Nosocomial transmission of sporadic Creutzfeldt–Jakob disease: results from a risk-based assessment of surgical interventions

Discussion

The key features of the present study design enabled us to address novel aspects of the potential of surgical transmission of CJD.9 The additional introduction of an aetiological classification, that is unmasking associations hidden by the body-system approach,17 24 revealed a number of statistically significant associations, associations of higher magnitude and new effects with a particular pattern at 10–19 years’ latency. Limitations, which in part are discussed elsewhere,9 comprise: the low statistical power for some latencies and exposure categories; missing information on interventions undergone prior to registration or as outpatients; and lack of control of potential confounders such as blood transfusion, overlooked dura mater implants or hospital hygiene level.

The new SP classification system was built in a tissue/structure classification reported in 200522 combining features of the first WHO Classification on Tissue infectivity25 and of experimental efficiency of prion disease transmission to animals when using different routes of inocula administration.26–29 The plausibility of the risk excess of surgery of retina and peripheral nerves seen here might be supported by studies in experimental scrapie (Sc). PrP^Sc injected into the eye travelling via defined neuroanatomical connections has been demonstrated to be able to reach larger brain regions.30 31 In hamsters, PrP^Sc spreads along the vagus nerve to the medulla, pons, midbrain, cerebellum and thalamus via neuroanatomical pathways.32 The increasing risk found for SP involving veins, peritoneal cavity and lymph nodes at longer latencies fits proposals on prion neuroinvasion and transport, suggesting that prions first replicate and accumulate in the lymphoreticular system (LRS) (see Aguzzi and Calella33 for a recent review). In addition, it would appear that risk excess and latency are inversely correlated: for surgery of retina, OR 5.53, at mean 11 years; for surgery of peripheral nerves, OR 4.41, at 10–19 years; and for lower-risk SP OR 2.4, at ≥20 years. In summary, our findings might be consistent with proposed biological mechanisms potentially underlying the rapid access to the CNS by direct contact,34 prion uptake through the skin, neuroinvasion from the spleen and spread of prions along peripheral and CNS pathways.33 35

Compared with other studies, the main contribution of the new methodology may be credibility to consistently positive results from large recent studies covering lifetime surgery and pointing to likewise underlying diluting effects.7 8 In a study with negative results, retina surgery was unfortunately not investigated separately from other ophthalmological surgery.12 Findings for lower-risk procedures at >20 years would correspond to a similar risk excess before reclassification for main surgical procedures.9 However, the association with coronary surgery seen in TW-3 when using unmatched controls as well as the body system approach does not have a corresponding finding here. Since the association of coronary surgery with sCJD has been reported for Alzheimer’s disease at a similar latency, confounding from vascular risk factors generating both dementia and coronary disease followed by coronary surgery may be proposed as a potential explanation unrelated to prion transmission consistent with absence of findings after reclassification.36

Unrecorded information potentially determining our results might be the length of the pathway to the brain, short in the case of retina and acoustic nerve. An overlooked autologous dura mater graft, implanted during the above-mentioned acoustic neurinoma intervention, was excluded by direct perusal of the surgeon’s report, issued in 1977, by an author, HL, who excluded an accidentally transmitted CJD by dura mater implant. Improved cleaning of instruments in recent times may in part explain decreased excess risk with shorter latencies.

