|
Items in cart [0] |
Questions? Call 888-624-8373 |
PAPERBACK PDF BOOK Free Resources |
||||||||||||||||
|
||||||||||||||||
|
|
|||||||||||||||
| ||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 25
II
Guarding the Blood Supply
OCR for page 26
OCR for page 27
The Retrovirus Epidemiology Donor Study:
Rationale and Methods
Thomas F. Muck
I am going to briefly outline the rationale and methods of the Retrovirus
Epidemiology Donor Study (REDS). I am going to provide no data except to
look at the enormity of the database that has been accumulated.
A request for proposals (REP) was published in 1988 by the National
Heart, Lung and Blood Institute (NHLBI), because of the unknown infectious
risk of transfusion, concern about HIV variants, the need to understand human
T-lymphotropic virus (HTLV) infection, a need to create repositories to
examine emerging infectious agents, and a need to evaluate emerging
technologies to detect these agents. The study will run from 1989 to 1998,
and it is likely that it will be extended beyond then. The purpose is to monitor
the safety of the nation's blood supply through studies of the epidemiology of
known agents, essentially retroviruses, among volunteer blood donors.
What I am going to share with you today has recently been published in
Transfus~on.37 Blood centers were selected on the basis of the quality of their
proposals. There are four high-risk centers and one low-risk center, risk being
defined as areas having a high background prevalence of AIDS. The REDS
high-risk participants are the Red Cross Greater Chesapeake and Potomac, the
Red Cross Southern Michigan, the Red Cross Southern California, and Irwin
Memorial Blood Center. Oklahoma was considered to be low risk. The
coordinating data center was Westat, Inc.
The scope of the study is $40
million over the course of 5 years, and it is considered the most complicated
study that NHLBI has ever launched.
The structure is governed by a steering committee that has two
investigators from each of the participating centers and the committee is
chaired by an independent center director, who happens to be me.
Subcommittees of this steering committee developed the proposals and
protocols that we have been following over the course of the study. We have
a continuing and an ongoing close relationship with the Centers for Disease
Control and Prevention (CDC).
37Zuck, TF, RA Thompson, GB Schreiber, RO Gilcher, et al. (1995). The retrovirus
epidemiology donor study (REDS): Rationale and methods. Transfusion, 35: 944-951.
27
OCR for page 28
28
attitudinal issues.
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
There are five major REDS components:
monitoring donors,
creating a general repository,
creating special repositories,
studying a cohort of people infected with HTLV, and
surveying donors concerning the prevalence of certain behavioral and
Three substudies are pursuing these five objectives:
establishing and maintaining a serum and cell repository,
following the cohort of HTLV-infected donors and patients, and
conducting the mail surveys directly.
There are three REDS repositories:
the General Serum Repository,
the General Leukocyte and Plasma Repository (GLPR), and
a Special Repository.
Serum taken from donors routinely is selected at random based on a
complicated sampling methodology devised by the statisticians at Westat.
Samples in the special repositories are: donations that are repeatedly reactive
for HTLV, but for which confirmatory testing is unclear; donations from sex
partners of HTLV-positive subjects and their controls; donations that were
repeatably reactive for HIV- 1 but which produced indeterminate Western blots;
donations that were repeatedly reactive for HIV-2 but HIV-1 negative; and
donations that were repeatably reactive for HIV but of unclear etiology.
The HTLV cohort study uses a case-control methodology to investigate
HTLV risk and transmission factors and to define the natural history of HTLV
infection. Other than some studies in Kyushu, Japan, we know little about the
natural history of HTLV infection. One of its outcomes, T-cell leukemia, is
so infrequent that it is difficult to estimate how often it occurs once an
infection has been identified.
There were also few data on symptoms related to HTLV-associated
myelopathy and tropical spastic paraparesis short of those two diseases
themselves. They are actually identical conditions but defined in different
parts of the world by different names. We were essentially searching for
unexpected clinical outcomes, because in 1988, when this study was designed,
the literature was unclear on the clinical outcomes of this infection.
OCR for page 29
GUARDING THE BLOOD SUPPLY
29
The donor mail surveys were done in waves. The survey subjects were
selected by sophisticated statistical techniques that randomized the selection
of survey recipients. The resulting sample was enriched with donors from
certain types of populations that we knew had high infection rates. The idea
was to ascertain risk behaviors of the donors. The survey was stratified by
several variables: center, race, age, sex, zip code, birth year, etc., trying to
focus again on those people among the donor population who were more likely
to engage in high-risk behaviors. This is randomized in a biased way in terms
of enriching it for younger people. We mailed out about 64,000
questionnaires; the response rate was about 70 percent.
