vCJD cases are presumed to be related to dietary exposure to BSE. 85

Iatrogenic Creutzfeldt–Jakob disease

The most common causes of iCJD were hGH and dura mater grafts obtained from human cadavers. A review of worldwide iCJD cases published by Brown et al. 3 identified 469 cases from dura mater grafts (n = 228), surgical instruments (n = 4), EEG needles (n = 2), corneal transplants (n = 2), hGH (n = 226), hGN (n = 4) and packed red blood cells (n = 3). 3

In the UK, 85 cases of iCJD were identified between 1970 and December 2016, and are described by the NCJDRSU. 1 In total, eight cases were from dura mater grafts, 76 from hGH and one from hGN. All cases have since died, with a mean age at death for the hGH/hGN group of 35 years (range 20–51 years) and for the dura mater cases 46.5 years (range 27–78 years).

Subsequent to the three cases of blood transfusion transmitted vCJD described above, no new cases of transfusion-associated infection have been identified since 2007, based on an epidemiological analysis of CJD cases and blood transfusion recipients by Urwin et al. 86 The Urwin et al. 86 study referenced the Davidson et al. 83 paper but not the Chohan et al. 82 paper. These two papers discuss three potential, but unconfirmed, cases of CJD transmission via blood transfusion. Ward et al. 87 studied the risks in treatment for haemophilia and concluded that it is unlikely that any of the UK vCJD clinical cases to date were infected through exposure to fractionated plasma products. 87 The evidence regarding the incidence of iCJD from surgery is discussed in the review on the risk of CJD transmission via surgery.

Variant Creutzfeldt–Jakob disease and bovine spongiform encephalopathy

The hypothesis of zoonotic transmission through dietary exposure from the BSE outbreak is largely upheld as the most plausible route of vCJD infection in humans, and transmission has been replicated in wild-type mice. 90 Moreover, a recent study by Diack et al. 91 examined two Spanish cases of vCJD: a mother and son who resided in a BSE-endemic area, who are thought to have ingested bovine brain. 91 The strain characteristics of both individuals are similar to the UK cases, implying BSE as the source of infection and supporting the hypothesis of risk via ingestion of high-titre bovine material.

The Appendix III study75,76 highlights that abnormally stained appendixes associated with vCJD prion accumulation have been confirmed in cohorts of people who were not considered to have had significant exposure to BSE because they were either from appendixes removed before the BSE epidemic in the UK (prior to 1980) or from appendixes from patients born after food safety measures to limit BSE were implemented (after 1996). The presence of seven positive samples in these cohorts could suggest that there is low background prevalence of abnormal prion protein staining in human lymphoid tissue that may not represent subclinical vCJD or be related to the BSE outbreak, and may be unlikely to progress to vCJD. Another possible interpretation is that the duration of the BSE epidemic and subsequent ingestion by humans through the food chain was longer than the presumed duration of human exposure to the BSE epidemic (between 1980 and1996). Moreover, planned statistical analysis, as described by Gill et al. ,74 found no difference between the prevalence observed in the cohort considered to be most at risk of the BSE epidemic (people born 1961–85) and an older cohort (born 1941–60).

These two possible explanations are considered by the ACDP TSE subgroup as not necessarily being mutually exclusive nor fully satisfactory.

Previous estimates of prevalence of abnormal prion in humans

Primary studies (published after 2005) that provide estimates for subclinical CJD in the general population based on analysis of peripheral tissue are described in Table 4. Central estimates range between 0 and 493 per million people in the population. Studies providing evidence of the prevalence of vCJD prions in lymphoid tissues published prior to 2005 are described in a review published by Olsen et al. 94 This review includes the cross-sectional study by Hilton et al. 7 that estimated the prevalence in the sample population to be 120 per million from 11,228 appendixes.

Obtaining definitive prevalence estimations

Subclinical vCJD can be detected through typical PrP staining in lymphoid tissue or through observation of the presence of florid plaques in the brain at autopsy; however, systematic lymphoid or neuropathological examination is not performed routinely in post-mortems. To collect a truly accurate picture of the prevalence of CJD through abnormal prion protein in humans, the UK Health Protection Agency proposed the creation of a post-mortem tissue archive. 95 The study required tissue from a large number of post-mortems and the participation of coroners in England and Wales. However, the Coroners’ Society of England and Wales (CSEW) declined to participate in the study, citing various issues including its putative legality, cost and feasibility. 96 The CSEW concluded that to participate in the study would ‘adversely affect the independence of the coronial service and would further erode public confidence’. 97 McGowan and Viens95 describe that as death investigation systems with substantial independence are not directly answerable to central government, they cannot be instructed to participate in any disease surveillance programme, regardless of how crucial it is to the protection of human health and safety.

Issues of reliability and validity in case–control studies

Because sCJD is idiopathic, its aetiological basis is presumed to be spontaneous but this is not known with any certainty. 89 Therefore, case–control studies are a frequently encountered design in estimating possible and plausible risk factors for sCJD. de Pedro-Cuesta et al. 112 caution about the potential biases in these study designs in an assessment of 18 case–control studies of CJD. From a combined analysis of studies, the authors found that history of surgery or blood transfusion was associated with a risk of sCJD in some, but not all, recent studies using a 10-year or longer lag time, when controls were longitudinally sampled. Furthermore, they found that none of surgical history, blood transfusion, dental treatments or endoscopic examinations was linked to vCJD. However, the authors highlight that the validity of the findings in these case–control studies may be undermined by (1) the selection of control cases; (2) exposure assessment in lifetime periods of different durations; (3) disregarding ‘at-risk’ periods for exposure in the controls, or asymmetry between the case and control data; and (4) confounding by concomitant blood transfusion at the time of surgery. They also postulate that surgery at early clinical onset might be over-represented among cases.

As a retrospective study design, case–control studies are prone to bias. The source of cases and the selection of control (matched or unmatched) cannot be performed blindly or impartially; therefore, there is a high risk of selection bias on the researcher’s part. Owing to long incubation periods and the reliance on family members’ reports of medical histories, there is also substantial likelihood of recall bias. Case–control designs are also less useful when the study exposures are rare, as in the case of surgery or blood transfusion. Therefore, the utility of these studies in attempting to fairly estimate risk factors is limited. However, as CJD is rare, fatal and has a potentially long latency period, there are few plausible alternative study designs to establish potential lifetime risk factors in humans. Therefore, the use of community controls and ascertainment of surgical exposures through the use of medical records in case–control designs is currently the most feasible approach for identifying the potential association between surgery and CJD at a population level.

Risk of Creutzfeldt–Jakob disease through occupational exposure for health-care professionals

In 2009, the Spanish CJD registry was notified of a case of sCJD in an experienced general pathologist/neuropathologist, which prompted investigation into the possible risks to health-care professionals in contact with CJD patients. 113 As a result, Alcade-Cabero et al. 113 reported the data requested from the EuroCJD surveillance network, which documented 65 physicians or dentists (including two pathologists) and 137 health-care workers from 8321 registered sCJD cases from 21 countries. Control data, which used ‘non-cases’ from five countries, recorded 15 physicians and 68 other health-care professionals among 2968 controls or non-cases, and suggested that there was no relative excess of sCJD among health-care professionals. The study authors also performed a literature review examining reports (n = 12) pertaining to 66 health-care professionals with sCJD, and analytical studies on health-related occupations and sCJD (n = 5). From a range of occupations, only people working at physicians’ offices were found to be at a statistically significant risk of sCJD [odds ratio (OR 4.6, 95% CI 1.2 to 17.6)]. The authors concluded that a wide spectrum of medical specialties and health-care professions are represented in sCJD cases and that there is no evidence of an increased occupational risk for health-care professionals. The authors do caution that there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue. The NCJDRSU continue to monitor occupational exposure to CJD in health-care professionals.

Risk of Creutzfeldt–Jakob disease in surgery and age

de Pedro-Cuesta et al. 114 performed a retrospective analysis of 167 cases of sCJD between 1987 and 2003. From a study of 167 probable or definite CJD cases and 835 matched controls, the authors suggest that a younger age at first surgery may increase the risks of acquiring sCJD: patients aged < 30 years (OR 12.80, 95% CI 2.56 to 64.00), patients aged 30–39 years (OR 3.04, 95% CI 1.26 to 7.33) and patients aged ≥ 40 years (OR 1.75, 95% CI 0.89 to 3.45), for anatomically classified surgical procedures. As highlighted by the same authors in a different study,112 caution should be urged when interpreting conclusions from analyses on indirect evidence in retrospective samples. Additionally, the ≥ 40-year age group contains those who are elderly and may die before clinical symptoms appear or may remain undiagnosed.

Risk of iCJD transmission through surgery can potentially occur when patients are unwittingly treated in hospital at the time of symptom onset. Cruz et al. 115 used a cross-sectional design to study surgical procedures in sCJD patients and controls to estimate subclinical and clinical risks to future surgery. The authors posit that patients with sCJD in the clinical stage undergo a considerably higher frequency of surgical procedures than non-CJD patients, including neurosurgery. The authors argue that identification of such potentially higher-risk events, where surgery is undertaken in infectious patients around the onset of clinical symptoms, but prior to CJD diagnosis, might well constitute a priority in clinical settings. A conference abstract by Kobayashi116 reinforces this concern by providing data from the Japanese CJD Surveillance registry. From an analysis of 760 CJD patients, Kobayashi116 identify that six patients had undergone neurosurgery after the onset but before the diagnosis of CJD during the period from 1999 to 2008. 116

Cases of suspected but unconfirmed Creutzfeldt–Jakob disease transmission via neurosurgery

Patients may be identified as being ‘at increased risk’ of CJD if they have had surgery using instruments that had been used on someone who went on to develop CJD or someone who was ‘at increased risk’ of CJD. 117 A study by Hall et al. 118 reports that 154 patients in the UK are considered to be ‘at increased risk’ of various forms of CJD following neurosurgery. This paper reports that of these 154 patients, only 129 have been informed that they are at an increased risk of CJD, either because of deaths before notification or because a local decision was taken not to inform the individual. Although no incidence of CJD has been reported within these 154 patients, the authors highlight that ‘at-increased-risk’ patients often have a relatively short life expectancy because of their medical conditions. Diagnosing asymptomatic infection requires testing specific tissues that are most readily available at post-mortem. Few post-mortems have been conducted when at-increased-risk individuals have died; therefore, some asymptomatic infections may have been missed.

