FDA Workshop
Immune Globulins for Primary Immune Deficiency Diseases Antibody Specificity, Potency, and Testing
Center for Biologics Evaluation and Research, FDA
Immune Deficiency Foundation
Plasma Proteins Therapeutic Association
HHS Office of the Secretary/Office of Public Health and Science
Lister Hill Auditorium
Building 35A
National Institutes of Health
Bethesda, Maryland
Printable Version (PDF, 401 KB)
Note: Documents in PDF format require the Adobe Acrobat Reader®. If you experience problems with PDF documents, please download the latest version of the Reader®.
April 25, 2007
Welcoming remarks
Jesse Goodman, MD, MPH, FDA
Marcia Boyle, Immune Deficiency Foundation
Jan Bult, PPTA
Jerry A. Holmberg, PhD, HHS
Introduction to the workshop, Dorothy Scott, MD, FDA
Keynote Address: Use of antibody in infectious diseases
E. Richard Stiehm, MD,Mattel Children's Hospital at UCLA
Epidemiology of infections in primary immune deficiency diseases (PIDD)
I. Epidemiology of serious infections in PIDD
i. Charlotte Cunningham-Rundles, MD, PhD, Mt. Sinai School of Medicine
ii. Rebecca Buckley, MD, Duke University School of Medicine
PIDD registries and surveillance for infections in patients treated with immune globulins
US Immunodeficiency Network (USIDNET) R. Michael Blaese MD, Immune Deficiency Foundation
European registry, Bodo Grimbacher, MD
Royal Free Hospital and University College, London
Panel Discussion:
Moderator: R.M. Blaese, MD
Panelists: E. R. Stiehm, MD, C. Cunningham-Rundles, MD, PhD. R.
Buckley, MD, B. Grimbacher, MD, D. Scott, MD, Hans Ochs,
MD, University of Washington School of Medicine
II. Antibodies to pathogens in current Immune Globulin Products
Current epidemiology of measles, polio and diphtheria in the US
Jane Seward, MBBS, MPH, CDC
i. Steffen Gross, PhD, Paul Ehrlich Institute
ii. Dorothy Scott, MD, FDA
iii. Peter Lerch, PhD, CSI, Behring
iv. Juan Jorquera, PhD, Grifols, SA
Emerging pathogens
Thomas Kreil,PhD,Baxter BioScience
Panel Discussion:
Moderator: Don Baker, PhD, PPTA,
Panelists: D.Scott, MD, J. Seward, MBBS, MPH, S. Gross
MD, P. Lerch, MD, T.Kreil, PhD, J. Jorquera, PhD, Carl
Frasch, PhD, Biologics Consultant, Basil Golding, MD,
FDA
Summary and action items with audience discussion
R. M. Blaese, MD, D. Scott, MD, D. Baker, PhD
P R O C E E D I N G S 8:10 AM
Agenda Item: Welcoming remarks
DR. GOODMAN: It is definitely a pleasure to welcome folks here for this discussion on immunoglobulins and there are a few people who are going to make introductory remarks but certainly we thank NIH and IDF and PPTA for their involvement in this and if I have left anybody out we thank them, too, and I know that Dot Scott has put a tremendous amount of energy into this, and this is, you know, I was just thinking about this. This is a very unusual situation where really because of the complexity of the product and our successes in many ways in prevention of infectious disease and vaccine, etc., the product has been changing.
There aren't large numbers of products that change with time and obviously this meeting is intended to assess some of those issues that are relevant to the product. Dot put together a couple of things here but just to point out this is very relevant to our core vision of what we are doing. Obviously we need to be sure that these products which so many patients both depend on either chronically for immune deficiency disease or acutely for other problems are continuing to meet our needs. So, I think it is good that we are recognizing these issues at the laboratory and process and production end rather than at the clinical end at this point, hopefully to prevent that and then I think also we have all recognized that supply and availability while waxing and waning remain consistent issues; so, if we can both assure the product is meeting our needs but also find ways to make the testing and release of product consistent with the medical and public health goal that would be good.
