2010 Meeting minutes

Public Health Service

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

December 15, 2010

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
Joseph Abrams, CDC (by speakerphone)
Ms. Kathy Kranzfelder, NIDDK
Mr. Ryan Maddox, CDC (by speakerphone)
Ms. Jody Nurik, NIDDK
Dr. B. Tibor Roberts, NIDDK
Ms. Rita Zeidner, NIDDK

The meeting began at 9:00 a.m.

1. Welcome

Dr. Rodgers welcomed the group and the members introduced themselves.

2. Epidemiology Study Status Report

As described in last year’s minutes, Dr. Leschek 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:

In 2010, no cases were added to either category I or II (confirmed CJD). 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. No deaths have been added to categories I or II since the 2008 meeting of the Committee.

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:

The Committee discussed five cases under investigation, including one carried forward from last year, that of a man whose father called to report that his son had been treated with hGH and had died in September 2009 (incorrectly reported as 2005 in the 2009 minutes). The father reported neurologic symptoms consistent with CJD, including loss of balance, impaired gait, shaking, depression, and diminished hearing and vision. The son had schizophrenia, which predated the other neurologic symptoms, and had not been under a doctor’s care for several years. A member of the cohort, he had been treated for short stature and constitutional delay from 1976-1979, and had no known pituitary problems. No autopsy was performed. The father has not released the medical records, and the death certificate lists the cause of death as “unspecified natural disease process altered by decomposition.” Dr. Leschek spoke with the mother, who confirmed that her son had lived alone, had received no medical care for years prior to his death, and continued to work intermittently up until or shortly before his death. She also described symptoms that included judgment issues, mild confusion, and upper but not lower extremity tremors, which she said had been present for more than 2 years prior to death. She reported having seen her son about a month prior to death, and having spoken to him about a week before his death. The case has not been reviewed by the NRG because there are no medical records to review. The Committee agreed that the lack of clinical or pathologic evidence of CJD, together with the reported capacity of the individual to live independently up until the time of his death, indicate this death was unlikely to be related to CJD. This case is therefore no longer considered to be under investigation.

Discussed for the first time by the Committee was a cohort member who died in 2004 at age 49, with “complications from craniopharyngioma” listed as the cause of death. The individual died in 2004, but the records only became available in the last year. The initial craniopharyngioma occurred at 9 years of age; the tumor was removed surgically, resulting in panhypopituitarism. The patient was diagnosed with bipolar disorder at age 29. The craniopharyngioma recurred twice, at ages 30 and 38. Records do not indicate how the recurrences were treated, but do show that seizures began to occur after the second recurrence, and continued to occur during the next decade. About 3 months prior to his death he was evaluated for frequent falls that were preceded by light-headedness. The falls had been occurring for 2 months prior to the evaluation, by an otolaryngologist who diagnosed him with benign positional vertigo. The case was reviewed by the NRG in 2007, which did not see significant evidence for CJD, but noted there was were inadequate medical records for the five months prior to death. The Committee agreed that this case, also, should no longer be considered under investigation.

Another case discussed for the first time was that of a cohort member who died in 2010 at 39 years of age. Dr. Leschek reported that she had not yet seen the death certificate, but rather that the death had been reported to her by the individual’s mother. Diagnosed with malignant, inoperable, non-secreting pituitary tumor at 12 years of age, the patient received radiation therapy, developed panhypopituitarism, and was treated with growth hormone from 1983 to 1984. As a young adult he worked and lived independently, but developed debilitating osteoporosis and degenerative disc disease attributed to steroid therapy, leaving him on disability from about age 30 or 31. Because of the disability, he began to live with his mother. He was treated with narcotics for severe pain from age 35, had severe hypertension resulting in 3 strokes also at age 35. The strokes left the patient with mild, expressive aphasia. The mother indicated to Dr. Leschek that the individual also developed “periods of confusion and sleep modes” during which the patient would “sleep for days.” The mother indicated that the “sleep” could include apparent wakefulness consisting of a blank stare, as well as consumption of fluids and use the bathroom, but not consistent use of his medication. The episodes would last for 5 to 6 days, followed by periods of lucidity during which he would eat, drink, and ambulate without difficulty. One week before his death, he saw a neurologist and a pain specialist for sleep difficulties; a test showed central sleep apnea. Prescribed continuous positive airway pressure therapy (CPAP) was not tolerated, and one week later he died in his sleep. Although she had initially indicated she would be glad to release the medical records, the mother returned the forms and indicated that she did not wish to participate in further evaluation. Dr. Leschek has made a number of subsequent polite but unsuccessful attempts to contact the mother for clarification. However, the Committee agreed that CJD was highly unlikely in this case, and that further efforts to obtain the medical records were not warranted, and the case need no longer be considered under investigation.