Two published papers119,120 from the USA report instances in which potential iCJD exposure via neurosurgery was investigated in hospitals; however, no confirmed cases of transmission were subsequently identified.

Risks in surgery other than neurosurgery

UK data on incubation

A summary of data on incubation periods for iCJD in the UK is presented in Table 8.

Dura mater grafts and genotypes

Frequency data and mean incubation periods by genotype are presented in Table 8 for the UK subset of CJD cases that are known to be caused by dura mater. The worldwide number of iCJD cases due to dura mater surgery exceeds 200, and it is known that the majority have occurred in Japan (n = 149). 35 Frequency data and mean incubation periods by genotype, extracted from Brown et al.,3 are also presented in Table 9 for subsets of the worldwide (excluding Japan) and Japanese affected populations. Hamaguchi et al. 147 reported a mean incubation period of 12.1 years (range 1–30 years) for 142 patients in Japan and 11.3 years (range 1–23 years) for a subset of 53 patients with published data from the other countries, although this subset did not include a Dutch case of dura mater-related iCJD that had an incubation period of 28 years, which is the longest reported incubation period outside Japan. 148

Meissner et al. 139 reported on a sample of 10 cases (nine from Germany and one from Croatia) of iCJD related to dura mater, which were identified between 1993 and 2006. The median incubation period was 18 years (range 9 to 23 years), with 90% of cases being homozygotes, the majority of which were the MM genotype (80%). This study also reviewed published evidence from the literature on 27 international patients with iCJD because of dura mater grafts who had MRI data. Data on incubation periods were available for 22 of these patients: the mean incubation period was 11.5 years (range 1.6–23 years), with 95% being homozygotes, mainly of the MM genotype (81%).

Human growth hormone and genotypes

Table 10 presents frequency data and mean incubation periods by genotype for a subset of the known CJD cases caused by hGH. It is reported that one particular preparation of hGH was most probably responsible for cases of iCJD caused by hGH in the UK, to date. 3,69

As reported in Table 7, 78 cases had been reported in the literature for the UK as of 2017,140 an increase from the 65 cases reported previously. 69 Ritchie et al. 140 present data on subsets of 21 and 37 patients with available tissue samples; analysis was conducted on frozen tissue samples for the former group. Both samples demonstrated the same pattern: patients with the MM genotype were fewer and had consistently longer incubation periods, whereas the VV genotype had the shortest mean incubation period. The heterozygous genotype MV was the most frequently identified genotype in both subsets. There is potential for some crossover of data between the included studies, which cannot be accounted for in this review.

These findings were broadly similar to those reported for another subset analysis of iCJD patients using imaging, molecular and autopsy data. 69 Rudge et al. 69 present data on a subset of 22 patients from 56 patients with genotypic data available. They studied a cohort of 22 patients diagnosed between 2000 and 2014, and combined relevant data from these patients with data for 34 published cases up to 2000. In the cohort of 22 patients, Rudge et al. 69 presented a range of possible incubation times calculated from (1) the last injection of any type of growth hormone to onset of symptoms; (2) the midpoint of that series of injections to onset of symptoms; and (3) the first injection to onset of symptoms. The mean and ranges were (1) mean 25.9 years (range 18.3–33.6 years); (2) mean 29.3 years (range 20.6–37.6 years); and (3) mean 32.8 years (range 23.2–43.3 years). 69 Incubation times between the cohort of 22 patients and a large subset of the UK group as whole were also compared. 69 The mean incubation times were longer in the latter cohort, but there was a noteworthy change in the proportion of MM and VV homozygote genotypes between the two periods; there was only one case of the VV genotype in the period 2000–14 compared with 14 occurring before 1998, whereas seven of the eight MM homozygotes occurred after 2004. 69 These findings are quite distinct from those for dura mater grafts in terms of the distribution of genotypes and their incubation periods: incubation periods for iCJD caused by dura mater grafts appear shorter and are dominated by the MM genotype (see Table 9). The group with iCJD affected by hGH are equally distinct in terms of genotype, from individuals with sCJD. 140

Infectious mass required to transmit Creutzfeldt–Jakob disease

The risk of any individual becoming infected by CJD is considered to be related to the dose of infectious material received. A quantitative estimation of infectivity in CJD is traditionally ascertained using end-point dilution titration and is expressed as median infective dose in terms of ID₅₀.

No new evidence regarding the quantity of infective material required to transmit CJD in humans was identified in the period covered by the searches. The estimations used in the original mathematical model to estimate the risk of vCJD transmission via surgery12,13 and implemented in IPG19614 are reported in Table 11.

Higher infectious titres than those estimated in Table 11 have been detected in animal studies using novel methods for end-point titration. For example, Makarava et al. 149 used protein misfolding cyclic amplification (PMCA) with beads to propagate abnormal prion protein scrapie (PrP^Sc) (infectious isoform/protease K-resistant prion protein) in Syrian hamsters. Using this method, they were able to detect infectious titres ranging from 10^8.6 to 10^12.8. A study by Halliez et al. 150 also found that it was possible to detect higher levels of vCJD infectious titre in a human spleen using a novel bioassay than with a gold-standard immunoblot bioassay. As methods for end-point titration improve, it is therefore likely that some variation in the estimated titres used in IPG196 and noted in Table 11 will be observed in the future.

Codon 129 genotype and susceptibility

All individuals, irrespective of genotype at codon 129 (MM, MV or VV), are now known to be susceptible to sCJD and secondary transmission of vCJD through routes such as blood transfusion; however, the phenotype (or observable physical properties) for MV and VV cases has been noted to be less predictable because of reduced transmission efficiency and increased incubation periods. 79,89 The vCJD prion or agent appears to replicate in lymphoid tissues during the asymptomatic phase of the incubation period. 151 A study152 of abnormal prion protein accumulation in peripheral tissues from MV individuals has been undertaken to understand the infectivity and the risk of horizontal transmission. Bishop et al. 152 inoculated mice with brain and spleen samples from a subclinical vCJD recipient and the clinical vCJD donor. They found transmission of vCJD from the spleen to the mice but not from the brain of the subclinical vCJD recipient, whereas there was transmission from both the spleen and the brain tissues from the clinical vCJD donor. The authors concluded that spleen tissue from the MV genotype can propagate the vCJD agent and that the infectious agent can be present in the spleen without central nervous system (CNS) involvement and that ‘silent’ spread within the human population is, therefore, a possibility from heterozygous carriers. This finding was also echoed by Halliez et al. 150 in their evaluation of novel methods for end-point titration of vCJD in the human spleen. The authors posit the notion that lymphoid tissue exhibits a higher capacity than the brain to replicate prions even after low-dose infection and highlight potential silent carriers of vCJD in lymphoid tissue as a key issue. 150

Subtype or phenotype of Creutzfeldt–Jakob disease

In sCJD, an interaction between the host genotype at codon 129 and the causative agent identified as either PrP^Sc type 1 or PrP^Sc type 2 produces different clinical and histopathological phenotypic expressions, which may be influenced by other factors such as route of infection or locations of the initial PrP^Sc conversion. 153 In sCJD, six major subtypes carrying diverse clinical and pathological features have been identified: (1) MM1/MV1, (2) VV2, (3) MV2 with kuru plaques (MV 2K), (4) MM2-cortical (MM2C), (5) MM2-thalamic (MM2T) or sporadic fatal insomnia and (6) VV1. 154 In mice studies, all subtypes have been found to be transmissible to at least one genotype. 155 Four major prion strains have been proposed to underlie sCJD, iCJD, kuru and some gCJD cases, which are termed M1, V2, M2 and V1. 89 Variant CJD, however, can be distinguished from other categories of CJD owing to the unique PrP^res biochemical glycotype referred to as type 2B or type 4, which are also found in cases of natural BSE and other BSE-related conditions. 90

Definitive information on the phenotype can be identified only following neuropathological examination, which provides the opportunity to establish whether or not CJD may have been acquired as opposed to being sporadic or genetic causes. Kobayashi et al. 98 propose the distinctive combination of the MM genotype at codon 129, kuru plaques and intermediate-type PrP^Sc as a reliable criterion for the identification of iatrogenically acquired CJD cases among presumed sCJD cases. Additionally, some studies highlight that, although exclusive type 1 (sCJDMM1) or type 2 (sCJDMM2) cases do exist, a frequent co-occurrence has been noted of both PrP^Sc type 1 and type 2 in sCJD in different areas, or the same area, of the brain from a single sCJD patient. 156 This finding complicates the diagnosis and the current classification of sCJD,153 with Parchi et al. 154 highlighting the importance of assessing the cerebral cortex from each of the four lobes (striatum, hippocampus, thalamus and cerebellum) to avoid misclassification of disease. For example, Jansen et al. 157 report from an analysis of CJD cases in the Netherlands that a ‘pure’ phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. Similarly, an abstract by Mackay et al. 158 reports that 26 out of 108 sCJD patients (24%) had both type 1 and type 2 proteins on Western blot analysis. Mackay et al. 158 argue that the lack of distinct clinical or pathological findings in the six discrete subtypes suggests that these groups do not represent unique strains of prions but rather groupings over a spectrum of disease. These findings underline the importance of neuropathological assessment of CJD cases to document the phenotypic variability and help to disclose the aetiology of CJD strains and efficiency of transmission, where possible.

