NR APWZ
AU Aguzzi,A.; Glatzel,M.
TI vCJD tissue distribution and transmission by transfusion - a worst-case scenario coming true?
QU Lancet 2004 Feb 7; 363(9407): 411-2
KZ Lancet. 2004 Feb 7;363(9407):417-21. PMID: 14962520 Lancet. 2004 Feb 7;363(9407):422-8. PMID: 14962521
PT comment; journal article
VT
See pages 417 [APWY] and 422
Two reports in today's Lancet advance knowledge of the transmission and tissue distribution of prions, the infectious agent causing transmissible spongiform encephalopathies. Prions are devoid of informational nucleic acids and are thought to consist of an "infectious" protein (PrPsc) that can convert the normal host protein (PrPc) into a likeness of itself. Although not highly contagious, Creutzfeldt-Jakob disease (CJD) has long been known to be transmissible. Variant CJD (vCJD) is probably caused by infection of human beings with bovine spongiform encephalopathy (BSE) prions. In sporadic (sCJD) and vCJD, and in all known transmissible spongiform encephalopathies of animals, the only organ system with histopathological damage of clinical consequence is the nervous system. However, prions can colonise extraneural organs, especially lymphoreticular organs such as spleen, lymph nodes, appendix, and tonsils. The spectrum of tissues harbouring infectivity partly depends on the "strain" of prions. Each strain has preferences for the host animal and the type of cells in which it replicates. Although extraneural tropism was thought to set the vCJD strain apart from sCJD, it was recently realised that prions can accumulate in lymphoid organs and skeletal muscle of sCJD patients.[1]
To a large extent, host factors control the tissue tropism of prions. For example, despite the widespread colonisation of extraneural tissues in vCJD, BSE prions are largely confined to the neural compartment of cows, even after oral exposure.[2] In cows fed BSE-infected brain, infectivity resides transiently in the terminal ileum.[3] Later, BSE prions can be found only in brain, spinal cord, and dorsal root ganglia, and sometimes in bone marrow and tonsil. The route of infection may account for variability in tissue tropism. Intraperitoneal administration of prions in rodents is followed by prion replication in the thoracic spinal cord, the projection site of splanchnic nerves.[4,5] Oral challenge favours vagal spread;[6] intraocular instillation preferentially affects optic pathways.[7] In all cases, lymphoid organs are rapidly colonised.
However, the neurophysiology and immunology of mice are different from those of human beings, hence mouse models may be misleading. In one of today's Lancet papers, C Herzog and colleagues report the oral or intravenous delivery of saturating vCJD inocula to cynomolgus macaques. Although not studied in detail, this protocol should definitely result in sustained prionaemia and exposure of virtually all body tissues to prion infectivity. Therefore study of PrPsc distribution in various organs when clinical transmissible spongiform encephalopathy develops should allow assessment of all tissues capable of replicating vCJD prions. Herzog and colleagues show that the gut is such a vCJD target tissue: PrPsc was detected in various intestinal segments independently of the route of challenge. But liver was always negative, which is somewhat unexpected because Kupffer cells should engulf some of the inoculum. Evidently these cells cannot replicate prions, although related CD11b+ cells express PrPc.[8] There was an interesting and unexplained hierarchy in the propensity of lymphoid tissues for prion replication, with tonsils consistently displaying the largest accumulation of PrPsc.
These data are highly informative for attributing relative risks of iatrogenic vCJD transmission during surgical procedures. Of the tissues tested by Herzog and colleagues, the tonsil appears to be the organ of choice for minimally invasive diagnosis of vCJD.
Intracerebral and intravenous challenge with similar doses yielded similar incubation times. However, this finding does not necessarily support Herzog and colleagues' argument that the efficiency of intravenous administration of prions is close to that of intracerebral inoculation. Even the lowest amount inoculated in their series (400 µg), is likely to be well above the minimum infectious dose. Hence no firm conclusion can be drawn about the efficiency of infection take without parallel titrations of intravenously and intracerebrally administered infectivity. However, it is interesting that the speed of pathogenesis is similar for both routes.
It may be difficult to extrapolate these results to transfusion medicine. From other animal models,[9] there is good reason to believe that blood from vCJD-infected animals contains prions. But the presumptive infectious titre of any blood unit is likely to be several orders of magnitude lower than those inoculated by Herzog and colleagues. It is impossible to predict whether pathogenesis after exposure to limiting dilutions of prions will be similar to that after a saturating challenge, because constraints in bioavailability might lead to different organ targeting. Further, any hypothetical prion infectivity in blood might physically differ from that of brain homogenate: prions may be complexed with serum proteins,[10] or may reside within blood cells, whose pharmacokinetics might differ from that of disrupted membrane fragments.