The most important outcome is the extensive databases that are available
for use today. We have demographic information Mom the donors of 4.9
million donations. The General Serum Repository contains 500,000 samples
stored in multiple vials which are now the property of NHLBI.
The GLPR has both leukocytes and plasma so that we can look at any
kind of virus that may be only intracellular, such as HTLV, in which the
genome is not free in the plasma. We have 546 HTLV-infected donors and
patients who have been enrolled and who are being followed longitudinally for
the presence or emergence of symptoms. The information in this database is
immense and enormously valuable. To date, the surveys have found that more
risky behavior is being encountered than predicted: up to 1 percent of people
report prior drug use, sexual activity with a previous drug abuser, etc.
The extensive data also permit incidence calculations. One of the
difficulties we have had over the years is dealing with prevalence. We know
what our current rate of infection in the donor base is, but in the past we could
not look at incident infections, that is, in how many people per year does it
occur? Those calculations are now being made. They contribute to the
decision making regarding HIV antigen testing in a negative way. They show
that antigen testing is probably not of great public health value.
We have established an orderly process to access the database. An
application is sent to the REDS Publication Committee, which looks at the
request to see whether we want to provide a series of samples or process a
request for data or data analysis. The committee then decides whether to
recommend to NHLBI that the database or the samples be accessed for the
requested purpose. NHLBI can veto the use of data or samples. This is
particularly important for samples because once you have thawed them and
then refrozen them, the test results gained from those thawed and refrozen
samples have less credibility with certain kinds of testing technology. Thus
NHLBI must carefully guard the repositories.
The contributions of REDS to date have been important, and I have
outlined just a few here that are by no means all inclusive. We were also
involved with a team dealing with the idiopathic CD4 lymphocytopenia (JCL)
crisis. Within days of the report of JCL, REDS formed a task force with CDC.
OCR for page 30
30
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
CDC had a meeting that included two Nobel laureates within 3 or 4 weeks of
the announcement in Amsterdam. We used the laboratory facilities of REDS
to work with the technology for CD4 counting. There were some
recommendations from the panel convened at CDC that perhaps we ought to
screen for CD4 counts. We quickly mobilized several REDS labs. We found
that the technology was not available to do it practically with reliable results.
It turned out that the data from people with JCL, so-called people with "AIDS
without virus," were merely outliers in the normal variation of T-cells counted
in blood donors, although it took us awhile to discover that. REDS was at the
center of that, with incredible cooperation from the CDC.
REDS also developed consensus conference data that were presented both
at an NIH Consensus Development Conference and at the Blood Products
Advisory Committee. These involved incidence data and window period
estimates for viral diseases and how much we would close the window by
antigen testing and whether there would be a magnet effect. REDS will
continue to make general contributions to the risk literature. We are still
probably the largest database of donors that can be accessed quickly with a
great deal of accuracy.
The Institute of Medicine report on HI V and the Blood Supply
recommended continuing monitoring for risks in the blood supply. REDS is
a very comprehensive database, and, importantly, can yield incidence data, and
the use of incidence data is really the most reliable way to make decisions on
what is happening. We can continue to track elements specified in the REP
which are the data elements that I have outlined. Most importantly, as with
ICE and the lessons with JCL, we were able to respond within days because
we had the five centers in place. We had Westat crunching the numbers. We
were able to respond in a way that no one else can because of the magnitude
of the database that we have to deal with.
One of the things that we might want to consider is not maintaining the
current level of funding, but using a reduced level of funding to keep the
REDS mechanism in place for the future so that we can respond and answer
queries when we need to. It took us 18 months to set up this system. It was
extremely difficult and it is extremely complicated, but it is in place now. It
is on autopilot. It would be a pity if we lost the opportunity to have
continuous surveillance and answer queries about unknown agents, new testing
technologies, and the like.
OCR for page 31
Demographic and Serologic Characteristics of
Volunteer Blood Donors38
lames A. Koreli~z
I would like to provide a brief overview of the demographic profile of
blood donors in the Retrovirus Epidemiology Donor Study (REDS) as well as
the prevalence of infectious markers that has been observed. I would then like
to share with you the attempts to estimate the incidence of infectious disease
markers, how incidence differs Tom prevalence, and how the incidence rate
can be used in conjunction with estimates of periods of true positivity but
seronegativity (window periods) to assess the risk of an infectious unit entering
the blood supply.