Route of transmission

The route of transmission may also be relevant to the infectivity of iCJD. A study of five dura mater iCJD cases conducted by Iwasaki et al. 159 indicated that the initial symptoms at perceived sCJD onset appeared to be closely related to the graft site in the brain, indicating a direct transmission of CJD from the graft site to the adjacent brain. Sakai et al. 160 also support the finding of a relationship between the initial clinical manifestation and the site of graft in patients with dura mater graft-associated CJD. 160 Beringue et al. 161 demonstrated in a study of transgenic mice that prion strain divergence can occur on transmission of human primary vCJD, and that peripheral exposure in mice resulted in inefficient neuroinvasion with asymptomatic, life-long infection of the lymphoid compartment. 161

Beringue et al. 162 raise the possibility that human-to-human transmission of vCJD might produce alternative neuropathological phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. Cali et al. 163 demonstrated that novel phenotypes may arise as a result of the adaptation of heterologous prion strains of sCJD through contaminated growth hormone. 163 A conference abstract by Peden et al. 164 also described that human-to-human transmission of prion disease may affect the seeding properties of the PrP^Sc associated with the disease. Their analysis compared the seeding properties of iCJD tissue samples (including both hGH and dura mater) with sCJD tissue samples using a real-time quaking-induced conversion (RT-QuIC) assay, which showed lower seeding properties for secondary iCJD cases than for sCJD cases. The authors note that their findings refute the hypothesis that secondary transmission of a human prion disease results in acquired virulence (or harmfulness). This is supported by a study by Galeno et al. ,67 which found that a novel strain from an atypical CJD in a heterogeneous 69-year old woman who had been treated with phospholipids extracted from bovine brains was not transmissible to transgenic mice but transmitted exclusively to bank voles. The authors note that bank voles are susceptible to a variety of human and animal prions with an efficacy that is often higher than that observed in transgenic mice. 67

Detection of Creutzfeldt–Jakob disease

Whether or not and when asymptomatic carriers of CJD become infectious is important in understanding the potential risks of contamination during surgery. Bougard et al. 165 described an assay that detected prions 1.3 and 2.6 years before the clinical onset of disease in plasma samples from two blood donors who later developed vCJD. The authors report that the ability to identify presymptomatic (n = 2) and symptomatic (n = 18) vCJD-positives in a blinded cohort of 256 plasma samples comprising sCJD, Alzheimer’s disease, Parkinson’s, other neurological diseases and healthy controls indicates the possibility of detecting incubating or silent carriage of vCJD prions.

Identification of abnormal prion accumulation in peripheral lymphoreticular tissue is commonly considered to be a marker of subclinical vCJD that may subsequently develop into clinical vCJD. However, the reliability of this marker for representing subclinical or indeed, clinical, vCJD has been questioned. Mead et al. 166 highlight a case of clinical vCJD whose presentation, imaging findings, cerebrospinal fluid investigation results and clinical progression were typical of other vCJD cases. However, subsequent examination of multiple tissues from a biopsy and at autopsy showed minimal deposition of disease-associated prion protein in tonsil tissue. 166 This patient also received a negative score from a blood test specifically for vCJD, the direct-detection assay. The authors note that this case demonstrates that even patients with end-stage vCJD may have minimal prion colonisation in lymphoreticular tissue.

Absence versus presence of abnormal prion accumulation may occur because of the sensitivity of the CJD assay employed. Examination of 14-3-3 proteins in both the cerebrospinal fluid and a RT-QuIC assay are commonly employed tests that are considered to be sensitive and specific for sCJD detection, although less so for vCJD. 167 For example, the identified heterozygous clinical vCJD patient, aged 36 years in 2016,37 tested negative for the 14-3-3 protein, RT-QuIC assay and vCJD-focused direct-detection assay, but immunoblotting of brain homogenate at autopsy confirmed the presence of vCJD prions. Moreover, immunostaining performed in this patient for abnormal prion protein-labelled amyloid plaques highlighted a relative lack of peripheral tissue involvement, with only minute amounts detected in the spleen and no detection in the appendix or mesenteric lymph nodes. However, Douet et al. 168 used a highly sensitive PMCA assay to assess abnormal prion accumulation in the identified heterozygous subclinical vCJD patient, aged 82 years in 2017. Previous investigations had not detected abnormal prion protein or infectivity in the brain, indicating a lack of CNS involvement at the time of death. 78,152 However, using this assay they found vCJD prions in all lymphoid organs and a wide variety of other tissues, including the salivary gland, lung and liver. The authors caution that the identification of wide vCJD involvement in the peripheral tissues of a preclinical patient further indicates the potential for iatrogenic transmission of this fatal neurological condition by surgical procedures.

Transmission to and from peripheral tissues

The infectious load is known to be higher in certain tissues, such as CNS tissues,14 and, therefore, the risk of infectivity from peripheral tissue has been questioned. Studies report conflicting findings regarding the infectivity of peripheral tissues. For example, Bishop et al. 152,169 reported that spleen tissue from the MV genotype preclinical vCJD blood recipient was transmissible in a study using transgenic and wild-type mice. The authors highlight that significant levels of infectious agent are present in the spleen before CNS involvement. 152,169 However, Wadsworth et al. 170 found from an animal study of transgenic mice that, although vCJD prion infection was readily reported following inoculation with frozen vCJD brain or appendix, and formalin-fixed, paraffin-embedded (FFPE) brain, no infectivity was detected from FFPE vCJD spleen or FFPE appendix samples. 170 The authors caution that the absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue does not definitively prove that vCJD transmission cannot occur through appendix specimens, as the assays used were not able to detect the low levels of infectivity previously found in the positive control lymphoreticular tissue following formalin fixation by Hilton et al. 7 However, in contrast, Halliez et al. 150 more recently found that lymphoid tissue exhibits higher capacity than the brain to replicate prions using novel detection methods.

Infectivity of genetic Creutzfeldt–Jakob disease

The potential for horizontal transmission of gCJD, as discussed previously, was raised by the unusually high prevalence of gCJD in Slovakia. 47 Ritchie et al. 171 report from an animal study of squirrel monkeys that no clinical or pathological signs of CJD were observed following blood transfusion of either sCJD or vCJD of the intracerebral-inoculated monkeys after euthanasia at 7 years. However, there was evidence that GSS, a form of gCJD, transmitted autopsy-proven disease to two intracerebral-inoculated monkeys after incubation periods of 34 and 39 months. Ritchie et al. 17 conclude that these results, and other studies from rodents and non-human primates, suggest that blood donations of GSS (and perhaps other familial forms of TSE) carry more risk than those from vCJD. 171 The infectiousness of CJD via blood is not directly relevant to the current decision problem of CJD risk via surgery. However, consideration of the potential differences of infectiousness of the CJD types may be relevant when considering the risks of horizontal transmission in the future and in particular localities.

MV genotype as protective: PrP^Sc allotype

Allotype refers to an inherited set of determinants or a sequence of amino acids and other proteins that demonstrate heterogeneity, which is specific for an individual but more common in an ethnic group. The relative contribution of each PrP allotype to the infectious disease associated with the abnormal isoform of prion protein (PrP^Sc) is unknown. Moore et al. 172 found from an analysis of four heterozygous cases of sCJD that the PrP^Sc allotype ratio is highly variable, with PrP^Sc (-M129 and -V129) differing markedly between different regions within the same sCJD brain. 172 However, an analysis of six heterozygous cases of iCJD found that the composition of PrP^Sc iCJD was more homogenous and tended to contain a higher proportion of PrP^Sc-V129 than heterozygous cases of sCJD. The presence of two different PrP allotypes in the same brain can often lead, in a dose-dependent manner, to inefficient PrP^Sc formation and increased disease incubation. However, the study authors report that in both types of CJD (sCJD and iCJD), the PrP^Sc allotype ratio had no correlation with CJD type, age at clinical onset or disease duration. This evidence suggests that, therefore, factors other than PrP^Sc allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD.

Studies reporting log-reductions of prion infectivity after autoclaving with/without other processes

Five studies174–178 reported log-reductions of prion infectivity after autoclaving with and without other decontamination processes (Table 12). In terms of prion strain, three studies used 10% brain homogenate of 263K hamster scrapie,174–176 two used vCJD,176,177 and the following prion strains were investigated in only a single study: 127S,177 M1000178 and BSE 6PB1. 176 All studies used steel wires contaminated with the prion (one study also used steel sheets176) and all studies investigated autoclaving at 121 or 134 °C for specified amounts of time, as a decontamination procedure.

The efficiency of autoclaving was assessed alone and in combination with a range of other decontaminants. These included sodium hydroxide (NaOH), sodium hypochlorite (NaOCl), sodium dodecyl sulfate (SDS), hydrogen peroxide (H₂O₂) and various other enzymatic and alkaline detergents. These decontaminants were also investigated alone or in combination with other decontaminants. Selected results from these investigations are reported in Table 13.