So, these are very consistent with our overall goals and the workshop is organized to look at issues of antibody in immunoglobulin as you know and I think it is timely to do that, both in essence the microbial world that our patients are exposed to and their immune status has changed and the donor status therefore in the immune globulins has changed, look at the issue of potency tests and specifically you know one issue which has attracted attention because of the declining levels is the measles antibody issue but I think this is sort of a probably what we have to think about here is not just what is on the table, the measles, the current released test but also think about that it is likely this product will continue to evolve.
You know the changes from natural to vaccine immunity I think for encapsulated organisms or from natural to a combination of vaccine in natural immunity for encapsulated organisms is something else to think about.
I know there are some data on that. So, that is really the purpose here and to be ahead of the curve to get input and our agenda reveals that those of you who are here and the speakers are a great group. This is a good partnership involving the treatment community, patients, the industry that supplies this and the government scientific and regulatory community.
So, it is also an area where we are very happy for people like Dot to sort of be providing what I would say is science based regulation really thinking about what we are doing here.
So, with that I guess I don't have the order in front of me but I guess Jan Bult might make a few comments from the industry point of view or Marcia Boyle from immune deficiency. I will leave it to you guys.
Okay, Marcia?
Anyhow, thanks, all for being here and I will try to come back and hear some of this meeting at least.
Thank you very much.
MS. BOYLE: Thank you. Can you hear me? I am Marcia Boyl, President of the Immune Deficiency Foundation. I am not Jan Bult. So, I am delighted to be here and we are delighted to be co-sponsoring this very important workshop with CBER, PPTA, the Office of the Secretary of Health and Human Services.
As you know this product, these products are absolutely essential to patients with primary immune deficiency diseases. They provide life, health and there are no alternatives.
It is actually refreshing today to be talking about efficacy and science rather than reimbursement which has been the topic that frankly I have spent the last 2 years worrying about and advocating about and Medicare and private insurance reimbursement continue to be threats to access to these products.
So, it is something we all have to keep in the back of our minds. For the well-being of our patients it is essential that we have this kind of partnership, that we have the FDA, the industry, the medical community and the patient community all sharing information and as Dr. Goodman indicated working in a partnership for the good of the patients.
A recent example of the success of this partnership was that the World Health Organization this week officially recommended that immunoglobulins be placed on the essential medicines list. They had been removed a couple of years ago.
So, that is a critical step and would not have happened if all stakeholders in the community hadn't worked hard on this issue.
I think during these meetings it is going to be valuable to discuss how the community can gather better data going forward and perhaps conduct better research perhaps using the tools, unique tools of the USIDNET and ESID registries for surveillance and better research and at IDF we have actually established a permanent survey research center so we can have more timely data on the experiences of really what is happening with our patients.
So, I want to thank Dr. Goodman, Dr. Scott, Dr. Holmberg, Jan Bult for their involvement in helping to organize this meeting.
So, I hope we will have some wonderful results.
Thank you very much.
MR. BULT: Thank you, Marcia. I understand it is now my turn and I would like to have the first slide. I am sure that somebody is going to put it up. I am going to start.
First of all thank you, Jesse and Marcia and Dot for all the work so far. I would like to join Dr. Goodman and Marcia Boyle in the welcoming remarks to today's workshop, and we are very pleased to co-sponsor this event together with the two already mentioned organizations.
We are the International training association and standard-setting organization for the major producers of plasma derived recombinant analog therapies and I think it is no surprise but our members are committed to assuring the safety and availability of these fairly important therapies.
The members of our organization provide about 60 percent of the world's needs for source plasma and protein therapies and that of course includes immunoglobulins that are needed to treat so many different diseases, one of them of course, the primary immune deficiency diseases.
The global companies that we represent you see five companies that actually provide their therapies into the American market Baxter Bioscience, Grifols, Optipharma(?), Telequist(?) and CSFDA(?).