In addition to standard questions, such as those regarding gender and age,
REDS collects information on additional donor demographics such as race,
ethnicity, education, country of birth, and transfusion history. The standard
battery of serologic tests is perfonned on all donations including tests for
retroviruses and hepatitis viruses. A key feature of REDS worth emphasizing
is that a unique donor identifier is created so that donations Tom the same
donor can be linked for farther analyses such as the incidence analysis, as well
as with other components of REDS.
What are the demographic characteristics of blood donors? Based on
approximately 2,000,000 donations (excluding autologous) collected during
1991 and 1992, we found that
· slightly more donations are from males than Tom females,
· more than 70 percent of donations are Dom the 20~9 age group, with
about 10 percent from those under 20 and about 20 percent fiom those 50 and
older,
over 80 percent of donations come Dom white, non-hispanic donors,
.
and
38Talk presented at Forum on Blood Safety and Blood Availability, July 12-13, 1994. An
updated analysis is given in Schreiber, GB, MP Busch, SH Kleinman, JJ Korelitz (1996). The risk
of transfusion-transmitted viral infections. New England Journal of Medicine, 334: 1685-1690.
31
OCR for page 32
32
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
.
donors are generally well-educated, 70 percent having some college
experience and almost 90 percent being high school graduates.
An important factor that will come up when we talk about incidence is the
fact that 79 percent of our donations are from repeat donors and 21 percent are
from first-time donors. It has been generally recognized that f~rst-time donors
have a higher prevalence of infectious disease markers compared with repeat
donors.
With that demographic profile in mind, what kind of prevalence values
are we observing? During 1991 and 1992, the prevalence of human
immunodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) were
each about 1 per 10,000 donations. For hepatitis C virus (HCV), based on 19
months of data corresponding to when the supplemental HCV test was
implemented at the blood centers, the prevalence was about 22 per 10,000.
Prevalence gives us an idea of how many people are currently infected, or
positive, for an infectious disease marker. It has obvious importance,
especially from a broad public health perspective, for estimating the current
magnitude of a health problem.
However, prevalence does not provide us with any indication of when the
infection occurred, and the timing of an infection is critical in the blood donor
setting. After all, people who were infected long ago will show up as
prevalent cases, but their donations will test positive and be excluded from the
blood supply. A more important question relates to the rate at which negative
donors are becoming positive, or seroconverting. People who have
seroconverted will test positive, and their donations will be excluded, but
people who are seroconverting may be in the window period where their
donations are infectious but not detected by current tests.
The definition of an incident case is fairly straightforward: it is when a
donor who previously gave a negative donation shows up and gives a positive
one. Remember that with REDS we have a linking donor identification
number, so these donors can be identified. The incidence rate is then
calculated as the number of incident cases divided by the total person-time
observed.
Let me give a brief example to explain person-time. Suppose person A
gives two seronegative donations 18 months apart, and person B gives two
seronegative donations 6 month apart. Neither one is an incident case, so we
could say the incidence rate is O out of 2 donors. This method treats each
donor equally. However, we would like to incorporate the fact that donor A
was observed to remain seronegative for a longer time period than donor B.
Likewise, suppose we observe two incident cases, or seroconverters, who
initially give seronegative donations but subsequently give seropositive
donations. The time between donor C's seronegative donation and seropositve
OCR for page 33
GUARDING THE BLOOD SUPPLY
33
donation may have been 20 months, whereas the time between donations for
donor D is 7 months. A way to express the incidence rate when subjects are
observed for varying amounts of time is to say there were 2 cases per 51
observed person-months (18 + 6 + 20 + 7), or 0.039 cases per person-month.
Thus, for each REDS donor, we determined whether or not they were an
incident case, and the person-time between their first and last donations.
Table 3 details each marker, the number of donors, the number of
observed person-years, the number of incident cases, and the resulting
incidence rate, expressed as number of cases per 100,000 person-years. The
HCV rate is based on data obtained after the second generation screening test
was implemented, so the sample size at this point is much smaller than for
other markers. The hepatitis B virus (HBV) incidence rate is based solely on
the HBV surface antigen (HBsAg) test. It does not include donors who went
from negative to positive on the antibody to hepatitis B core antigen test.
TABLE 3 Preliminary Results of Incidence Analysis39
Number of
Number of Person- Incident Incidence
Marker Donors Years Cases Ratea
Anti-HIV 426,149 421,777 11 2.61
Anti-HTLV-I 426,134 421,767 3 0.71
Anti-HCV 151,708 62,444 4 6.41
HBsAg 426,101 421,734 28 6.64
Per 100,000 person-years.