The log-reductions produced by autoclaving at 134 °C for 18 minutes for the 263K prion strain ranged from 4.11174 to > 5–6,176 with transmission rates of 57% and 50%, respectively. The log-reduction was only 2.2 (100% transmission) for the M1000 strain. Autoclaving at 134 °C for 18 minutes combined with NaOH or an alkaline detergent produced log-reductions of > 5 to 6, as well as lower transmission rates (28% for NaOH and 0% for the alkaline detergent) for the 263K prion strain. 176 Autoclaving at 134 °C for 5 minutes combined with alkaline cleaners or 0.2% SDS or 0.3% NaOH at different concentrations and/or different durations, also produced log-reductions of > 5.5 for the 263K prion strain. 175

The only process reported to have produced a log-reduction of > 5 and a transmission rate of 0% is autoclaving at 121 °C for 20 minutes plus 0.3% rapid multienzyme cleaner trial formulation (RMEC) B at 60 °C for 30 minutes. 178

The aim of some studies is development of a prion detection assay, rather than the development of the decontaminant. 177

Studies reporting log-reductions of prion infectivity after processes other than autoclaving

Eleven studies reported log-reductions of prion infectivity after various decontamination processes, principally enzymatic detergents that did not use autoclaving (Table 14). In terms of prion strain, seven studies used 10% or 20% brain homogenate of 263 K hamster scrapie,174–176,179–182 three used vCJD,177,179,180 two used ME7183,184 and the following prion strains were investigated in only a single study: Rocky Mountain Laboratory (RML),185 BSE 6PB1 and TGB1,181 M1000178 and 127S. 177 Nine studies used steel wires contaminated with the prion, one study used steel tokens183 and one used steel sheets. 176

The efficiency of a range of decontaminants was assessed. Selected results from these investigations are reported in Table 15. It was reported by Edgeworth et al. 185 that the following processes inactivated RML prions below the detection limit of the in vitro standard steel-binding assay (SSBA), stated to be equivalent to a reduction of 8 logs: Rely-On PI (DuPont), Prionzyme plus 2 M NaOH, and 2 M NaOH. It was noted, however, that the decontaminating effect of Prionzyme (Genencor) was indistinguishable from that of the diluent in which the decontaminant was prepared (2 M NaOH solution, following the manufacturer’s instructions), that is treatment with 2 M NaOH alone also resulted in no detectable infectivity remaining on the steel surface. The only process reported to have produced a log-reduction of ≥ 5 and a transmission rate of 0% for the RML prion strain was Rely+On PI.

The only process or combination of processes reported to have produced a log-reduction of ≥ 5 and a transmission rate of 0% for the 263K prion strain were 0.2% SDS/0.3% NaOH in 20% or 30% n-propanol;179 0.2 mol/l NaOH at 15 °C for 60 minutes; 0.45 mol/l NaOH at 15 °C for 15 or 30 minutes; 0.45 mol/l NaOH at 25 °C for 240 minutes; 0.45 mol/l NaOH at 40 °C for 5 minutes; 0.1 mol/l NaOH at 45 °C for 5 or 15 minutes;180 2 mg/l gaseous H₂O₂ at 30 °C for 3 or 6 pulses;181 H₂O₂ for 30 minutes; AF (alkaline detergent, surfactants, chelatant) for 10 minutes; and combinations of enzymatic detergents and disinfectants Np-Dp-H₂O₂/Cu (for 10 minutes – 5 minutes – 15 minutes),174 the alkaline detergent B at 1% for 10 minutes at 55 °C, the Sterrad NX1 advanced cycle and Sterrad NX2 continuous advanced cycles (H₂O₂ and gas plasma), and the alkaline detergents A or B at 1% for 10 minutes at 55 °C, in combination with the Sterrad NX1 advanced cycle,176 and cold atmospheric plasma. 182 According to Rogez-Kreuz et al. ,176 no insoluble prion (PrP^res) signal was detected for BSE 6PB1 or vCJD ‘after exposure to steam in either of the two Sterrad systems’. The only process reported to have produced a log-reduction of ≥ 5 and a transmission rate of 0% for the BSE prion strains 6PB1 and TGB1 were 2mg/l gaseous H₂O₂ at 30 °C for three pulses. 181 None of the treatments for the ME7, vCJD, 127S or M1000 prion strains reported a log-reduction of ≥ 5 and a transmission rate of 0%. 177,178,182,184

Supplementary evidence: studies reporting outcomes other than log-reductions after autoclaving with/without other processes

Six studies185–190 reported outcomes other than log-reductions (Table 16). In terms of prion strain, two studies used 10% or 20% brain homogenate of RML186 and two studies investigated sc237 and sCJD,187,188 with the following prion strains investigated in only a single study: 263K scrapie,189 and 301 V BSE and cattle BSE. 188 Five studies used steel wires contaminated with the prions and one study189 used steel spheres. All studies investigated autoclaving at 121, 134 or 137 °C for specified amounts of time as a decontamination procedure; one study investigated autoclaving at 65 and 121 °C. 188

The efficiency of autoclaving was assessed alone and in combination with a range of other decontaminants. These included SDS, acetic acid (AcOH), NaOH, radiofrequency (RF) gas plasma, Trigene disinfectant and various other enzymatic detergents. Selected results from these investigations are reported in Table 17.

Only one study reported the outcome ‘tissue culture infectious units on wires’ (TICU_w). 185 This study recorded that autoclaving at 134 °C for 18 minutes reduced the TICU_w measure of the RML prion strain to 0.03, which is reported to be equivalent to a reduction of 5.5 logs (see Table 15).

The remaining studies all reported transmission rates. The transmission rates produced by autoclaving at 134 °C for 15 minutes and 30 minutes for the 301 V BSE prion strain were 96% and 57%, respectively, and for cattle BSE they were 84% and 100%, respectively. 190 The transmission rates produced by autoclaving at 134 °C for 20 minutes for the RML prion strain ranged from 25% (1/4) to 100% (13/13) in Tg20 mice and 0% (0/9) in CD-1 wild mice. 186 The unusually high transmission rate in the larger sample of Tg20 mice was explained by the autoclaving process being affected by partial sealing of the glass tubes containing the steel wires, which impaired the penetration of the steam. 186 The transmission rates produced by autoclaving at 121 °C for 15 minutes and 30 minutes for the Sc237 prion strain were 100% and 20%, respectively, and for sCJD, 22% and 0%, respectively. 187,188 Finally, the transmission rates produced by autoclaving at 134 °C for 15 minutes and 30 minutes for the Sc237 prion strain were 87% and 55%, respectively, and for sCJD 73% and 63%, respectively. 187

The following combinations of autoclaving and other processes are reported to have produced a transmission rate of 0% or ≤ 5%: autoclaving at 134 °C for 15, 30 or 120 minutes plus 4% SDS and 1% AcOH for the 301 V, cattle BSE,190 Sc237 and sCJD prions strains;187 autoclaving at 121 °C for 15, 30 or 120 minutes plus 2% SDS and 1% AcOH for the 301 V and cattle BSE prion strains;190 and autoclaving at 65 °C for 18 hours plus 2% SDS and 1% AcOH for the Sc237 and sCJD prions strains. 188 Autoclaving at 134 °C for 20 minutes plus SDS-proteinase K (PK)-Pronase at 40 °C for 60 minutes also produced a 0% transmission rate for RML prion strains. 186

Without autoclaving Trigene disinfectant and RF gas plasma, and SDS-PK-Pronase at 40 °C for 60 minutes, also produced transmission rates of 0% in the 263K and the RML prion strains, respectively. 186,189

Supplementary evidence: studies reporting evidence for levels of protein residue on surgical instruments after cleaning

Nine studies183,191–198 reported this outcome after autoclaving with and without other decontamination processes (Table 18): seven studies192–198 for surgical instruments and two studies for endoscopes. 183,191 All studies were conducted in the UK. Seven studies183,193–198 reported on protein residue on instruments acquired between one and nine NHS trusts; the number of trusts involved was not reported in two studies. 191,192 All studies reported that cleaning essentially involved conventional procedures for the equipment concerned. With the exception of two studies,192,193 the assay appears to have involved detection of protein in situ on the instruments. Where reported, the number of instruments ranged from 2 to 1000.

There was no consistency in the measures used to quantify and report the residual protein contamination of surgical instruments after conventional cleaning and sterilisation in a sterile service department (SSD). Murdoch et al. 193 reported a mean amount of protein per instrument of 71.67 µg (range 8–91 µg); Baxter et al. 192 reported a median range of 163–756 µg per instrument; Lipscomb et al. 194,195 reported residual contamination using an unvalidated ‘contamination index’ and reported that 56% of instruments (out of a total of 23) from a single NHS trust showed severe contamination (contamination index score of > 3–4) in at least one of the sample regions, whereas 66% of instruments (n = 260) from nine NHS primary care trusts showed equivalent severe contamination (contamination index score of > 3–4). According to this contamination index, a classification of 3 represents 0.42–4.2 µg of protein/mm² and a classification of 4 is > 4.4 µg of protein/mm². The most recent study,196 reported residue ‘per instrument side’ for evaluated instruments from craniotomy sets (n = 187): 87% of instruments were found to have < 5 µg per instrument side and 96% were found to have < 10 µg per instrument side. Two papers did not explicitly quantify the residual protein but only noted its presence. 197,198 The studies assessing endoscopes reported either < 10 ng of protein/mm² after processing183 or the ‘equivalent to 1–4 µg of proteins per channel, except in one channel which harboured . . . equivalent to almost 33 µg of residual proteins for the whole channel’. 191

Studies reporting the impact on protein absorption and/or the relative efficacy of cleaning when keeping instruments wet or dry before processing

Four studies (five papers) reported a comparison between ‘wet’ and ‘dry’ instruments in terms of precleaning protein absorption or post soaking or cleaning protein residue (Table 19). All studies were conducted in the UK, used steel tokens or wires and the same contaminant: 1 µl drops of ME7-infected brain homogenate. Detection was made of in situ contamination using the same techniques: SYPRO^® (Life Technologies Corporation, Carlsbad, CA, USA) ruby protein stain and episcopic differential interference contrast/epifluorescence microscopy. Across the studies, drying times before assessment ranged from 15 minutes200 to 24 hours. 200,201

The process to keep steel tokens or wires ‘wet’ was different in each study: Secker et al. 98 used a ‘wet bag’ (Humibag), that is a sealed bag containing 35 ml of distilled water for set time periods; Secker et al. 201 used an air-tight container lined with moist tissue for 17 hours; Howlin et al. 184 treated steel wires immediately, rather than allowing them to dry; and Lipscomb et al. 199 treated steel tokens with one of four presoak treatments for 5 minutes, followed by 17 hours’ drying time. The dry conditions for comparison were: air dry or a ‘dry bag’ for comparable times to the ‘wet bag’;200 air dry for 24 hours;201 air dry for 16 hours;184 and air dry for 17 hours. 199 Different temperatures were evaluated but this text will focus only on the findings for room temperature (or the closest available data) across studies. Three of the four studies used the enzymatic cleaner Klenzyme (Steris, Mentor, OH, USA).

