2011 Meeting Minutes

Public Health Service

Meeting of the Interagency Coordinating Committee on Human Growth Hormone and Creutzfeldt-Jakob Disease

November 2, 2011

National Institutes of Health - Bethesda, Maryland

Committee Members Attending Also Attending
Dr. Judith Fradkin, NIDDK
Dr. Ellen Leschek, NIDDK
Dr. James Mills, NICHD (by speakerphone)
Dr. Griffin Rodgers, NIDDK, Chairman
Dr. Lawrence Schonberger, CDC (by speakerphone)
Dr. Diane Wysowski, FDA (by speakerphone)
Joseph Abrams, CDC (by speakerphone)
Mary Harris, NIDDK
Ryan Maddox, CDC (by speakerphone)
Jody Nurik, NIDDK
Dr. B. Tibor Roberts, NIDDK
Dr. Julie Wallace, NIDDK
Dr. May Wong, NINDS (by speakerphone)

The meeting began at 1:30 p.m.

1. Welcome

Dr. Rodgers welcomed the group, and those attending introduced themselves.

2. Epidemiology Study Status Report

Dr. Leschek reviewed activities under the contract with Westat for the follow-up of deaths in the cohort and ascertainment of CJD cases. According to Committee practice, she then reviewed both confirmed and possible U.S. cases of CJD in the following categories:

  1. Neuropathologically confirmed CJD
  2. Clinically confirmed CJD
  3. Clinically suspicious - neurologic findings of uncertain etiology with insufficient information to confirm or exclude CJD
  4. Deaths under investigation

Case Categories I, II, and III:

Dr. Leschek reported that during 2011 the Public Health Service learned of a new neuropathologically confirmed case of CJD. The cohort member, who had received NHPP growth hormone from 1965 to 1970, had died in May of 2009. The National Prion Disease Pathology Surveillance Center contacted Dr. Schonberger to inform him of a death, reporting that autopsy confirmed CJD. This will be listed as the 29th case of CJD in the cohort. However, while the cohort member’s sister has authorized release of medical records, Westat has not yet received either the records or the death certificate. For this technical reason, the official number of confirmed cases remains 28, at present. Of interest, this case lengthens the potential incubation period for CJD. The incubation period for this case was at least 39 and possibly as long as 44 years, while the previous longest possible incubation time was about 33 years. Dr. Leschek will consult the physician to try to determine the date of symptom onset, and report an incubation period for the fact sheet from initial treatment to onset of symptoms. Because the increase in potential incubation time is so significant, Dr. Wysowski also recommended checking all of the information we had on treatment dates for this individual, to ensure that source documents are in agreement.

Since this case is not yet “official,” no cases were added to either category I or II (confirmed CJD) in 2011. Therefore the total number of deaths in the cohort attributable to CJD remains 28, including 13 in category I (neuropathologically confirmed) and 15 in category II (clinically confirmed). All deaths confirmed as CJD received at least some of their hGH treatment prior to 1977, when Dr. Parlow’s laboratory began producing hGH for the National Hormone and Pituitary Program.

The number of cases regarded as “clinically suspicious—insufficient information to confirm” (category III) remains 4. Cases are placed in category III when there is a difference of opinion among members of the Neurologic Review Group (NRG) about the likelihood of CJD, and no further clinical information is likely to become available.

Case Category IV:

Dr. Leschek reminded the group that only one case remained under investigation following the 2010 Committee meeting. This was that of a cohort member who died at 35 years of age in 2004, with “encephalopathy” listed as the cause of death, with no autopsy performed. Records indicate that she received hGH from ages 14-16, necessitated by tumor and tumor-related radiotherapy. Although Dr. Leschek was unable to locate next of kin, Dr. Schonberger was able to obtain some medical records via CDC channels. These included several electroencephalograms (EEGs) from the period leading up to onset of mental deterioration. These tests did not show periodic, generalized sharp wave complexes characteristic of CJD. One EEG did reveal focal epileptiform abnormalities consistent with the individual’s ongoing seizure problems, and therefore underlying neurological pathology may help account for some of the cerebral deterioration that occurred in her last year of life. Significantly, two months before her death she was alert and “at her baseline” functionally, according to staff at the nursing home where she lived—able to propel herself in a wheelchair and feed herself, for example. Computed tomography (CT) scans and other records similarly indicate severe, chronic neurological issues, rather than CJD. The records were sent to the Neurology Review Group (NRG), which had not yet provided their opinions as of the date of the Committee meeting, but Dr. Leschek felt it was highly unlikely they would consider this to be a case of CJD.