We are responsive to the needs of the community that depends on these very important immunoglobulins both in terms of composition and delivery mechanisms. While we recognize and Marcia mentioned access issues and we are working with the community to remedy the reimbursement practices that threaten the availability of products we can demonstrate that our industry is doing all it can to ensure that the products are safe and of sufficient quantity for the community.
Manufacturers have included various steps both by chemical means and partitioning to address viral safety and have conducted numerous studies to demonstrate experimentally the efficiency of the manufacturing steps in reducing a prion risk.
In terms of supply the industry has increased the distribution of IVIG by 85 percent between 2000 and 2006 and in the year 2000, 17.5 million grams of IVIG were distributed in the US market and in 2005 we had a record of 28 million grams and we all believed that was a number that was really remarkable but that number was shattered in the year 2006 with the distribution of 32.4 million grams into the United States market.
Factors in this growth certainly are the increase in the amount of IVIG produced by the manufacturers with yield improvement technologies which of course allows more retrieval of IVIG from each liter of plasma, the increase of plant capacity and the development of new therapy formulations in order to achieve the success.
PPTA really welcomes this opportunity today in this workshop to explore additional areas for continuous improvement of therapies.
The FDA regulatory requirements for lot release of immune globulins by testing the potency of antibodies against diphtheria, polio, measles are decades old. We believe it is good to periodically look at the lot release requirements and the composition of immune globulin preparations with respect to the needs of the patients and the antibody distribution and levels in a donor population. The agenda of this workshop was designed to delve into these issues and the organization committee and speakers are to be commended for this work and we look forward to participating fully in the discussions during the next day and one-half.
Again, from PPTA we wish to welcome all participants to this very important workshop.
DR. HOLMBERG: Good morning and welcome. I am Jerry Holmberg. I am with the Department of Health and Human Services and he senior adviser for blood policy to the Assistant Secretary for Health.
I want to welcome you all and thank you for the opportunity to have this workshop first of all and I would like to thank FDA and especially Dr. Scott for putting this together and the planning committee that worked hard on this and also for the organizing groups such as IDF and PPTA for this workshop.
You know when we look back over the last decade there has been a lot of changes. We have covered a lot of ground in the whole field of plasma proteins and their therapeutic use.
I think in the last 2 years we have really addressed another issue and that was availability and access and as Marcia commented earlier it is refreshing to be able to talk about some scientific issues today.
I have really been dealing with a lot of the access and availability issues. Although the reimbursement is a center for Medicare or Medicaid services issue we are very much involved within the department since that is one of our operating divisions but they do call the shots on the reimbursement and so it is refreshing to be able to look the progress that has been made.
We do know that worldwide there has been an increase in the utilization of the product and I look forward to this workshop to focus on the, not only to focus but to hear comments on the quality and characteristics of this product and also to ensure the purity, potency and efficacy of IGIV.
So, thank you for coming to join us and I am looking forward to the comments from the speaker. Thank you.
Agenda Item: Introduction to the workshop
Dorothy Scott, MD, FDA
DR. SCOTT: Welcome, everybody and I just want to mention I have recently been informed on a historical note that today is the 62nd anniversary of the first meeting of the UN. I think that is highly auspicious for a meeting like the one we are having today where we are bringing a lot of folks together to discuss our immune globulins in order to benefit the patients and to move the process forward, the scientific process where we look at our potency testing.
What I am going to do right now is just introduce an overview of the goals and issues that we have for discussion today, but first I would like to thank our sponsors not only for their financial assistance in putting this workshop together but even more so for the intellectual contributions hat we have from the presenters and from the sponsors in organizing the presenters and helping us to get some excellent speakers. I, also, want to thank Jennifer Sharp and Rhonda Dawson for taking care of a lot of the technical aspects of the workshop in making sure that everything got done and my office and my center for all of their support and help.