Although the rate for HTLV is based on only 3 incident cases,
it is
interesting that although the prevalence of HTLV was a little higher than the
prevalence of HIV, the incidence of HIV is considerably higher than the
incidence of HTLV. The next question is exactly how do you use, or what is
the relevance of, an incidence rate? Using HIV as an example, exactly what
does 2.61 cases per 100,000 person-years mean?
The incidence rate, when it is a small number such as 2 or 3 per 100,000
person-years, is essentially equivalent to a probability, or risk. So we can say
that if the rate is 2.61 per 100,000 person-years, the risk of a person
seroconverting within a 1-year period is 1 in 38,000. Normally, we think of
39See Schreiber et al. (op cat) for an updated analysis.
OCR for page 34
34
BLOOD AND BLOOD PRODUCTS: SAFER AND RISK
using incidence rates or probabilities to predict the future. That is, we might
say that 1 in 38,000 donors will become infected within the next year. But
you could also use this figure to say that 1 in 38,000 donors were infected
within the past year.
The reason I make this distinction is that in the blood donor setting, the
key question really is not "What is the probability that a donor will become
infected after donating blood?" The critical question is, "What is the
probability that a donor was infected before donating blood?" As I said
before, if the donor was infected long enough ago, the serologic test will be
positive and the donation will not enter the blood supply. For example, if
everyone who was infected more than 6 months ago tests positive, then the
question is, "What is the probability that a donor who shows up today to
donate blood was infected within the past 6 months?" This is because only
this infected donor will test negative and this donation might be used for
transfusion.
If we calculated a risk of being infected within the past year to be 1 in
38,000, then the risk of being infected within half of that time, or 6 months,
should be half of the risk, or 1 in 76,000. Likewise, we can estimate the risk
of being infected within any time frame to be proportional to the risk
calculated on a "per year" basis. If we believe that the window period is 45
days, that is, only people who were infected within the past 45 days will have
a negative serologic test today, then the risk of one of today's donors being
such a person is 1 in 311,000.
On the other hand, remember that we calculated our incidence rate from
donors who gave at least 2 donations during our study period. What about
first-time donors? It is generally assumed that first-time donors will have
higher rates than repeat donors. To see what impact this can have, we can just
assume a certain rate for first-time donors relative to that for repeat donors and
weight that rate by the percentage of first-time donors in our study.
For example, let us use the observed incidence rate of 2.61 per 100,000
person-years and say the window period is 45 days. If the rate in first-time
donors is the same as that in repeat donors, then the risk is 1 in 31 1,000. But
suppose the rate in f~rst-time donors is 50 percent greater than the incidence
rate in repeat donors. This means that the rate in first-time donors is about 3.9
per 100,000 person-years. We observed, and other blood donor studies have
also reported, that about 21 percent of donations come from first-time donors.
So, if we count the 3.9 rate for 21 percent and the 2.6 rate for 79 percent, then
the weighted average, when combined with a 45 day window period, adjusts
the risk up to 1 in 281,000. Of course, the 50 percent increase was arbitrary.
It could be 80 percent, 100 percent or some other value. One previous study
estimated that first-time donors would have 1.8 times the incidence rate of
OCR for page 35
GUARDING THE BLOOD SUPPLY
35
repeat donors.40 Table 4 delineates the impact of varying ratios of incidence
rates for first-time versus repeat donors. The point here is that while the risk
goes up, it is not overly sensitive to the unknown rate among first-time donors.
TABLE 4 Adjusted Risk of HIV Transmission for First-Time Donors a
If the ratio of incidence rates
for first-time vs. repeat donors
Is:
Then the risk of
window-period
donation is:
1.0
1.5
1.8
2.0
1:3 1 1,000
1:28 1,000
1 :266,000
1 :257,000
a Assumptions are that donors have (1) an incidence rate of 2.61 per 100,000 person-
years and (2) a window-period of 45 days, and that (3) 79 percent of donations from
repeat donors.
It is interesting to view this risk estimate in light of previous studies.
Table 5 presents a partial list of risk estimates in the literature. This is a
mixed bag of studies that used different study designs and methodologies to
estimate risk. It does show a range of estimates, and depending on what range
of variation you are used to working with, you might conclude that they are
all in the same ballpark, or you might feel that the estimates are widely
disparate. One important factor in looking at risk estimates for HIV is the
time frame. As you know, we have had a very dynamic situation with HIV
in teens of donor screening and testing.
The studies are listed according to the year that the study ended. The risk
estimate from each study is multiplied by 18,000,000, which is the number of
donations or units that are collected each year in the United States, to get the
number of window-period donations that would be expected to enter the blood
supply each year. There appears to be a trend of decreasing risk with time;
that is, more recent risk estimates appear to be lower than older risk estimates.