Dr. Leschek next presented the case of a man who died in August 2007 at 51 years of age, with extrapontine myelinolysis listed as the cause of death, and hyponatremia and hypopituitarism listed as contributing causes. As a teenager he was treated with surgery and radiotherapy for a pituitary tumor, leaving him with panhypopituitarism, which was the reason for his growth hormone therapy during a period beginning in 1974 and ending in 1977. An autopsy has been performed, but the parents have refused participation in our study, so the results are not available. Dr. Fradkin suggested, however, that if the autopsy turned up anything unexpected, an amended death certificate might have been filed. Dr. Leschek will try to determine whether that occurred.

Dr. Leschek then told the Committee about a man who died at age 33 in 2008 of anoxic encephalopathy (“10 day duration due to respiratory failure.”) Dr. Leschek noted that this was suggestive of some acute etiology. He was treated with growth hormone from 1980 through 1982 for isolated growth hormone deficiency. No autopsy was performed, his parents are deceased, and Dr. Leschek is proscribed by IRB rules from contacting his spouse for additional information. This case is unusual, considering the age and cause of death together with the lack of known neurological issues. Although the Committee agreed that the limited available data are by no means strongly suggestive of CJD, Dr. Schonberger and Dr. Maddox agreed to try to obtain more records through CDC channels, noting that where (which state) the person died can strongly affect the probability that such an inquiry will be successful.

Dr. Leschek then described a living recipient previously under consideration for possible CJD. Dr. Leschek had been contacted by the sister of this man, who is not in the cohort. The sister explained that he was treated with growth hormone between 1960 and 1962, and had developed some signs of possible CJD. The individual was still alive, however, and the sister recently reported that a change in medication regimen over the last year seemed to greatly alleviate symptoms. Thus, the man’s condition improved during 2011, and there is no longer any evidence of CJD.

Case Summary by Category (resulting from adjudication during this meeting):
Category # cases Net change since 2010
I 13* 0*
II 15 0
III 4 0
IV 2 +1

*The numbers for category I are expected to increase by one, however, when the medical records for the apparent new case are received.

Possible CJD Case Associated with Commercial Pituitary-Derived GH

Dr. Schonberger discussed the case of a 33-year old who died in 2011, with CJD listed as cause of death. This individual did not receive NHPP hormone, but evidently was treated with growth hormone from two commercial producers (at 5 years 7 months and at 7 years 6 months, suggesting an incubation period of approximately 26.5 years). Despite the listed cause of death, Dr. Schonberger noted that the diagnosis was not yet confirmed by CDC or NRG experts, although it seemed probable, based on data received from the woman’s endocrinologist. Clinical evidence suggestive of CJD included onset of progressive dementia beginning in approximately October 2010, as well as cerebellar issues, and pyramidal and extrapyramidal signs. In addition, there was an MRI reportedly consistent with CJD, and possibly a positive cerebrospinal fluid tau test. That there was less than 2 years from first clinical observation of neurological symptoms until death is also consistent with CJD. The physicians were evidently convinced enough of the diagnosis not to request an autopsy. Dr. Schonberger is attempting to obtain the medical records, so the diagnosis can be independently confirmed. Dr. Fradkin noted that the commercial purification procedure employed size-exclusion chromatography similar in principle to that used post-1977 in the NHPP, but that available data do not allow for a comparison of quality between the different preparations. Permissions have been given to share the medical records, but at this stage CDC has not received them. Attending physicians are apparently interested in publishing details of the case.

Dr. Fradkin noted that the summary and comprehensive fact sheets list the question, "How many people treated with pituitary hGH in the United States got CJD?" In light of this case, the question may need to be rephrased to something like "How many people treated with NHPP-distributed hGH got CJD in the United States?" Dr. Mills suggested that if that change is made, it may be advisable to say we also know of at least one commercial U.S. case, but that we do not have information about how many people were treated with commercial hormone. Dr. Schonberger suggested waiting to make any such change unless and until confirmation of the diagnosis, and there was general agreement. Dr. Leschek pointed out that it may be advisable, however, to go ahead and revise the comprehensive information page, which includes the question, “What is my risk for getting CJD from pituitary hGH?” She suggested clarifying that this only pertains to risk for people who received hGH from the NHPP. Ms. Nurik noted that because these are web documents, it should be a fairly simple matter to update them quickly when new data are received.