This is a very brief overview of our workshop goals. In particular we want to assess the current potency testing of immune globulins and underneath this is really what we want to do in the first couple of sessions today.
One is to list the antibody specificities needed to protect primary immune deficiency disease patients from infections; what is relevant; what is important now? We would like to identify candidate antibody specificities for potency testing of immune globulins for treatment of primary immune deficiency. These two things are somewhat different. One is saying, "What do the patients need?" and the other is to say,"What is feasible to test for?"
We would also like to tomorrow address approaches to provide protection from measles with immune globulins, despite the diminishing measles antibody levels in the plasma donor population and therefore in our products.
I am going back to basics with some regulatory definitions. I am glad it is the morning so people can stay awake. The word "potency" is interpreted to mean the specific ability or capacity of the product as indicated by appropriate laboratory tests to affect a given result and I only put this up, well, it is obviously very important. It is our fundamental definition of potency but it links the laboratory testing to the effect in the patient.
We, also, have requirements for laboratory controls and this really provides us a regulatory underpinning for considering the science behind potency testing and also in the CFR it states that lab controls should include establishment of scientifically sound and appropriate specifications and test procedures to assure that drug products conform to appropriate standards of identity, strength, quality and purity. Okay, so, what does this mean for us?
The rationale behind all of this testing for potency is assurance of strength and quality but what do our specifications provide exactly and there are several different things that we would like to have out of a specification. One is it should be a measure for immune globulins of lot-to-lot consistency in production. This is one of the original reasons for looking at potency testing. It provides or it can provide an assurance of product integrity, that is if you are looking at tests that measure not only the presence of antibody and its ability to bind but its function and it should be a measure of activity that is relevant to the indication and in this case we are talking about patients with primary immune deficiency.
So, immune globulins are a bit unlike any other product I could think of that we regulate. Unlike other biologics that are comprised of multiple specificities there are millions of unique antigen specificities and that reflects the diversity of the antibodies in each individual donor as well as across the donor population. So, we are not talking about just one potency really.
The potency for specific pathogens within the immune globulins might vary due to differences in the donor population due to age, vaccination status, epidemiology, that is have they been exposed to infectious diseases; what are those, and in fact, there are of course seasonal variations in exposures which might be reflected in the immune globulins depending on the time that donor plasma was collected, and finally if that weren't enough the patient population is exposed to diverse pathogens.
Dr. Goodman mentioned this as well. The appropriate antibodies I have seen defined. I believe it was by Charles Janeway as antibodies against those pathogens to which patients are exposed. So, it is a rather broad definition.
So, how did we start out with this and it is a little difficult to get the history. There is no one place to find out what happened but in 1943; that is a salient date, the first immune globulin was licensed and that was manufactured by Massachusetts Biologic Laboratories and it has actually been produced nearly up to the current day and after that in 1952, Bruton described treatment of a patient with immune deficiency with immune globulin. So, this was licensed before people were really using it to treat primary immune deficiency.
I will go back and tell you what it was licensed for. In 1953, we were able to excavate the Department of Health, Education and Welfare minimum requirements for immune serum globulin which was the name of the current intramuscular immune globulin and here they state, this is the earliest information we can find something about potency testing and that is the ability of the manufacturing method to recover specific antibody shall be demonstrated by titrations for several antibodies for which there are recognized methods of titration.
Several lots of material shall be shown by clinical trials to be effective in the prophylaxis of measles and in fact the first immune globulin was licensed among other things for prophylaxis of measles.
In 1961, we distributed the first measles antibody standard called lot one for measuring anti-measles antibodies in immune serum globulin and somewhere between 1965 and 1968, the CFR requirement for measles, diphtheria and polio neutralization assays to demonstrate potency was published. Unfortunately, we just have CFRs before that time and CFRs after that time and I think it will take a reference librarian to find out when exactly that appeared, but in those days we didn't have the extensive Federal Register explanations of proposed rules and actual rules and a rationale behind those. That is something we have yet to find.