This downward trend over time is what you would expect if you were
decreasing the incidence rate (by effective donor screening) and/or decreasing
the window period (by improved HIV tests).
40Cumming, PD, EL Wallace, JB Schorr, RY Dodd (1989). Exposure of patients to human
immunodeficiency virus Trough the transfusion of blood components that test antibody-negative.
New England Journal of Medicine, 321(14): 941-946. Comment in New England Journal of
Medicine, 322(12): 850-851.
OCR for page 56
56
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
source of infection. Also, the system will be used to monitor the regional
trends and variations in blood-borne infections.
Finally, I would like to talk very briefly about the potential risk of
Creutzfeldt-Jakob disease (CJD) being transmitted in blood products.
Currently there is no evidence that it is transmitted in blood products.
However, the risk cannot be assessed with any degree of accuracy. It is felt
by everyone to be extremely low, if at all, and remains a theoretical risk at
best. The troublesome thing is that it can be transferred to experimental
animals by a transmittable agent, and the agent is present within the blood of
the patients with CJD. That makes it a theoretical risk. The epidemiologic
question is how do you do surveillance on a disease that has an incubation
period of 20 to 30 years? It is not impossible, but it doesn't lead to any kind
of ideal solution where you ascertain the risk very quickly. The hemophilia
community is quite concerned about CJD, and they are anxious to have
answers as soon as possible. The only way we can reasonably approach this
problem is with a special study.
Currently, 400 deaths occur annually in the hemophilia community in the
United States. About 300 of these are caused by AIDS; the other 100 are
caused by non-AIDS-related events. Of the 300 who die from AIDS, about 30
to 50 have central nervous system (CNS) AIDS. The hemophilia population
has been routinely receiving concentrates for 20 and 25 years now. We would
thus expect that if CJD was caused by a transmittable agent in blood products,
you might be seeing cases now in individuals with hemophilia. The only
condition that could be misdiagnosed would be individuals who have been
diagnosed as having CNS AIDS. I have received several letters from
individual physicians who treated hemophilia patients who had died with CNS
AIDS before the publicity on CJD. There were no autopsies and no post-
mortem examinations of these patients. Now these physicians are wondering
if these might have been possible cases of CJD.
It is this kind of rumor that spreads quite quickly in the hemophilia
population because it is a very small, closed community. Both the physicians
and the hemophilia patients now agree that the only solution to this is to try
to obtain as many postmortem examinations as possible in individuals who die
with CNS AIDS over the next several years. We have established a
collaborative project between ourselves and Dr. De Arman at the University
of California, San Francisco, the various hemophilia treatment centers, FDA,
and NIH, as well as the various peer groups from the hemophilia population.
We hope to obtain 10 to 15 brains per year for this study.
The basic design of this study is to obtain permission at the time of death
to remove the brain for a CNS autopsy. One-centimeter cubed biopsy
specimens will be removed from the frontal, midparietal, and cerebellar regions
and frozen. The remainder of brain will be placed in formalin for 2 weeks.
OCR for page 57
G UP RDING THE BL OOD SUPPL Y
57
These specimens will then will receive a routine pathologic workup for
dementia and an examination for the prion protein. Suspect cases will be
reviewed by a panel of neuropathologists selected by ourselves, NIH, and
FDA. A single case of CJD under the age of 40 would be very significant.
A CJD case in an individual over the age of 40 could mean that we must
continue this study, since a case of CJD in an older person won't carry the
same weight as one in someone who is young.
In summary, the collection systems, with the exception of CJD, which is
a special study, are part of a national program designed to assist in lowering
the complications of hemophilia. These data collection tools, however, can
also be utilized very effectively to monitor blood-borne infections in this
community and for observing whether there is any new incidence of unusual
diseases. It may be that the only way that we will be able to obtain the
information needed to monitor blood safety for relatively rare events or
unknown events in a cost-effective manner.
DISCUSSION
Paul Russell: What evidence do you have that it takes 20 or 30 years for
Creutzieldt-Jakob disease to be manifested?
Bruce Evatt: It comes from several types of data. Some of it is Tom studies
of cannibals in terms of kuru and other types of slow virus diseases.
Certainly, the delay in onset was much shorter than 20 to 30 years in the cases
of growth hormone-induced transmission. Thus, the delay is probably related
to the dose of the agent, although it is probably related to other issues as well.