3. Report on CJD in foreign GH recipients

Dr. Schonberger reported that three additional cases of CJD linked to hGH treatment have been reported in the United Kingdom. This brings the total number of CJD cases outside the United States that are attributable to hGH to 196. There was some question as to where to report the likely U.S. commercial case discussed above, if confirmed. There is not an obvious place to list it on either fact sheet.

Reported cases by country as of November 2011:
Country Reported Cases
France 119
United Kingdom 64 1, 2
New Zealand 6
Brazil 2
Holland 2
Australia 1
Austria 1
Qatar 1
Non-U.S. Total 196

1 does not include four known cases of iatrogenic CJD from Australian pituitary gonadotropin (one in the UK, three in Australia).

2 includes one individual still surviving as of November 2, 2011.

4. Update on Fact Sheet and Public Inquiries

Ms. Nurik reviewed changes to the comprehensive and summary information pages, including:

  • Upon confirmation of the 29th case, the plan will be to:
    • change the number of U.S. NHPP cases to 29;
    • change to 37 the total number of people who may have gotten CJD after treatment with pituitary hGH made in the United States;
    • change the average length of treatment for those who developed CJD, lowering that number from 8.5 to 8.4 years
    • change the longest known incubation time from treatment to onset of symptoms.
  • International numbers will be changed to reflect Dr. Schonberger’s report
  • The recent publication from Abrams, et al. will be added to the resource list
  • As suggested by Dr. Wysowski, Ms. Nurik will also add papers on human growth hormone by Bell, et al. and by Wilton, et al.

Dr. Fradkin noted that the estimates of risk (for the whole cohort, as well as for those treated before 1970) should be updated in light of the cases that have arisen since the old numbers were calculated. There was general agreement to round to the nearest 5. (Thus, “Overall, one out of about 265 people [29 out of 7,700 people] who were treated with NHPP hGH got CJD. However, one in about 95 people who began treatment before 1977 got CJD.”) Ms. Nurik noted that whenever an update is made to an issue addressed in both the summary and the comprehensive documents, changes will be made to both to keep them in alignment.

Ms. Harris reported that there had been 15 public inquiries pertaining to the NHPP from January 1 through October 2011. (For reference, there were 12 in 2009 and 22 in 2010, but note that the 2011 calls were only through October.) Nine of this year’s calls were from people who turned out to be in the cohort. Seven of those nine were submitting address changes and/or requesting updates; one was to notify us of a patient death (unrelated to CJD); another called to report health problems, and was referred to Dr. Leschek.

5. Proposal To Study Incidence of Other Neurodegenerative Diseases in the Cohort

In September, Dr. Schonberger was contacted by Drs. John Trojanowski and David Irwin of the University of Pennsylvania, expressing interest in assessing potential iatrogenic transmissibility of neurodegenerative proteinopathy disorders other than CJD. Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and Amyotrophic lateral sclerosis (ALS)—like CJD—are all characterized by deposition of amyloid protein deposits in brain. Each has its own characteristic amyloid, and none involve the prion protein, PrP. Tissue culture and animal model experiments have contributed to a proof of principle that if circumstances are sufficiently permissive, these amyloids or their oligomeric precursors can act in an infectious fashion. However, to date there is no known evidence of clinical transmission in humans. Drs. Trojanowski and Irwin therefore propose that we investigate whether any of these diseases have occurred at higher than expected frequencies among members of the cohort. At the same time, Drs. Trojanowski and Irwin plan to analyze pituitary tissue from AD, PD, FTLD, and ALS patients with the intention of eventually preparing a manuscript for publication that combines laboratory and cohort data.

Dr. Schonberger proposed reviewing mortality data to date as an initial step. Dr. Mills pointed out that such an analysis would potentially miss some cases of these diseases, if and when they did not materially contribute to death, in the opinion of the coroner. For example, while ALS is eventually fatal, PD typically is not. Further, he was concerned that these conditions may not be consistently reported on death certificates. Indeed, Dr. Schonberger noted that AD is known often to be left off death certificates, and it would therefore be necessary to include a control group such as the post-1977 cohort.