However, it makes a lot of sense that measles, diphtheria and polio were selected at that time because these were endemic and epidemic diseases in the US. So, the current US product potency tests that are used for immune globulins intravenous, all the immune globulins used for primary immune deficiency are antibodies to measles, diphtheria and polio and we also request testing for hepatitis B surface antigen.
Now, all of these tests except for anti-HBS are neutralization assays and this is specified in the Code of Federal Regulations. I will just mention that the anti-HBS provides an additional assurance of viral safety because it helps to clear virus and to neutralize hepatitis B virus that might exist in immune globulins.
Now, of course, we have a lot of testing but this test has stayed. We are not going to consider it further today because the immune globulins are not indicated for prophylaxis of hepatitis B.
So, rather this was put in as a safety measure rather than as a potency measure per se.
So,what is going on now? Well, we know our products are changing, because the epidemiology of antibody specificities in the donors are changing and this was made most evident to us by the decline I measles antibody titers to a point where it is conceivable that lots of immune globulin intravenous could fail their lot release testing. This presents a regulatory and a practical problem because it is very important from the regulatory standpoint for products to pass their lot release testing and in fact the compliance regulations tell us that if a lot doesn't pass its lot release testing that it needs to be reworked or discarded.
So, that doesn't mean we should necessarily change what we ask for as a measles antibody titer but it does mean we have to think about how to address this problem.
That is actually what triggered this workshop. We began by considering the measles antibody and then we thought it would be a very good idea to reconsider what we are already doing for all of these specificities that are potency tested in the immune globulins.
In addition to the products changing the patient epidemiology of what we know about it might have changed and we would like to know what are the current most important needs for infection prophylaxis in primary immune deficient patients.
Dr. Finlayson who is here today said in 1979, at an immune globulin workshop as the spectrum of products has progressed so have the techniques of potency measurement and protein chemistry. I am glad he said that in 1979 because since then not a lot has changed. We are still using the tests and the potency specifications that were decided upon in the mid-1960s.
There are challenges though to changing any potency tests because the current tests are well validated and they are routine within industry. So, changing tests like this would require a lot of expense and effort and there are some technically desirable attributes of any new test.
First of all it must be validated. It must be validatable(?). Standards have to be available. Ideally potency test would demonstrate functional antibody activity such as neutralization or opsonization and these tests are more difficult and have more variability than for example binding assays like ELISA, and ideally such tests would not require the use of animals.
So, briefly here is the structure of the workshop and this is what we are going to be asking of you, the audience, the panel and the speakers is to identify the most relevant antibody specificities needed by primary immune deficiency patients and to review the data that we have now on antibody levels in the current products and to combine this information in order to think about which antibody specificities would be useful and relevant to measure with respect to clinical importance and to assure lot-to-lot manufacturing consistency.
So, we have really two sessions today. One is the clinical session and one is I would say the product session and then we want to put those together at the end of the day.
Dr. Blaese from the Immune Deficiency Foundation will be moderating the first session and in particular the questions there, what are the major infections in primary immune deficiency patients now, whether or not they are treated with IGIV that need to be prevented and also we have an opportunity here to ask what more do we need to know about infection epidemiology in the patient population today.
We have some reports of surveillance that are ongoing in the EU and also that are beginning in the US through USIDNET and our opportunity is to look at the USIDNET new database and to offer ideas for additional questions that would respond to the needs up here
The goals are to list the relevant antibody specificities and to identify the information gaps in epidemiology to assist in the USIDNET efforts and Dr. Blaese is going to talk about that in a lot more detail.
The second part is to look at the levels of antibodies against pathogens in our products. Obviously if we have a concordance between what we need in patients and we have tests that we can do and where we know that there is some degree of consistency from lot to lot those might be good tests to consider as potency tests.
As I have mentioned measles, polio and diphtheria our current potency tests for immune globulins, Dr. Seward has come from CDC to tell us about the current epidemiology of those infections in the US population.
