Iatrogenic CJD is the one human prion disease whose exposure source, route and approximate timing are often known, which makes it the natural material for questions about strains, incubation and what else travelled with the infectious agent. Plain-language pages: iatrogenic CJD and the more detailed version.
Were the French and UK growth hormone epidemics caused by different strains?
This was the standing hypothesis. France recorded 122 and the United Kingdom 81 growth hormone cases, and the two cohorts differed in the frequency of the PRNP codon 129 genotypes and in the incubation periods associated with each, which had been read as evidence of different agents.
Douet and colleagues tested it by inoculating brain homogenate from 11 UK and 11 French cases, covering MM, MV and VV genotypes from both countries, into mouse models expressing human PrP, with UK and French sporadic CJD cases as controls. The strains identified corresponded to the two commonest sporadic strains, M1 and V2. In the large majority of cases from both countries, V2 or a mixture of M1 and V2 was found. The authors state the result contradicts the hypothesis: the strains in the two cohorts were not radically different, so the epidemiological and genetic differences between the cohorts cannot be attributed to strain alone.
What remains unexplained is therefore the exposure side: how the hormone batches were prepared, how much material each recipient received, and over what period. Strain typing in humanised mice also reports which strain dominates after a species-matched passage, which can simplify a mixture present in the original patient.
What else was in the hormone?
Duyckaerts and colleagues examined amyloid beta deposits and tau pathology in 24 French patients who died of iatrogenic CJD after exposure to cadaver-derived growth hormone in the 1980s, and assayed 24 hormone batches produced between 1974 and 1988.
Amyloid beta deposits were found in only one patient, who had one of the longest incubation periods, and three patients had intracellular tau accumulation. In the batches, the authors report for the first time the presence of amyloid beta contaminants in 17 batches and tau contaminants in 6. Prion disease incubation in the French patients was shorter than in two previously published British series, and the authors interpret the low frequency of amyloid beta in the French cases as a consequence of that shorter incubation, implying a mean incubation for detectable amyloid beta deposits of more than 18 years after first exposure. They hypothesise that tau pathology may also be transmissible in humans.
The inference chain here is longer than in the strain study. Contamination of batches is directly measured. Transmission of amyloid beta pathology to recipients is supported by one case with deposits and by the incubation argument, and transmissibility of tau is advanced as a hypothesis, not a finding.
Does iatrogenic disease differ molecularly from other forms?
Vanni and colleagues measured SERPINA3 transcript in 128 frontal cortex samples: 20 variant CJD, 11 iatrogenic CJD, 23 sporadic CJD, 17 familial CJD, 9 FFI, 4 GSS, 14 Alzheimer disease and 30 age-matched controls, using four reference genes. SERPINA3 was strongly up-regulated in the brain in all human prion diseases, at both mRNA and protein level, with the degree differing by disorder, and only mildly up-regulated in Alzheimer disease. They suggest it may be involved in pathogenesis and progression and could help distinguish forms of the disease.
Post-mortem transcript levels in end-stage brain cannot separate cause from consequence, and group sizes for the rarer forms are small. The finding is useful as a marker of the glial response rather than as a diagnostic test.
What does the tissue evidence imply for ongoing risk?
The historical routes, cadaveric growth hormone and dura mater grafts, are closed. The remaining concern is surgical instruments, which depends on which tissues carry the agent. Peden and colleagues found PrPSc in autopsy skeletal muscle in 2 of 5 iatrogenic cases, alongside 8 of 17 variant and 7 of 26 sporadic cases, localised to structures with the characteristics of nerve fibres. For the decontamination evidence built on this see decontamination and tissue and organs.
What is unresolved?
- How long incubation can run in the remaining exposed cohorts, which bears on surveillance duration. Case counts by country are on epidemiology.
- Whether tau or amyloid beta pathology was transmitted to recipients who did not develop prion disease.
- Why codon 129 genotype distributions differed between national cohorts exposed to similar material.
Related: kuru, GSS, diseases hub and current trials.
Sources for this page
- Douet JY and others (2021) Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients, Acta Neuropathol Commun 9:145
- Duyckaerts C and others (2018) Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches, Acta Neuropathol 135:201-212
- Vanni S and others (2017) Differential overexpression of SERPINA3 in human prion diseases, Sci Rep 7:15637
- Peden AH and others (2006) Detection and localization of PrPSc in the skeletal muscle of patients with variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease, Am J Pathol 168(3):927-935