Dr. Mills was concerned that we not jump to the conclusion that just because the post-1977 procedure was known to reduce or eliminate CJD infectivity, it can also be assumed to have eliminated any other hypothetically infectious particle. He noted that there are other potential problems with selecting a different control group; however, because cohort members are likely to utilize the medical system at a higher rate than the population as a whole, that could lead to ascertainment bias. In addition, cohort members are more likely to have underlying neurological issues that could make accurate diagnosis of these diseases challenging. He further noted that depending on the incidence of these diseases in the general population, it may be possible only to detect a difference in risk in the cohort if it exceeds—for example—20-fold: it would be difficult to rule out smaller effects. Dr Wysowski supported the general principle of exploring whether unexpected frequencies of health effects are observed in the cohort. Dr. Mills was concerned about dilution of statistical effect (because of the multiple hypothesis problem) if we cast too broad a net. He noted that focusing on the relatively rare and more frequently fatal conditions—ALS and FTLD—would be most likely to detect a meaningful signal, if one exists.

Dr. Schonberger stressed that Dr. Trojanowski doubted these diseases could be transmitted, and that therefore an examination of the cohort could serve a valuable purpose by refuting the hypothesis that non-CJD proteinopathies may be transmissible. Dr. Roberts noted that even limiting the investigation to the four neurodegenerative illnesses of particular interest to Drs. Trojanowski and Irwin, such a refutation will not be possible. If no statistically meaningful cluster of any of these diseases is present in our cohort, that would suggest that either: 1) the diseases cannot be transmitted; 2) the source pituitary tissue had no AD/PD/FTLD/ALS-transmitting material; 3) the processing of the tissue had eliminated infectivity; 4) the incubation period had not yet been long enough; or 5) the administration route had been inappropriate to achieve infectivity. Thus, an examination of our cohort cannot rule out the possibility of iatrogenic transmission via another procedure, such as a dura mater graft, contaminated surgical instruments, or even administration of differently processed pituitary material. As a result, data from the cohort might support an infectivity hypothesis, but cannot refute it.

Dr. Schonberger mentioned that Dr. Fradkin had expressed the opinion over email that any resource expenditure incurred through minute inspection of medical records should be commensurate with the scientific value of the information to be obtained and should not detract from having sufficient resources to pursue our primary objective—determining the risk of CJD transmission. He noted that Dr. Trojanowski offered to staff such a review. Dr. Leschek explained that unfortunately such extramural staffing would not be permissible under IRB guidelines. However, she noted that a simple, low cost approach would be to ask Westat to organize a spreadsheet with causes of death and contributing factors, and to search that for instances of the four proteinopathies among the deceased members of the cohort. If one or more of the diseases do appear with what seems to be a higher than expected frequency, it could be pursued further. If not, Dr. Rodgers suggested the Committee let Drs. Trojanowski and Irwin know that due to limitations of the approach, there is nothing further we can provide at this time. There was a consensus to proceed in this fashion.

6. Brief Highlights of Progress in CJD Research

Dr. Schonberger selected the following four papers:

  • A review by Jones et al. (Acta Neuropathol., 2011. 121:135–143) on cell free prion conversion models and their usefulness in understanding human disease;
  • A soon-to-be published paper by Peden et al. (Ann Neurol., 2012. 72:278–285) testing a diagnostic method developed to detect BSE for capacity to detect cases of sporadic CJD;
  • The paper by Abrams et al., along with Committee members, (JCEM, 2011. 96:E1666-E1669) showing that infectivity was greatly reduced or eliminated by the NHPP purification process used beginning in 1977.
  • A paper by Hoffman, et al. (Vet Res., 2011. 42: 21-43), defining bovine tissues in the alimentary canal that are potentially infectious in cattle with pre-symptomatic BSE.

Although he was unable to attend the 2011 meeting, Dr. Major sent Dr. Roberts an email asking him to bring a paper by Sigurdson, et al. (J Neurosci., 2011. 31: 13840–13847) to the attention of the Committee. This paper characterizes a mouse PrP point mutation that results in spontaneous development of CJD in transgenic animals, and underlines the importance of the β2–α2 loop of PrP in mediating pathologic misfolding.

The meeting was adjourned at 3:08 p.m.

Griffin P. Rodgers, M.D.
Director, NIDDK