The next case discussed is 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. Attempts to locate next of kin have been unsuccessful. Interviews conducted in the 1980s indicate that he received hGH from ages 14-16, necessitated by tumor and tumor-related radiotherapy. Dr. Leschek noted that she considers the listed cause of death to be a strong reason to pursue the medical records, but despite her best efforts it has been impossible to find anyone who can release them. Dr. Fradkin suggested that CDC may be able to obtain a record, if the death certificate is available. Dr. Leschek noted that Westat is required to destroy the death certificate after 1 year, but that they can request another copy, which she would attempt to obtain and send to Dr. Schonberger.

The final case was of a man who is not in the cohort, but who came to the Committee’s attention because his sister contacted Dr. Leschek to say he was treated with growth hormone between 1960 and 1962, and had developed some signs of possible CJD. The individual was still alive as of the date of the Committee meeting. Diagnosed with schizophrenia in his teens, he was stable on medication into his 50s, when neurocognitive deterioration began. In his 60s he was diagnosed with frontotemporal dementia. Treatment with donepezil seemed to inhibit further cognitive deterioration for a few years. Over the course of the summer of 2010, a rapid decline began, marked by loss of ability to communicate, ambulate, or feed himself. Neither a lumbar puncture nor a brain biopsy has been performed, but his sister believes death may be imminent, and she has indicated her willingness to allow an autopsy. The Committee noted that alternative explanations for the individual’s progressive decline may be at least as likely as CJD given the available information on his concurrent neurological conditions, but felt that a definitive post-mortem diagnosis is important: although a finding of CJD in this individual would not be attributable to NHPP hormone (which was not distributed until 1963, after his hGH treatments were complete), a confirmed case of CJD would significantly increase the longest known incubation period following hGH treatment, to at least 47 years. Dr. Leschek indicated that she would have Westat work to facilitate an autopsy, if necessary.

Case Summary by Category (resulting from adjudication during this meeting):
Category # cases Net change since 2009
I 13 0
II 15 0
III 4 0
IV 2 +1

Dr. Leschek noted that Westat continues to be very responsive, and to execute its responsibilities well, on time, and within budget as the contractor for the Committee.

To conclude the epidemiology status discussion, the Committee discussed the manuscript Dr. Abrams and others had developed regarding the apparently lower risk of CJD transmission to cohort members treated only after 1977, when production of NHPP growth hormone was transferred to the laboratory of Dr. Albert Parlow. The paper is currently under review at CDC, prior to journal submission. He and Dr. Schonberger requested that their co-authors on the Committee to please confirm to CDC their willingness to be included as co-authors, so that publication can move forward. At Dr. Fradkin’s request, some of the co-authors in attendance agreed to have a brief meeting after the formal Committee meeting to discuss some possible edits to the manuscript.

Drs. Abrams and Schonberger discussed the paper in some detail. The authors estimated the number of cases that would have been expected in the post-1977 portion of the cohort if they had the same risk for infection as those in the earlier group of recipients, controlling for duration of treatment and length of follow-up time. Despite the generally lower duration of treatment and the shorter follow-up time in the post-1977 group, if CJD risk were the same between the groups, they determined we would expect to have seen about six CJD cases in the later treatment group. Because there have been no cases in the group, the authors found that there was a statistically significant difference in risk between the pre- and post-1977 groups. Dr. Schonberger emphasized that the statistics were based on data from the 2006 National Death Index (NDI), and because the CDC usually receives notification of cases of CJD more promptly than the complete NDI data, and they have not been notified of such cases in among members of the post-1977 group, the data may in fact be more significant than is stated in the paper. Indeed, based on the average incubation period of cases from the pre-1977 group, he said we would today likely be experiencing a rising number of cases if the levels of risk in the two groups were the same.