David Rothman: When you made hemophilia a reportable disease, did you
already know all about stigma? Do you have any built-in patient
confidentially in any of these surveillance efforts?
Bruce Evatt: Yes, we worried about a reaction from the hemophilia
community. You have to understand that one of the issues that you deal with,
confidentiality, is of utmost importance in this community, especially as it
concerns HIV and AIDS. One of the problems we had during the 1980s was
the fact that the hemophilia population didn't want to be identified. There was
no registry of hemophilia patients. Even if you wanted to, you could not have
notified them of risks associated with a new disease because they didn't want
their names obtained by anybody. The lack of a registry in the hemophilia
community has been a major issue. Obtaining a complete accounting of all
individuals with hemophilia in the six states has been accomplished very
successfully. We managed this in two ways.
OCR for page 58
58
BLOOD AND BLOOD PRODUCTS: SAFER AND RISK
First, the state health departments are the only entities that have the
names. They have the right to do that in all of these states. They all have
normal procedures to keep names confidential. In many states people in state
health departments can go to jail for breaking confidentiality. Thus, they have
a track record of maintaining confidentiality over a long period of time; that
reassures people. Furthermore, there was an encryption of the identifiers. We
do not know who, where, or what they are. It is to maintain a unique
identifier for the database so that they can be followed subsequently by the
state health department.
The second way this was managed was that personnel Tom the state
health departments met with the hemophilia chapters to explain the study.
They told the chapters how the study is to the benefit of their community
because it helps maintain resources and safety for them. Without this database
in the system, they are at increased risk for unknown events. The personnel
from the health departments regularly attended hemophilia board meetings, so
that if there were complaints, somebody was there Mom the state level who
could answer the questions and solved problems very quickly. One or two
states ran into a few problems, but that was because of some unwise choices
and not because they did not inform the community early and often. Those
problems were also rectified, but it was not as smooth as in the states where
they worked with the community in a more direct way.
The hemophilia registries are unusual in that hemophilia is a chronic
condition, whereas most diseases reported to state health departments are
infectious diseases. However, in the states where this surveillance was
implemented, the health departments are addressing the issues of chronic
diseases. They are more sympathetic to these approaches than health
departments in some of the states where acute diseases are the only things that
are reportable.
David Rothman: It is still a moderately scary precedent to have state
legislatures pass these laws.
James Allen: It is obviously a very complex problem. It is not only a chronic
condition, it is also a genetic condition, and that has many other implications.
OCR for page 59
CDC Surveillance for Unknown Pathogens
Scott Wetterh all
Surveillance has to be linked to public health action. The purpose of
surveillance is to assess status, define priorities, evaluate programs, and
stimulate research. The thesis that I am going to make, quite frankly, is that
surveillance systems per se probably will not detect unknown pathogens or
unknown etiologic agents. However, having ongoing surveillance systems
provides a contact, an infrastructure, and a series of relationships such that
detection can occur and a response can be mounted.
Some fundamentals are needed to do surveillance, such as an organized
health care system, a system for classifying disease and injury, and
measurement techniques. Surveillance has many different activities. For the
purposes of this group, I would focus on triggering investigations or detecting
epidemics as the best uses for public health surveillance.
You have heard about a number of different surveillance systems in the
United States. Of these, the notifiable disease reporting system is the one that
probably would serve as the basis for recognition of some sort of unknown
pathogen or etiologic agent. This system exists in each of the 50 states and
serves as a significant link between the Centers for Disease Control and
Prevention (CDC) and the state health departments. There are other systems,
and others are being developed-among them laboratory-based surveillance for
antibiotic resistance patterns and hospital-based surveillance.
What is a notifiable disease? Some people don't realize this, but CDC
cannot designate which diseases are notifiable. This authority is within the
purview of either the state health board or the legislature of any given state.
When AIDS became a notifiable disease in the 1980s, it was because laws or
regulations were passed in each of those states. CDC works with the Council
of State and Territorial Epidemiologists to determine what the notifiable
diseases are. We currently have 51 diseases on our list. Diseases are added
and deleted from this list. For instance, Escherichia cold 0157 has been
added, as has antibiotic-resistant Streptococcus pneumonias. Cases of these
diseases are reported to CDC on a weekly basis.
59
OCR for page 60
60
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
You have heard a little bit about passive versus active surveillance. A
passive system is one where physicians are required by regulation or law to
report these diseases to local or state health departments. An active system,
on the other hand, is one where reporting is initiated by a state health
decal l~nent.