In the second Lancet paper, C Llewelyn and colleagues present a patient who died of vCJD 6.5 years after receiving a transfusion of red blood cells donated by an individual who subsequently developed vCJD. They do not present direct evidence that the disease was transmitted by blood transfusion, but the chance that this case is not transfusion-related is very small.
Shocking as it may be, the finding that vCJD can be transmitted via blood transfusion is not surprising. Stringent studies in sheep show that prion diseases can be transmitted via blood,[9] even if blood is collected in preclinical stages of prion disease.[11] By December, 2003, 153 cases of vCJD were reported worldwide. Although the epidemic may have peaked in the UK, the probable existence of subclinical vCJD carriers raises concerns of an iatrogenic human-to-human wave of vCJD transmission.[12]
Should Llewelyn and colleagues' case really represent transfusion-related transmission of a human prion disease, does it vindicate the beleaguered supporters of hypercautionary measures against the theoretical risk of blood-borne propagation of vCJD? Many countries have implemented leucodepletion of blood units, and some are banning donors from regions with a high prevalence of BSE. We suspect that the, admittedly unproven, potential of leucodepletion for prion reduction might offset its high cost. But nobody knows whether leucodepletion is sufficient, or even necessary, for protecting transfusion recipients from vCJD prions. To make matters worse, many of the countries banning UK (or even all European) donors have discovered BSE in their own herds immediately after deployment of properly done cattle surveillance. What is the point of banning donors on the basis of their country of residence, say sceptics, if the country's own national donors might also have been exposed to BSE prions?
The tragedy of iatrogenic prion transmission emphasises again the need for high-throughput and reliable detection methods for prion-tainted blood units. Although PCR-based assays have all but eliminated the risk of transmission of several blood-borne viruses, no tools of similar potency are available for prion detection.[13]
Public-heath authorities are faced with considerable insecurity about the prevalence of subclinical prion carriers, and any human-to-human transmission will complicate estimation of the size of the vCJD epidemic. Although cross-sectional studies to assess the prevalence of prion carriers pose organisational and ethical problems, there is no alternative for assessing the future of the vCJD epidemic.[14]
We have no conflict of interest to declare.
1 Glatzel M, Abela E, Maissen M, Aguzzi A. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. N Engl J Med 2003; 349: 1812-20.
2 Wells GA, Hawkins SA, Green RB, et al. Preliminary observations on the pathogenesis of experimental bovine spongiform encephalopathy (BSE): an update. Vet Rec 1998; 142: 103-06.
3 Terry LA, Marsh S, Ryder SJ, Hawkins SA, Wells GA, Spencer YI. Detection of disease-specific PrP in the distal ileum of cattle exposed orally to the agent of bovine spongiform encephalopathy. Vet Rec 2003; 152: 387-92.
4 Kimberlin RH, Walker CA. Pathogenesis of mouse scrapie: patterns of agent replication in different parts of the CNS following intraperitoneal infection. J R Soc Med 1982; 75: 618-24.
5 Glatzel M, Heppner FL, Albers KM, Aguzzi A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 2001; 31: 25-34.
6 Beekes M, McBride PA. Early accumulation of pathological PrP in the enteric nervous system and gut-associated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett 2000; 278: 181-84.
7 Fraser H. Neuronal spread of scrapie agent and targeting of lesions within the retino-tectal pathway. Nature 1982; 295: 149-50.
8 Watarai M, Kim S, Erdenebaatar J, et al. Cellular prion protein promotes Brucella infection into macrophages. J Exp Med 2003; 198: 5-17.
9 Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. Transmission of BSE by blood transfusion in sheep. Lancet 2000; 356: 999-1000.
10 Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A. Binding of disease-associated prion protein to plasminogen. Nature 2000; 408: 479-83.
11 Hunter N, Foster J, Chong A, et al. Transmission of prion diseases by blood transfusion. J Gen Virol 2002; 83: 2897-905.
12 Collins PS, Lawson VA, Masters PC. Transmissible spongiform encephalopathies. Lancet 2004; 363: 51-61.
13 Aguzzi A, Polymenidou M. Mammalian prion biology: one century of evolving concepts. Cell 2004; 116: 313-27.
14 Glatzel M, Ott PM, Lindner T, et al. Human prion diseases: epidemiology and integrated risk assessment. Lancet Neurol 2003; 2: 757-63.
MH Animals; Blood Transfusion/*adverse effects; Cattle; Creutzfeldt-Jakob Syndrome/physiopathology/*transmission; *Disease Transmission, Horizontal; Encephalopathy, Bovine Spongiform/blood; Human; Prions/*blood/physiology; Tissue Distribution; Tropism/physiology
AD Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland. adriano@pathol.unizh.ch
SP englisch
PO England