So, we are going to look at our current tests and what they are actually telling us now. The goals of the second part are to identify specificities that are useful and relevant to measure in immune globulins for their clinical importance and for lot-to-lot consistency, to identify gaps in information about specific antibody levels in products and to identify approaches to new test characterization and development.
Okay, so we are having a workshop. What happens next? I think that we do have some goals and some outcomes that we would like to achieve.
One is to help USIDNET with their surveillance project and I say, "Improvements," but actually the fortunate thing is that this workshop coincides with the roll out of the new USIDNET efforts for surveillance. We would like to address knowledge gaps so that we can identify studies on current products that would fill these gaps and we would like to consider the possible development of new potency tests.
Now, there is a regulatory pathway for these changes. We don't make regulatory decisions at a workshop and these would include consideration by the Blood Products Advisory Committee and potentially guidance. I, also, think that this workshop could result in some very good industry, FDA and academic collaborations on tests and standards development and of course tomorrow we are going to address the decline in measles antibodies in products and for that we can also, we have the option of seeking regulatory advice from the Blood Products Advisory Committee.
So, with that I hope people have a sense of where we are and where we are going today. I would like to introduce Dr. Stiehm. He has been a long time researcher and clinician for primary immune deficiency and immune globulins in general.
He has over 500 publications. He is currently a professor of pediatrics at UCLA, but I remember him from previous workshops as being a real advocate of looking at different markers of potency in immune globulins and the antibody specificities in immune globulins. I would say his interest has gone back quite far. I looked in his earliest paper on immune globulins which was in 1961 when he was looking at the effects of papain digestion on immune globulins.
I would like to welcome you, Dr. Stiehm and thank you for coming and for giving us the benefit of your thinking on the potency test and the antibody specificities and the impact on patients that need to receive immune globulins.
Agenda Item: Keynote Address: Use of antibody in infectious diseases, E. Richard Stiehm, MD, Mattel Children's Hospital at UCLA
DR. STIEHM: That is my disclosure. Thank you very much for inviting me here and Dr. Scott for all her good work in putting this very interesting symposium together. I look over at 100 different people, all experts in the field with about 500 different fixed opinions on what we should do and with that in mind I just want to relate a little story I heard that was kind of interesting about a woman who arrived at Ronald Reagan Airport and she found out her plane was 2 hours delayed. So, she bought a cheap novel and a bag of cookies and sat down to wait and she took a cookie and then the man next to her took a cookie from the same bag, and she thought well, that poor guy is kind of hungry. I will overlook that cookie thief and she took another cookie, and he took another cookie, and it went on until all the cookies were gone. Every other one she took, he took, and finally at the end there was only one cookie left. He broke it in two and gave her half and ate the other half.
Well, by this time she was really steaming, but she decided to keep her cool and she got on the plane and got herself all settled and then opened up her bag and there was her bag of cookies.
(Laughter.)
DR. STIEHM: So, that reminds me of this little poem. If mine are here, she moaned with despair then the others were his. He tried to share. Too late to apologize she realized with grief, I was the rude one, the ingrate, the thief.
So, being sure is not the same as being right. So, let us take a look back at where we have come in terms of the use of antibody in infectious disease and then the last 5 or 10 minutes where we should be going and of course, it all started out in Germany in 1890, and diphtheria horse antitoxin was developed in the 1890s shortly after the toxin was identified.
It had been used in both prevention and treatment and still used as equine antitoxin in the treatment of diphtheria antitoxin.
Emil von Behring was awarded the first Nobel prize in medicine in 1901 for the development of diphtheria and tetanus antitoxins and his citation reads, "For his work on serum therapy especially the application against diphtheria by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physicians a victorious weapon against illness and death."
So, what are the different agents that we have as passive immunization areas? Well, we still use animal sera or globulin and a few of these are fragmented so that they disappear more rapidly.
The best example is Digibind for digitalis overdose. We can use whole blood, sera or plasma and then we have a number of human immunoglobulins which are the subject of today's conference.