The data are transmitted to CDC from state health departments
electronically on a weekly basis and are published in the Morbidity and
Mortality Weekly Report. For example, Figure 1 shows data tracking the
decline in the number of cases or rate of malaria following World War II and
subsequent rises primarily from returning veterans or foreign immigration.
These data are available, and they are used to follow long-term trends.
1000
-
ct too
U)
c'
~ to
ce
-
Ct 0.1
a:
l ~
Relaoses -- Overseas cases
\ ~ Relapses from Korean veterans
~ Retuming Vietnam veterans
/~\ JIBE
/ \/
~ foreign immigradon
..... - .
0.01
1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 tam 1~ 1~5
FIGURE 1 Reported cases of malaria per 100,000 population in the United States,
19301992.
How good are the data? Notifiable diseases carry with them regulations,
fines, and various admonitions if a physician does not report a case of a
particular notifiable disease. Yet we clearly know that there is a lot of
underreporting. Table 7 presents data from Vermont comparing the number
of patients hospitalized with notifiable diseases with the percentage of cases
that are actually reported. Underreporting clearly is a problem, even though
reporting is mandated by law.
OCR for page 61
GUARDING THE BLOOD SUPPLY
TABLE 7 Evaluation of Notifiable Disease Reporting, Vennont,
1982-198352
61
Disease Hospital Cases Percent Reported
Hepatitis 64 31
Aseptic meningitis 127 6
Bacterial meningitis 65 62
Gonorrhea 30 95
Pertussis 15 40
Salmonellosis 63 67
We have similar data from Washington, DC. They are about 10 years
older, but the trends have basically been the same. There is tremendous
underreporting of disease, except when new diseases occur, such as AIDS.
The case reporting for AIDS has actually been fairly good for two reasons: it
is a relatively new disease and it is an exotic disease. Also, a lot of money
was put into surveillance for it.
There are several reasons for underreporting, and these are basically
relevant to any surveillance system, particularly passive ones. There is often
a lack of knowledge of reporting requirements, and there are negative attitudes
toward reporting. There are misconceptions and even suspicion of the
government and what it may be doing with this particular data.
What are the ways to improve the surveillance system? Make it simple.
Systems are often far too complex for what they are intended to do. Provide
frequent feedback, widen the net, get increasing sources of information, and
conceivably, do active surveillance. There has been talk about active
surveillance. The advantages are that you can identify all the cases, you get
better-quality data, and some of the data may be useful in special
circumstances. The disadvantages are that it is incredibly time-consuming and
costly, and the additional data may not be worth the cost, except in special
circumstances.
When new diseases emerge, we must have sufficiently simple, flexible,
and acceptable systems already in place such that surveillance for these new
pathogens or new disease entities can be incorporated into these systems quite
readily.
Using as an example the current attention being directed toward emerging
infections, CDC is undertaking efforts to improve its surveillance activities in
52 Vogue, RL, SW Clark, S Kappel (1986). Evaluation ofthe state surveillance system using
hospital discharge diagnosis, 1982-1983. American Journal of Epidemiology, 123: 197-198.
OCR for page 62
62
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
this arena. A number of major factors are contributing to the emergence of
infectious diseases: human demographics and behavior, technology and
industry, economic development and land use, international travel and
commerce, microbial adaptation and change, and breakdown of public health
measures. Increased population density and population encroachment, along
with increases in international travel, are the same factors that would likely
result in the introduction of some particular pathogen into the blood supply.
The top seven emerging infectious diseases in 1993 were cryptosporidiosis,
coccidioidomycosis, E. coliO157:H7 disease, multidrug-resistant pneumococcal
disease, vancomycin-resistant enterococcal infections, influenza A/Beijing/
32/92 virus infections, and hantavirus infections.
I don't think these are necessarily ones that could be found in the blood
supply, but the potential is always there for some emerging pathogen to find
its way into the blood supply. These are new diseases or emerging diseases
for which we need to fonn responses. Figure 2 provides data on the incidence
of one of these, hantavirus. Hantavirus is a good example of the detection of
a disease that wasn't previously notifiable. Emerging diseases are reported
because people at the front line of public health (the public health nurses,
physicians, primary care doctors, and medical examiners) notice an unusual
syndrome and call up health officials. That is how you detect unusual or new
diseases.
14
12
10
8
4
2
~J
S N |J ~ J S N
1992 1 1993
J ~J
1 994
FIGURE 2 Reported cases of hantavirus pulmonary syndrome in the United States,
January 1-August 31, 1994 (1 1 cases prior to 1992 not shown).