Blood transfusion has not been identified as a risk factor for sCJD; however, Riggs et al warn about the weaknesses of case–control studies frequently reporting protective effects.37 Inability to adjust for blood transfusion is a limitation of the study, since it has been estimated that blood transfusion is present in 50% of all major surgical interventions38; blood thus comprises a potential confounder.39 Since it would appear that the excess risk seen here for some tissues, for instance for retina surgery, is difficult to attribute to simultaneous blood transfusion, some of the present results might be consistent with confounded effects of surgical instruments and blood. This view contradicts observations on variant CJD, where transmission by blood has been demonstrated,40–43 but not risk excess for surgery.44 However, differences between sCJD and vCJD or Kuru are so large that inferences should perhaps be inappropriate. Furthermore, the exposures studied might not be independent phenomena representing either a potential entry site for prions or the above-mentioned uncontrolled confounding. For example, cohorting of surgical instruments occurs, and an instrument used once for retina surgery, for example, has in all likelihood been repeatedly used for retina surgery. It is therefore possible that our findings could in part be explained by infectivity determined by tissue remnants adhered to instruments (not controlled for here) rather than by the putative entry site (ie, tissue contacted). Consequently, the 18%9 to 35%7 proportion of sCJD which has been suggested might be causally related to surgery, while in theory consistent with observations from animal models, would be difficult to ascribe to a single biological mechanism based on these data.

The results might be surprising, since identified iatrogenic events related to surgery appear to be very rare. Surveillance since 1993 by 11 countries at the EUROCJD consortium includes data on more than 6000 sCJD cases (http://www.eurocjd.ed.ac.uk/genetic.htm). The number of iatrogenic cases related to surgery are 53 assigned to dura mater, two to corneal implants and nil to neurosurgery. However, routine surveillance data will usually not recognise surgical risk exposures for iatrogenic CJD other than grafts. Reasons to explain this might be: (1) the overwhelming difference in annual cohort size, that is >100 000 surgical in-patients per million in Sweden 2004 (http://192.137.163.40/epcfs/index.asp?modul=ope), versus approximately 200 dura mater grafts per million in the 1990s in Japan45; (2) the comparatively large attrition by low survival of neurosurgical and dura mater grafted cohorts45–47; (3) surveillance encompasses the end of the iCJD epidemic48; (4) large differences in duration of incubation periods, mean 11 years for iCJD by dura mater reduce differences in cumulative risk48; (5) similar genetic susceptibility might be a strong determinant of surgical risk linked or not to grafts, and is shared by iCJD and sCJD as shown by homozygosity at codon 12948 49 but can be interpreted in different ways. CJD surveillance captures epidemiologically compelling evidences required for correct CJD diagnosis; the OR for exposure to cadaveric dura mater for CDJ in Japan50 was 32.5 95% CI (2.6 to infinity). Our three cases with history of retina surgery were first discharged with CJD diagnosis from three different hospitals, at different years, in two countries, and most probably diagnosed by different clinicians. Views for iCJD from surveillance and results of this study are perhaps not so difficult to reconcile when biology, diagnosis, epidemiology and public-health practice51 are simultaneously considered.

The potential applicability of results in prevention is complex. Cautiousness might be recommended for planning of surgical interventions for patients where CJD diagnosis has been considered, and for decontamination and quarantining of such surgical instruments, avoiding reuse during the interval CJD diagnosis has not been excluded. Established instrument-quarantining, -tracking, -cleaning and prion-disinfection policies, which generally target infrequent procedures, such as neurosurgery and ophthalmological, spine and ear surgery,38 52 are based on decontamination of remnants and applied to surgical activity defined by the type of surgeon, that is, by body-system group. Current sterilisation procedures undertaken in hospitals for delicate instrumentation are insufficient to ensure total removal of infectious prion protein, and carriers of infective prions are difficult to detect.52 53 Extension of such measures, after appropriate assessment, to instruments contacting or potentially contacting veins, female genital organs, peritoneal cavity, peripheral nerves and muscle could be a priority. In addition, new decontamination procedures54 may have a wider-than-expected field of application.

To sum up, these results suggest that surgery constitutes a risk factor for sCJD, acting with long incubation periods, and less frequently with shorter latencies when the central- or peripheral nervous system as well as skeletal muscle are implicated. In addition, results are in concordance with animal models of experimental prion transmission through various routes of inoculation that may mimic accidentally transmitted CJD, and might have implications for prevention of CJD spread in medical settings.