Both Secker et al. studies200,201 reported on protein residue after 24 hours at room temperature before cleaning: 324.7 ± 15.0 ng of protein/mm² for the air dry conditions compared with 6.0 ± 3.5 ng of protein/mm² for the wet conditions (98.2% reduction compared with air dry; p ≤ 0.001)201 and 1000 ± 205.0 ng of protein/mm² for the air dry conditions compared with 31.9 ± 5.3 ng of protein/mm² for wet conditions. 200 After the application of presoaks or cleaners, Lipscomb et al. 199 reported a reduction in protein between 64% and 96% on the presoaked or treated tokens compared with the dry, untreated controls and Howlin et al. 184 reported a reduction of approximately 2 logs in protein residue for tokens treated immediately (not allowed to dry) with the PreKlenz presoak compared with wires that were allowed to dry for 16 hours. Secker et al. 200 and Lipscomb et al. 199 also reported that the longer the drying times, the more difficult it was to remove the contamination.

Elicitation methods

The 2018 elicitation session was conducted using the Sheffield Elicitation Framework (SHELF). Four experts participated in a face-to-face facilitated workshop. The experts first completed a training exercise (using a quantity known to the facilitator, but unknown to the experts) to familiarise themselves with the elicitation methodology. For each parameter, the experts first recorded their probability judgements individually without conferring. Experts were asked to separately consider lower and upper plausible limits; different scenarios that might lead to high values or low values of the parameter. Probabilities were not attached to these plausible limits; the purpose of eliciting the limits is to mitigate the effects of anchoring and overconfidence, which may occur if a ‘best guess’ is first provided, followed by some assessment of uncertainty around such a guess.

The experts were then asked to provide median values by dividing their plausible ranges into two intervals judged to be equally likely. They were then asked to divide each interval into two further equally likely intervals, hence providing their lower and upper quartiles.

Each expert then declared his/her judgements to the facilitator, who then presented a graphical comparison of all the experts’ individual judgements. Disagreements between the experts’ judgements were highlighted and the experts were invited to justify their own opinions and question each other. Following the discussion, the experts were asked to imagine a rational impartial observer (RIO): an independent observer who has heard and understood the discussion, and on that basis formed his/her own probability judgements. It was for the experts to decide how much weight a RIO would give to the different opinions/arguments that had been stated; if the experts disagreed, with no convincing experts to favour one side over the other, RIO’s uncertainty would be expected to reflect the disagreement.

The experts agreed on a median and quartiles for RIO’s distribution. The facilitator then fitted a probability distribution to these judgements, by choosing a parametric family of distributions and selecting parameter values using a least-squares fit to the cumulative distribution function. The selected distribution was presented to the experts, with feedback in the form of 5th and 95th percentiles (which had not been directly elicited). The experts were asked to comment on whether or not the fitted distribution was an acceptable representation of RIO’s uncertainty and whether or not the level of uncertainty would be justified based on the proceeding discussion. The distribution would be modified as necessary, before being adopted within the ensuing calibration and probabilistic sensitivity analysis (PSA).

Experts were recruited from within the NICE advisory committee. We believed that the workshop format was important to allow for sufficient training of and discussion between the experts. However, owing to the time scale of the project, it was possible to convene only one workshop with four experts.

The underlying probability of Creutzfeldt–Jakob disease prions within central nervous tissue in the asymptomatic population

The experts in the elicitation session indicated that the previously elicited distributions relating to the prevalence of CJD prions in all tissue for patients aged 16–39 years in 2005 could still be used for the prevalence of CJD prions in central nervous tissue in 16- to 39-year-olds in the current analysis; although, they acknowledged that the range would produce an overestimate as the probability in all tissue would be greater than that confined to just the CNS. The experts disagreed with the previous experts in whether or not the prevalence would be greatest in the 16–39 years age group compared with the 0–15, 40–69 and ≥ 70 years age groups. The current experts believed that the elicited distribution should be used for all age groups. The distribution used to populate the model is shown in Figure 6 and represents a beta (1.240, 2225.393) for the prevalence. The distribution provides a 95% credible interval (CrI) ranging from 26 to 1875 people per million.

FIGURE 6.

The prevalence of CJD prions within central nervous tissue.

The NICE committee asked for two scenarios to be evaluated, which used different assumptions for the patients born after 1996, henceforth denoted the P96 group. In one scenario, it was assumed that the P96 group were not infectious, as they were assumed unlikely to have been exposed to the BSE epidemic; in an alternative scenario it was assumed that the P96 group had the same probability of being infectious as the general population.

The residual mass per surgical instrument

The ScHARR report11 assumed that the mass on an individual instrument was 2.88 mg of wet-tissue equivalent for instruments used for tonsillectomies, and 1.26 mg of wet-tissue equivalent for instruments used in general surgery. This mass was assumed to be independent of size and complexity. The source for this was ‘provided by Professor Baxter and colleagues from the University of Edinburgh’,11 with these data reported in a different form within Baxter et al. 192 It was assumed that the tonsillectomy value was generalisable to the residual mass on a brain and posterior eye surgery. When multiplied by the number of instruments assumed to be in each set, this equated to 51.84 mg of wet-tissue equivalent on brain surgery instrument sets and 25.92 mg of wet-tissue equivalent on posterior eye instrument sets. Each SI would have a wet-mass equivalent of 2.88 mg. These values were assumed fixed.

During discussions on the parameterisation of residual mass, a committee member highlighted a recently published article,196 which suggested that the residual protein mass is likely to be < 5 µg protein mass per instrument side. This is considerably less than that used in the previous ScHARR report,11 which was 576 µg of protein mass (2.88 mg of wet-tissue equivalent).

A preliminary inspection of articles discussing residual mass was undertaken, which indicated that protein mass ranged between 163 and 756 µg (120 instruments) in Baxter et al. 192 and between 8 and 91 µg (mean 71.67 µg; 43 instruments) in Murdoch et al. 193 Lipscomb et al. 195 presented further evidence, which was based on a set from each of nine NHS trusts (260 instruments in total), and reported that 66% of all instruments showed severe contamination in at least one sample area, equating to > 4.4 µg of protein/mm2.

Examining the data in Baxter et al. 192 and Murdoch et al. ,193 the mean residual protein mass per instrument in 2004 was set to 200 µg (95% CI 150 to 250 µg) in consultation with NICE committee members.

However, the data reported in Smith et al. ,196 and further data marked as academic-in-confidence obtained from a NICE committee member (anonymous, May 2018), indicate that there has been a reduction in mass over time for the hospitals where data has been recorded. In discussion with committee members, it was assumed that this change, which is assumed to be related to guidance on keeping instruments moist prior to decontamination, would have occurred in 2012 in line with the purchase of new instruments for those units that had adhered to IPG196. Following discussion with committee members, the mean residual mass for those units that were compliant with guidance to keep instruments moist was assumed to be 10 µg. In the 90% of units that did not adhere to IPG196, it was assumed that two-thirds of these (i.e. 60% of total units) would not keep instruments sufficiently moist and that 200 µg of residual mass would remain on each instrument, with the remaining third (i.e. 30% of total units) adequately keeping instruments moist. It was assumed that the reduction in protein residue on instruments will translate into a reduction in the possibility of transmission of stCJD.

This conceptual model was operationalised by assuming that the mass harvested from a patient from 2012 onwards was 5% (10/200) of the mass assumed to be harvested prior to 2012. Any infectious mass already on an instrument was assumed to remain on the instrument following measures to keep instruments moist.

The proportion of residual mass on brain and posterior instruments that is transferred to a patient

This value was estimated in the original elicitation exercise, which was undertaken to inform the previous work by ScHARR. 11 A depiction of the distribution for the proportion of residual mass transferred to the patient is provided in Figure 7. This has a mean of 31.5% and a 95% CrI 0.4% to 87.1%, showing considerable uncertainty.

FIGURE 7.

The proportion of residual mass transferred to a patient.

The proportion of residual mass on brain and posterior instruments that is removed in a subsequent decontamination cycle

This value was estimated in the original elicitation exercise, which was undertaken to inform the previous work by ScHARR. 11 A depiction of the distribution for the proportion of mass transferred to the patient is provided in Figure 8. This has a mean of 0.9% and a 95% CrI of 0.0% to 4.0%.

FIGURE 8.

The proportion of residual mass removed in a subsequent decontamination cycle.

The proportion of mass on instruments that is replaced with new tissue per brain or posterior eye operation

In accordance with the previous ScHARR model,11 it was assumed that the residual mass on an instrument was in steady state. Therefore, the sum of the mass transferred to the patient and the mass removed in the next decontamination cycle equals the newly acquired mass from the operation. The mean value of the proportion of the mass removed from instruments during an operation is 32.4%, with an estimated 95% CrI of 1.1% to 88.4%. Any SIs that were used were assumed to gather the same mass as instruments in the main set.

Residual mass, proportion transferred to a patient, proportion removed during the operation and the mass harvested during neuroendoscopy

The spreadsheet calculations that were performed to obtain the proportion of mass transferred to the patient and the proportion removed in the next decontamination cycle for rigid neuroendoscopes and flexible neuroendoscopes used in the previous modelling work11 could not be retrieved, but the values used in the PSA were available. These values have been re-used in the modelling, although it appears that there was a discrepancy between the mass transferred from a patient to a rigid neuroendoscope lumen used in the model and the mass that was reported in table 11 of the ScHARR report,11 with the former being 10 times smaller. For the updated work, we have erred on the side of caution and assumed that the greater mass is harvested per operation.

For information, key statistics on the proportion of mass harvested from a patient, the proportion of mass transferred to a patient and the proportion of mass removed in the next decontamination cycle are provided in Table 24.

The assumed infectious titre of tissues containing Creutzfeldt–Jakob disease prions

In the previous modelling undertaken,11 brain and posterior eye tissue were assumed to have 10⁸ ID₅₀ per gram, with this value assumed to be fixed and applied from the moment the patient became infectious to the moment when clinical symptoms of CJD were observed, in which instance reusable instruments would not be used on the patient.