Dr. Rodgers asked if anyone had ever analyzed risk based on age of growth hormone administration. Because the hGH dosage was based on the weight of the patient, older, larger children would be expected to have received larger quantities of infectious material. Dr. Fradkin suggested that there might be an interaction between age of treatment and duration of treatment with those starting at younger ages treated longer. She suggested an analysis that compares duration of treatment to age at treatment as a predictor of CJD risk in the pre-1977 group. Dr. Leschek noted a possible limitation of the analysis, owing to the fact that in the early years of the NHPP, supplies and dosages are said to have been inconsistent. For this reason, and because he thought there was likely a significant range of size per age, or even of physician recommended dosage in mg/kg, Dr. Mills thought it might be difficult to persuade a journal to publish such an analysis unless the trend were very compelling. However, he agreed with Dr. Fradkin that it might we worth having Westat examine the data.

In any case, Dr. Mills pointed out that Dr. Abrams’s findings show how a change in purification protocol can significantly change risks and outcomes for a group of patients. Dr. Fradkin noted that it will be important to update the Fact Sheet website to explain the new findings after the paper is published.

3. Report on CJD in foreign GH recipients

Dr. Schonberger reported that five additional cases of CJD linked to hGH treatment have been reported in the United Kingdom, and four more in France. This brings the total number of CJD cases outside the United States that are attributable to hGH to 193.

Reported cases by country as of December 2010:
Country Reported Cases
France 119
United Kingdom 611, 2
New Zealand 6
Brazil 2
Holland 2
Australia 11
Austria 1
Qatar 1
Non-U.S. Total 193

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 at time of meeting.

The data on the NHPP Fact Sheets should be updated to reflect these new figures. Dr. Schonberger also reported that he has received unconfirmed reports of a possible case in Ireland and a possible case in Sweden. He is following up on these reports. He notified the Committee that 222 vCJD cases are known to him as of the meeting date, including most recently an individual from Taiwan who had lived in the U.K. from 1989-1997. This is significant because food control measures intended to safeguard the food supply from infectious PrP, were instituted there in 1988.

4. Update on Public Inquiries

Ms. Zeidner reported that there had been 22 public inquiries pertaining to the NHPP in 2010. Inquiries about why they have not recently received a letter from the Committee remain a common reason for contacts from cohort members. When she handles such calls, she refers people to the Fact Sheet website as the best source for updated information. Dr. Leschek noted that this appeared to be a significant increase in traffic from 2009, when there were only 12 such calls.

5. Brief Highlights of Progress in CJD Research

Dr. Schonberger highlighted a paper on the risk of CJD transmission from hGH treatment in Australia (Boyd et al., 2010; MJA193: 366-369) which suggests that in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting. This conclusion was offered as a subject for debate in the Australian health care community, not as a formal public health directive. Another paper of interest (de Marco et al., 2010; J Pathol. 222:380-387) was an analysis of specimens from tonsillectomies in British citizens in the age group at highest risk of having acquired vCJD from infected beef. Because the one possible positive sample (out of 9160) came from a person who has one copy of the PrP gene that encodes methionine at position 122, and one that encodes valine at that position, a genotype apparently unrepresented among people who have developed vCJD in Britain to date, it is possible that the finding predicts a future bolus of cases in people with this genotype. A similar effect may be observed in our cohort. He next noted a paper on development and Darwinian selection of distinct prion conformers both in cell culture and in vivo (Li et al., 2010; Science 327: 869-872). They conclude that prions, although devoid of a nucleic acid genome, are nevertheless subject to “mutation” and selective amplification. Another paper (Angers et al., 2010; Science 328: 1154-1158) analyzed prions associated with chronic wasting disease, which is analogous to CJD in deer and elk, and is now found in many wild U.S. herds of these animals. This research group found that two such “conformational mutants” (also called prion “strains”) were common among infected deer and elk. Although there have been no recorded cases of CJD from consumption of infected venison, because the two strains had different biological properties and different capacities for transmission to susceptible rodents, and because additional strains may arise, Dr. Schonberger suggested that caution may be warranted before concluding such transmission cannot occur.

The meeting was adjourned at 10:35 a.m.

Griffin P. Rodgers, M.D.