OCR for page 63
GUARDING THE BLOOD SUPPLY
63
There have been several notable instances of outbreak detection going
back to the 1970s. Legionnaires' disease was first detected when a Veterans
Administration pathologist came in to the morgue over the weekend and found
three or four elderly men who had died from pneumonia. He called up a
friend at CDC to report that something was going on. You know the story of
AIDS in terms of a physician noting a cluster of illnesses in a certain group
as well as the increased medication use that was alluded to earlier. Hantavirus
was reported by a medical examiner who called up a medical examiner at
CDC. E. cold 0157, which caused the famous multistate hamburger outbreak,
was detected because a pediatric gastroenterol-ogist noticed hemolytic-uremic
syndrome in a young child. The salmonella-contaminated ice cream outbreak
that began in Minnesota was detected by the use of state lab serotyping data.
In the state lab in Minnesota where the serotyping takes place, they found an
increased incidence in one of the serotypes, which resulted in an investigation
and detection of a multistate outbreak.
Surveillance provides an infrastructure and relationships such that if
something does happen, the person who notices something unusual can make
the phone call. The calls can then be channeled to the appropriate persons.
The CDC Epidemic Intelligence Service (EIS) is the active aim of CDC in
terms of doing outbreak investigations. It was founded in 1951 because of
concerns about biological and chemical warfare at the height of the Cold War
and the Korean crisis. It is a training program that has graduated
approximately 2,200 individuals from the program since its inception.
EIS officers are not the only ones who may detect outbreaks, but the
training program serves as a very useful informal network, linked by a yearly
directory, for making contacts with our colleagues as we identify new and
unusual things. We are ingrained Mom day one as EIS officers with the steps
of an outbreak investigation:
.
.
.
.
establish existence of outbreak,
verify diagnosis,
define and identify cases, and
characterize by time, person and place.
Then we must
studies, and
.
develop hypotheses,
evaluate hypotheses,
refine hypotheses and conduct additional lab and environmental
implement control measures.
OCR for page 64
64
BLOOD AND BLOOD PRODUCTS: SAFETY AND RISK
You learn these in a relatively rote way, but you find that they are useful for
almost any situation, including the unknowns.
In the EIS network, 50 officers are currently have assignments in 26 state
health departments. We have graduates in field epidemiology training
programs in 19 countries. We also have a very active international visitor
exchange program, such that often colleagues who are overseas detect things
such as the Ebola virus outbreak in Zaire. They then give us a call and things
begin to move along. It is an informal network, but it is a relatively effective
one. It has worked well in the past in terms of identifying unknown
pathogens.
Finally, we are researching the history of the n otifiable disease
surveillance system because it underscores a lot of interesting relationships
between the federal government and states. Disease reporting is a state
function, and Henry Baker, who was quite clairvoyant back in the beginning
of this century, made this argument for collecting information on disease and
health. "The only way to learn what diseases cause most sickness is to collect
the statistics of sickness."53 That serves as our foundation for identifying
new and unusual pathogens. We continue to do that. Hopefully, we can do
a better job at it.
DISCUSSION
Bernard Horowitz: You described a system that was put in place several
years ago that is an extension of an older one for monitoring hemophiliacs.
One of the arguments is to assess blood safety. By the very nature of the
treatment of hemophilia A or hemophilia B patients, who are largely treated
with concentrates which are highly purified and virally inactivated with
solvent/detergent or other other techniques, it is not as complete a reflection
of safety from viruses as, for instance, the use of other patient groups such as
those with thalassemia. Are you aware of comparable systems for other
groups of patients, or in what way are you using rare hemophiliacs to
understand the infectivity of donated blood?
Bruce Evatt: I am not aware of other groups. I think that hemophilia
patients are a unique group in that they are exposed to blood products from
large numbers of donors. They are a sentinel group, but they now are also
53U.S. Public Health and Marine Hospital Service (1903). Transactions of the First Annual
Conference of State and Territorial Health Officers with the United States Public Health and
Marine Hospital Service. Public Health Bulletin, No. 11.
OCR for page 65
GUARDING THE BLOOD SUPPLY
65
receiving more and more purified kinds of products. It is expected that their
transfusion exposure will decrease in future years as they go to all recombinant
products, except for the blood transfusions that they require.
James Allen: If money is to be made available for surveillance for
transfusion-transmitted diseases or special issues of that sort, we need to be
certain that we have a very strong local, state, and federal disease investigation
system and general surveillance process rather than looking to build a
superspecialized type of vehicle for something unknown. Instead, our general
surveillance system must be very strong. I have very real concerns about the
strength of that today.
OCR for page 66
Representative terms from entire chapter:
incidence rate