The NICE committee requested, based on the collective experience of its members, that the previous assumptions were amended to allow more heterogeneity in patients who have CJD prions in high-risk tissue. First, the mean infectious titre was varied between 10⁷ and 10⁹ ID₅₀ per gram, assuming a uniform distribution. Second, it was assumed that 20% of patients would have an infectious titre 1 log higher than the mean and that 20% of patients would have an infectious titre 1 log lower than the mean, with the remaining 60% of patients having the mean value. This approach incorporates uncertainty around the mean estimate as well as patient heterogeneity, with individual patient values ranging from 10⁶ to 10¹⁰ ID₅₀ per gram.

The effectiveness of current decontamination processes in reducing infectivity

The distributions produced from the elicitation exercise to inform the ScHARR report11 were considered appropriate by the NICE committee. These were split into three categories: (1) the effectiveness of infectivity reduction in the first decontamination cycle, (2) the effectiveness of infectivity reduction in subsequent decontamination cycles and (3) the mass removed in second and subsequent decontamination cycles. The model assumes that there have been no improvements in the reduction in infectivity since 2004.

The effectiveness of infectivity reduction in the first decontamination cycle

The distribution assumed for the infectivity reduction associated with the first cycle of autoclaving is displayed in Figure 9. This has a mean log-reduction of 2.50 and a 95% CrI log-reduction of 1.42 to 3.58.

FIGURE 9.

The reduction in infectivity in the first autoclaving cycle.

The distribution assumed for the infectivity reduction associated with the first cycle of detergents is displayed in Figure 10. This has a mean log-reduction of 0.64 and a 95% CrI log-reduction 0.04 to 2.03. Note that detergents used in cleaning neuroendoscopes were assumed to not reduce infectivity.

FIGURE 10.

The reduction in infectivity in the first detergent cycle.

The effectiveness of infectivity reduction in subsequent decontamination cycles

It was assumed in the ScHARR report11 that the second and third autoclaving cycles would reduce prion infectivity, although this would be to a lesser extent than the initial autoclaving cycle. These further autoclaving cycles would occur following a subsequent operation. The log-reduction on the second and third autoclaving cycle was expressed as a proportion of the reduction estimated in the first cycle. The distribution assumed for the multiplier is shown in Figure 11. This distribution has a mean of 0.157 with a 95% CrI of 0.043 to 0.330.

FIGURE 11.

The proportion of autoclave cycle 1 log-reduction achieved by cycles 2 and 3.

It was assumed in the ScHARR report11 that the second detergent cycle would reduce prion infectivity, although this would be to a lesser extent than the initial autoclaving cycle. The log-reduction on the second and third autoclaving cycle was expressed as a proportion of the reduction estimated in the first cycle. The distribution assumed for the multiplier is shown in Figure 12. This distribution has a mean of 0.474 with a 95% CrI of 0.047 to 0.931.

FIGURE 12.

The proportion of detergent cycle 1 log-reduction achieved by cycle 2.

The probability of disposing of a reusable instrument

In the ScHARR report,11 it was assumed that following use an instrument had a 1/250 probability of being disposed of (range 1/200–1/300) with all infectious load on the instrument destroyed. In discussions with the committee, it was believed that the serviceable life of a reusable instrument was longer than that previously assumed and the probability of an instrument being disposed of was reduced to 1/2500 with a range of 1/2000–1/3000.

For each instrument that was disposed of in a brain surgery set, it was assumed that between 0% and 12% (sampled from a uniform distribution) of infectious load was removed from the set. For each instrument disposed of in a posterior eye surgery set, it was assumed that between 0% and 25% (sampled from a uniform distribution) of infectious load was removed from the set. The midpoints of these distributions (6.0% and 12.5%, respectively) were chosen such that it was close to the proportion of the set that one instrument comprised. This is (see Parameters relating to instrument migration, costs and safety) a 1/14 probability (7%) for an instrument in a neurosurgery set and a 1/9 probability (11%) for an instrument in a posterior eye surgery set. Uncertainty was incorporated by allowing a range between 0% and approximately twice the midpoint value.

The instruments assumed on model set-up

In the modelling undertaken for the ScHARR report,11 it was assumed that there were 12 brain surgery sets with 18 instruments assumed to come into contact with potentially infectious mass; 12 posterior eye surgery sets with nine instruments assumed to come into contact with potentially infectious mass; and one rigid neuroendoscope and one flexible neuroendoscope, both of which had a single accessory.

Following discussion with the committee, it was assumed that the number of instruments coming into contact with high-risk tissue in brain operations was lower than previously thought, with the number reduced to 14 instruments (previously 18).

For brain and posterior eye sets, the instrument sets were used in rotation. For neuroendoscopy operations, it was assumed that 75% were undertaken with rigid neuroendoscopes (which can be autoclaved) and 25% were undertaken using flexible neuroendoscopes (which cannot be autoclaved).

Brain and posterior eye sets were also complemented by six types of SI, each of which had six instruments that were used in rotation. During each operation, each SI had a 20% chance of being required.

For neuroendoscopy, IPG196214 recommended that all neuroendoscopy accessories became single use. For simplicity, however, it was assumed that this was not followed, based on the committee’s estimation of units that had adhered to IPG196 and with an assumption that one SI was used in all operations. If a large number of deaths was observed related to neuroendoscopy, this assumption would be amended.

Recommendations on instrument migration and use of supplementary instruments in IPG196

Maintaining the integrity of surgical instrument sets was shown to be a key parameter affecting the incremental cost-effectiveness ratios (ICERs) associated with the introduction of single-use surgical instruments. 12 The ScHARR report11 made the following assumptions in relation to set integrity:

1. That the probability of an instrument being swapped with a similar instrument in a separate set was 50%, while the set was undergoing the decontamination process. This value was selected following discussion with clinicians and review of evidence. When instruments migrate between sets it was assumed that between 0% and 20% (sampled from a uniform distribution) of the infectious material in ‘set A’ would move to ‘set B’, with between 0% and 20% (sampled from a uniform distribution) of the infectious material in set B being moved to set A. These values were chosen as there were approximately 10 instruments in a surgical set, which would be expected to contain 10% of all mass (infectious or not) and that there would be expected uncertainty around the proportion of mass contained on individual instruments.

2. That when a SI was used, there was a 50% chance that this instrument would join the set with a similar instrument from the set becoming the ‘new’ SI. When this occurs, all infectious load on the SI is added to the set, and between 0% and 10% of the infectious load (sampled from a uniform distribution) in the set is assumed to reside on the new SI. The distribution used to model infectious mass transference as a result of SI migration is associated with smaller mass levels than non-SI instruments.

The model has the facility to alter the levels of set migration following the publication of IPG196,214 which recommended that migration of instruments between sets should be abolished and that SIs that come into contact with high-risk tissues should either be single-use or remain with the set to which they have been introduced. However, owing to logistical and/or financial problems in implementing IPG196,214 these recommendations were not fully adhered to by all hospitals. The model has been set up so that it is assumed that after 2012 no SIs are used for those units that are assumed to adhere to IPG196.

The costs associated with single-use instruments

A NICE committee member stated that the costs of single-use sets are likely to lie in the region of £350–500 and that the cost of a single-use rigid neuroendoscope is £710; no cost was identified for a single-use flexible neuroendoscope (anonymous, May 2018).

The costs associated with reusable instruments

In the ScHARR report,11 it was assumed that a brain surgery set costs £3500 and that a posterior eye set costs £1000. Based on the number of instruments that come into contact with high-risk tissue, the cost of an individual reusable instrument is likely to be in the region of £100–200.

The ScHARR report11 assumed that a reusable rigid neuroendoscope costs £397 and a reusable flexible neuroendoscope costs £9300. More recent prices estimate that a reusable rigid endoscope set including instruments would cost approximately £8850, with a flexible endoscope costing approximately £21,000. Although there will have been inflation during the period, the increase in prices for rigid neuroendoscopes in particular, look high. Clinical advice suggests that in 2005 these were very cheap, disposable rigid neuroendoscopes, but that these have since been withdrawn. This puts downwards pressure on the costs of the reusable rigid neuroendoscopes and, furthermore, it is likely that the volume of sales of neuroendoscopes has decreased resulting in an increase in the price. Whatever the reasons underlying the increase, the NICE committee were comfortable that the prices used in this report was appropriate.

The costs associated with decontaminating reusable instruments

Data provided by a committee member indicated that the cost of decontaminating a reusable instrument was, on average, £0.60 in Scotland (personal communication, May 2018). Assuming that this result is generalisable to England, this would correspond to a decontamination cost of £8.40 for a high-risk tissue brain set and £5.40 for a high-risk tissue posterior eye set.

The costs associated with disposing single-use sets

For simplicity, we have assumed that the costs of disposing of single-use sets are included within the purchase price. Given the relatively wide range in the costs assumed for a single-use high-risk tissue set (£350–500), the authors of this report deemed that this simplifying assumption would not cause significant inaccuracy.

The costs associated with keeping instruments moist

Data reported in Smith et al. 196 state that the cost of NHS bags would be £440 per 7355 neurosurgical trays reprocessed, equating to £0.06 per bag. Calculations based on the additional savings that could be made ‘using tap water and tray liner’ suggests that the costs of these elements are also £0.06 per tray. Thus, it has been assumed that the cost of keeping instruments moist was £0.12 per set conditional on using NHS bags, tap water and a tray liner.

The assumed safety of single-use instruments

In the base case it is assumed that the complication rates and outcomes are identical for reusable instruments and single-use instruments. The NICE committee believed this assumption was reasonable.

The costs associated with systems to allow instruments to be tracked

NICE committee members provided data from an unpublished Society for British Neurosurgeons survey and from costs recorded at their own units, which indicated that £750,000 across a 5-year period, including necessary equipment, would be a reasonable estimate (anonymous, May 2018). Sensitivity analyses were intended using £500,000 and £1,000,000.

The conceptual model of estimating the probability of infection when prions are transferred to the patient

In the earlier ScHARR model,11 the probability of infection was estimated using the mass transferred to the patient (in grams) and the infectious titre of the mass (in terms of ID₅₀ per gram, where an ID₅₀ is the dose required to infect 50% of the susceptible population). It was assumed that the relationship between the number of ID₅₀ and the probability of infection was:

such that 2 ID₅₀ or more would result in a certain infection. In the earlier ScHARR model, the use of a geometric sequence was used, such that 2 ID₅₀ would result in only 75% of patients being infected (1–0.5²). However, the committee did not want to use this assumption because the dose to infection was not robustly known and high levels of ID₅₀ transferred could be associated with definite, rather than a high probability of infection, and the committee wished to err on the side of caution. The linear assumption was upheld by the NICE appraisal committee.

The mass assumed to be transferred per operation is detailed in The proportion of residual mass on brain and posterior instruments that is transferred to a patient and the assumed infectious titre per gram is detailed in Parameters relating to the decontamination of surgical instruments.

In a key change from the ScHARR report,11 it was assumed that all patients, regardless of age or genotype, were susceptible to CJD infection.

The incubation period following surgically transmitted Creutzfeldt–Jakob disease infection

The incubation period associated with stCJD was elicited from clinical experts in January 2018 (see Appendix 4). The results are contained in Appendix 1, but are briefly detailed here. The elicited results differed from those previously elicited in that (1) distributions were no longer elicited for each genotype, as it was assumed that a single distribution could cover all genotypes given the incubation period would be affected by the genotype of the recipient, the infecting prion and the infectious dose provided; (2) uncertainty in the mean estimates was formally captured; and (3) it was assumed that all genotypes were susceptible to CJD.

Four incubation intervals were specified; in the base case, each interval was assumed to be equally likely. These were (1) 0.25 to 2 years, (2) 2 to 10 years, (3) 10 to 20 years and (4) 20 to 50 years. Within each time interval a uniform distribution was used on the assumption that each value was equally likely to occur. To allow for uncertainty around the mean incubation period, it was proposed that the first probability of being in the first three intervals would range between 10% and 40%, whereas the probability of being in the fourth interval (20 to 50 years) would lie between 15% and 35%.

As indicated in Figure 5, should the incubation time be less than the patient’s life expectancy (sourced from the Office for National Statistics217), the patient would display clinical symptoms. Otherwise, the patient would die without CJD symptoms. Each year a proportion of patients incubating CJD die as a result of non-CJD-related reasons, in line with data reported by the Office for National Statistics. 217 The probability of non-CJD-related death was dynamic between 2005 and 2014, using the appropriate life table, but was assumed to use life tables from 2014 to 2023.

The infectious period following surgically transmitted Creutzfeldt–Jakob disease infection

The proportion of the incubation period associated with stCJD for which a patient was considered infectious and able to pass CJD prions to instruments was taken from the elicitation session used to inform the earlier ScHARR report. 11 This distribution is shown in Figure 13. The mean of this distribution is 20.0%, indicating that the patient is infectious for only the last 20% of the incubation period. The 95% CrI for this parameter ranged from 15.3% to 25.2%. It has been assumed that the infectious titre of CJD prions is at the maximum value for the entire infectious period.

FIGURE 13.

The proportion of the incubation period during which the patient is infectious.

Estimations of the relative likelihood of returning to high-risk surgery

Patients who are infectious can return to surgery and may do so at a quicker rate than people who have not experienced prior surgery. The earlier ScHARR report11 assumed that (1) people who had previous brain surgery were 43 times more likely to have a further brain operation than people without a history of a brain operation; (2) people who had previous posterior eye surgery were 60 times more likely to have a further posterior eye operation than people without a history of a posterior eye operation; and (3) people who had previous neuroendoscopy were 761 times more likely to have a further neuroendoscopy than people without a history of a neuroendoscopy. These values were based on Hospital Episode Statistics (HES) data that were extracted by a third party (Northgate Information Solutions; Zellis, Hemel Hempstead, UK) and were assumed to be applicable for use in the updated modelling. Having performed sensitivity analyses in the construction of the model, by increasing the relative rates by 10, the model did not appear sensitive to this variable and the values were left at the values used previously.

The assumed costs and quality-adjusted life-years associated with Creutzfeldt–Jakob disease

Once clinical symptoms have developed, it is assumed that patients accrue no further QALYs as a result of the severity of the condition. The earlier ScHARR report11 used a value of £40,000 for the costs associated with treating a case of CJD. This has been updated using the inflationary indices,218,219 which estimate an inflation value of 302.3/240.9 (1.25) between 2005–6 and 2016–17 using the Hospital and Community Health Services index. Data reported in Barnett and McLean220 indicate that costs of additional care and/or equipment were approximately £10,500 per person from invoices received from 33 patients, although the authors of the paper state that ‘local agencies contributions have not been quantified’. This is lower than that assumed in the original ScHARR model, which has been maintained as the base-case value and is favourable to strategies to reduce future stCJD cases. For simplicity, we have assumed that the cost, from a NHS and Personal Social Services perspective, in 2017–18 for a CJD case was £50,000.

The probability that a person with Creutzfeldt–Jakob disease symptoms are not diagnosed with Creutzfeldt–Jakob disease

It is possible that patients with CJD may be diagnosed with another neurodegenerative disease. This possibility was not considered in the initial ScHARR report,11 but was requested following a meeting of the NICE committee. The distribution of patients who were presumed to be diagnosed with another neurodegenerative disease was elicited from experts in January 2018 (see Appendix 1 for full details) for two age bands, with the experts willing to allow the misdiagnosis in the aged 60–80 years category to be the average of the two other age bands: those aged < 60 years and those aged > 80 years. The distribution for those patients aged < 60 years is shown in Figure 14.

FIGURE 14.

The proportion of patients < 60 years with clinical CJD symptoms who are diagnosed with another neurodegenerative disease.

The mean value is 13.0% with a 95% CrI 0.4% to 26.8%. The distribution for those patients aged > 80 years is shown in Figure 15. The mean value is 55.0% with a 95% CrI of 18.6% to 88.4%. The simulated distribution for patients aged between 60 and 80 years of age inclusive is shown in Figure 16. This distribution has a mean of 34.0% with an estimated 95% CrI of 13.5% to 54.3%.

FIGURE 15.

The proportion of patients over 80 years with clinical CJD symptoms who are diagnosed with another neurodegenerative disease.

FIGURE 16.

The simulated proportion of patients aged between 60 and 80 years inclusive with clinical CJD symptoms who are diagnosed with another neurodegenerative disease.

It should be noted that based on the advice of clinical experts on the committee, there has been no change in CJD case ascertainment levels since 2005. This is partially supported by data from the NCJDRSU in the UK (25th Annual Report (see Figure 32), which showed similar age-specific mortality rates between 2005–9 and 2010–16 in those aged 60–64 years and those aged 75–79 years. However, the age-specific mortality rates were higher in the 70–74 years of age group in 2010–16 than in 2005–9, which could be indicative of better ascertainment in recent years. The assumption of equal ascertainment would favour single-use instruments.

In patients who are correctly diagnosed with CJD, the model does not explicitly distinguish between sCJD and stCJD and thus the probability node at the far right of Figure 5 is not contained in the model. However, it is appreciated that patients with stCJD may be categorised as sCJD, and these are used when calibrating the model output to the numbers of observed cases. This is described in more detail in The potentially unobserved number of surgically transmitted Creutzfeldt–Jakob disease cases between 2005 and 2018.

The operations considered to be at risk

In consultation with NICE, only high-risk operations are modelled, which have been subdivided into those related to the brain, those related to posterior eye operations and those involving neuroendoscopy. The operations, using HES data to four characters, that are considered to be high-risk were identified by an expert on the NICE committee and are contained in Appendix 5. For brain operations, an expert on the NICE committee grouped the operations into those with normal life expectancy, those where the patient would be expected to survive 18 months, and those with a 50% probability of death at 18 months and a 50% probability of a normal life expectancy.

Only the main procedure codes have been used rather than all the procedure codes, as there is a possibility that more than one high-risk HES code is undertaken within the same operation, using the same instrument set. In the modelling, the HES data have been inflated by 15% as in the ScHARR report11 to take into consideration that not all of the additional operations (between the main procedure and all procedures) are conducted simultaneously with another high-risk code, and also to incorporate operations undertaken by the private sector in non-NHS hospitals.

The estimated number of operations reported within the HES data since 1 January 2005 is provided in Table 25. For future years, the average number of operations in the last 3 years was assumed to continue. Operations were assumed to happen at a constant rate throughout the year. It should be noted that the values in Table 25 are those reported in the HES data as main procedures and have been increased by 15% within the model in line with the earlier modelling undertaken by ScHARR.

Hospital Episode Statistics data provide age breakdowns for each code, with more granularity from the year 2012 than prior to this date. Analysis of these data indicated that the age profile of patients remained relatively stable across time for each of the three brain operation groupings, for neuroendoscopy and for posterior eye operations. Therefore, for simplification, the age profile within 2016–17 was assumed to apply throughout the model. Depictions of each assumed age profile are provided in Appendix 6.

The observed number of surgically transmitted Creutzfeldt–Jakob disease cases between 2005 and 2018

There are no cases of CJD that have been categorised as stCJD during this period.

The potentially unobserved number of surgically transmitted Creutzfeldt–Jakob disease cases between 2005 and 2018

There are two possible ways in which patients with stCJD can be misdiagnosed. The first is that another neurodegenerative disease is diagnosed; this has been discussed in The costs associated with decontaminating reusable instruments. The second way that stCJD can be misdiagnosed is that a different form of CJD (in particular sCJD) is the presumed diagnosis, as a previous operation may not be recalled. The potential number of patients misdiagnosed as a different form of CJD was investigated.

Data were supplied to a NICE committee member by the NCJDRSU, which detailed whether or not patients who had a diagnosis of CJD since 2005 had a history of neurosurgery or posterior eye surgery, as well as a brief description of the operation. These data were reviewed by a NICE committee member who categorised each patient as having an operation that was of high risk (and, therefore, potentially a stCJD case) or not. The committee member erred on the side of caution, stating whether or not the operation could have the potential to transmit CJD prions to the patient. However, it is possible that some of the cases reviewed occurred in other parts of the UK than England, to which this guidance is limited, which would result in an overestimated calibration target.

For posterior eye surgery, there were potentially 24 individuals who had undergone surgical operations that could have transmitted CJD, although only 10 of these had operations in 2005 or later. The year of the operation is important, as we want to calibrate the model only to cases where the patient had been infected during the modelling period. For brain surgery, there were potentially 13 individuals who had undergone operations that could have transmitted CJD. There were no dates provided for the operations and thus it was assumed that the proportion of operations conducted in 2005 or later that were observed for posterior eye surgery (10/24) were applicable to neurosurgery, which equates to a possible five cases of stCJD since 2005 (rounding to the nearest integer). The sum of these calculations implies that there could have been 15 cases of stCJD transmitted since 2005 that had been misdiagnosed as another form of CJD, or just over one case per year on average.

Interpretation of the scenario analyses results using the base case as the foundation

These results are subject to Monte Carlo sampling error, particularly in relation to the RNs exhausted within a simulation. For example, in the scenario analysis that changed a unit from S2 to S1, at the start of 2019 this model run will have used significantly more RNs than a comparison with S1 alone. This is a result of the RNs required in selecting from 2012 onwards, the SIs used in an operation and the migration of instruments between sets (which is a feature of S2 but not of S1). This misalignment of RNs between runs will result in different simulated outcomes.

Despite the presence of Monte Carlo sampling error, the results generated are broadly consistent between comparable units, which offers support that the values are relatively robust. However, caution is advised in trying to interpret differences in the results of the scenario analyses (see Table 27) and the base-case results (see Table 26), as these differences could be artefacts of the RNs selected. Significantly more computational time would be required to provide an accurate comparison of the scenario analyses and the base-case results; this was beyond the time scales of the project.

Results for S1 and S4 units

For surgical units that adhere to IPG196 and keep instruments moist, the only strategy currently available to reduce the potential for stCJD is to use single-use instruments. Based on the values reported in Table 28, it is estimated for a S1 unit that the additional net cost of single-use instruments per unit would be £1,814,139, which would produce an expected 0.459 QALYs, thereby resulting in a cost per QALY gained of £4.0M. For a S4 unit, the net cost was similar (£1,814,545) with fewer QALYs gained (0.275), resulting in a cost per QALY gained of £6.7M. Both cost-per-QALY estimates are markedly higher than the thresholds commonly used by NICE.

Results for S2 and S5 units

For surgical units that do not adhere to IPG196 but keep instruments moist, two strategies are currently available to reduce the potential for stCJD: the use of single-use instruments and adhering to IPG196.

Based on the values reported in Table 28, it is estimated for a S2 unit that the additional net cost of single-use instruments per unit would be £2,562,829, which would produce an expected 0.874 QALYs, thereby resulting in a cost per QALY gained of £2,933,530. For a S5 unit, the net costs were similar (£2,563,238) with fewer QALYs gained (0.736), resulting in a cost per QALY gained of £3,484,476. Both cost-per-QALY estimates are markedly higher than the thresholds commonly used by NICE.

For a S2 unit, adherence to IPG196 is estimated to have a net cost of approximately £750,000 and provide an increase in QALYs of 0.415, resulting in a cost per QALY of approximately £1.8M. For a S5 unit, adherence to IPG196 is estimated to have a net cost of approximately £750,000, an increase in QALYs of 0.461, resulting in a cost per QALY gained in the region of £1.6M. Both cost-per-QALY estimates are markedly higher than the thresholds commonly used by NICE.

Results for S3 and S6 units

For surgical units that are neither adhering to IPG196 nor keeping instruments moist, three strategies are currently available to reduce the potential for stCJD: the use of single-use instruments; adhering to IPG196 and keeping instruments moist; and keeping instruments moist.

Based on the values reported in Table 28, it is estimated for a S3 unit that the additional costs of single-use instruments per unit would be £2,550,760, which would produce an expected 4.009 QALYs, thereby resulting in a cost per QALY gained of £636,292. For a S6 unit the costs were similar (£2,552,043) with fewer QALYs gained (3.485), resulting in a cost per QALY of £732,364. Both cost-per-QALY estimates are markedly higher than the thresholds commonly used by NICE.

For a S3 unit, keeping instruments moist is estimated to produce a cost saving (as the costs of potential prevented CJD cases outweighed those associated with keeping the instruments moist) and to provide an increase of 3.135 QALYs, suggesting that keeping instruments moist is dominant (lower costs and more QALYs produced). For a S6 unit, there was also an expected cost saving of an increase in QALYs of 2.749, resulting in keeping instruments moist being dominant.

For a S3 unit, having initially kept instruments moist, the cost-effectiveness of adhering to IPG196 would be similar to that of moving from S2 to S1, that is in the region of £1.8M per QALY gained. For a S6 unit having moved to a S5, the cost per QALY gained of adhering to IPG196 would be in the region of £1.6M.

Estimating the probabilities that each type of surgical unit or using single-use instruments are the most cost-effective strategies assuming that a centre does not currently follow IPG196 nor keep instruments moist

The probabilities of each surgical unit and using single-use instruments being the most cost-effective are provided in Figure 19 when it is assumed that the P96 group are infectious, and in Figure 20 when it is assumed the P96 group are not infectious. These results assume that all surgical units are currently S3 or S6. Both figures have similar characteristics in that S2/S5 (units that keep instruments moist but do not follow IPG196) have the highest probability of being cost-effective, followed by units that continue to ignore IPG196 and those that do not keep instruments moist. Even at high cost-per-QALY thresholds, the probability that single-use instruments are the most cost-effective is negligible. The probability of being most cost-effective accord with the scenarios (S2 and S5) that are estimated to be the most cost-effective.

FIGURE 19.

The probabilities that S1, S2, S3 and single-use instruments are the most cost-effective at a range of cost-per-QALY thresholds. SUI, single-use instrument.

FIGURE 20.

The probabilities that S4, S5, S6 and single-use instruments are the most cost-effective at a range of cost-per-QALY thresholds. SUI, single-use instrument.

Sensitivity analyses results for S1 and S4 units

The ICER for single-use instruments for a S1 unit became £2.9M, whereas the ICER for a S4 unit became £4.9M. Neither value was below the commonly used NICE thresholds.

Sensitivity analyses results for S2 and S5 units

The ICER for single-use instruments for a S2 unit became £2.4M, whereas the ICER for a S5 unit became £2.9M. Neither value was below the commonly used NICE thresholds.

For a S2 unit, adherence to IPG196 is estimated to have an ICER of approximately £1.2M, whereas for a S5 unit this ICER was approximately £1.1M. Neither value was below the commonly used NICE thresholds.

Sensitivity analyses results for S3 and S6 units

For a S3 unit, keeping instruments moist remains a dominant strategy. This is also the case for a S6 unit.

For a S3 unit, having initially kept instruments moist, the cost-effectiveness of adhering to IPG196 would be similar to that of moving from S2 to S1, that is in the region of £1.2M per QALY gained. For a S6 unit, the cost-per-QALY of adhering to IPG196 would be in the region of £1.1M, which is similar to moving from a S5 to a S4 unit. These values are similar rather than identical, as there may be more infectious material on instruments in the S3 and S6 units than in S2 and S5 units.

Search strategy

1. exp Creutzfeldt–Jakob Syndrome/

2. ((creutzfeldt jakob or creutzfeldt-jakob) adj (disease or syndrome)).tw.

3. (cjd or vcjd or v-cjd).tw.

4. exp Prion Diseases/

5. exp Prions/

6. ((transmissible or spong*) adj encephalopath*).tw.

7. (prion* or tse).tw.

8. prp.tw.

9. or/1-8

10. (surgery or surgical* or operat*).tw.

11. risk*.mp.

12. 9 and 10 and 11

13. limit 12 to yr=“2005 –Current”

Search strategy

1. exp Creutzfeldt Jakob disease/

2. ((creutzfeldt jakob or creutzfeldt-jakob) adj (disease or syndrome)).tw.

3. (cjd or vcjd or v-cjd).tw.

4. exp prion disease/

5. exp prion/

6. ((transmissible or spong*) adj encephalopath*).tw.

7. (prion* or tse).tw.

8. prp.tw.

9. or/1-8

10. (surgery or surgical* or operat*).tw.

11. risk*.mp.

12. 9 and 10 and 11

13. limit 12 to yr=“2005 -Current”

Search strategy

1. # TS=(creutzfeldt jakob NEAR/1 disease) OR TS=(creutzfeldt jakob NEAR/1 syndrome) OR TS=(creutzfeldt-jakob NEAR/1 disease) OR TS=(creutzfeldt-jakob NEAR/1 syndrome)

2. # TS=((cjd or vcjd or v-cjd))

3. # TS=(transmissible NEAR/1 encephalopath*) OR TS=(spong* NEAR/1 encephalopath*)

4. # TS=(prion* or tse or prp)

5. # #4 OR #3 OR #2 OR #1

6. # TOPIC: ((surgery or surgical* or operat*))

7. # TOPIC: ((risk*))

8. # #7 AND #6 AND #5

9. # #7 AND #6 AND #5 Refined by: PUBLICATION YEARS: (2006 OR 2012 OR 2016 OR 2015 OR 2007 OR 2013 OR 2005 OR 2009 OR 2010 OR 2017 OR 2014 OR 2011 OR 2008)

Individual judgements

Without conferring, the experts made the probability judgements for parameter 1 as shown in Table 31.