We have regular, intramuscular IG polyvalent and we have a number of very high titered IGs, hepatitis B immune globulin, tetanus immune globulin. We have a number of different IVIGs and then we have several high-titered intravenous immune globulins, cytomegalovirus immune globulin, up to recently RSV immune globulin. We have anti-D immune globulin and of course the biggest area is the release and licensing of monoclonal antibodies. The first one was OKT3, a murine monoclonal antibody against T cells still used today but nowadays we have 19 different licensed monoclonal antibodies and one or two are being licensed about every year.
So, how are these immunoglobulins used in the treatment of infectious disease? The first use as I mentioned was in toxin-mediated diseases such as this little baby who has tetanus. These toxin-mediated diseases notably diphtheria and tetanus but a few others are readily prevented by immunization and we still use these today as tetanus immune globulin for the prevention and treatment of tetanus and diphtheria antitoxin for the prevention of exposed susceptibles and these are necessary in treatment because not only do you have to get rid of the bacteria, you also have to neutralize the toxins which are causing the damage and that is why these are used in toxin.
We occasionally use these intrathecally. In fact a large meta analysis has recently shown that tetanus immune globulin given intrathecally is better than just giving it intramuscularly alone.
Another increasingly use in diseases that we seeing is botulism and there are three forms of botulism. We have inhaled botulism which a bioterrorist threat. We have wound botulism which is shown here and then of course we have food poisoning and then a boutique use of botulism antibody is in the treatment of botulism in the newborn and this shows a baby that has hypotonia and failure to suck because he has newborn botulism.
So, botulism is food borne, wound botulism and this seems to be an epidemic because of increasing use of injection for illegal drugs.
There is an equine antiserum distributed by the Centers for Disease Control. Human botulism is indicated for the treatment of infant botulism. It is called BABY BIG botulism immune globulin and the cost for one treatment is $45,000 and it is distributed by the California Public Health Department.
Clostridium difficile a severe pseudomembranous colitis refractory to vancomycin is sometimes treated with IVIG with efficacy and there are a number of studies particularly not in this country of oral bovine anti-clostridial antibodies used for treatment of botulism.
The subject of today which initiated this was this illness. This is scarlet fever. You can see the strawberry tongue and the red rash and after the use of antibodies for the treatment of tetanus and diphtheria and prior to the development of antibiotics immunoglobulin or passive antibody was the only treatment for bacterial respiratory infections and in the twenties and thirties streptococcus, staphylococcus, pneumococci, Neisseria, H. flu were all treated with antibody and of course these are the same organisms that patients with primary immunodeficiency had and specific antisera were developed for each of these and they were used sometimes in conjunction alone or with use of sulfa drugs.
In fact there was a product that was never licensed called bacterial polysaccharide immune globulin which was tested and shown to dramatically increase the incidence of not only meningitis but otitis and respiratory viral infection.
So, gamma globulin works dramatically in bacterial respiratory infection. It also works in certain toxins associated with staphylococcus and this is a woman that has the staph toxic shock syndrome. Staph toxic shock syndrome is associated with a cytokine storm associated with TSST release of toxin with a tremendous amount of cytokines released.
Staph epidermidis is a major pathogen particularly in newborns and premature infants particularly with the use of increasing amounts of lines and hyperimmune IGIVs are under study, have a high titer of Staph epidermidis. Refractory staphylococcal infections are sometimes benefitted by IGIV and they are synergistic with antibiotics as shown in laboratory tests and there is about eight or nine different monoclonal antibodies against staphylococcal antigens which are under study and some of these look extremely promising. So, the role of antibodies in staphylococcal infection is an area of keen research interest.
Streptococcus is also a problem and this shows a child with severe streptococcal toxic shock syndrome. These patients with severe strep get necrotizing fascitis, necrotizing myositis and these again can be treated with IVIG because immune globulin has antibodies to pyrogenic exotoxins A, B, and C.
Then there are a number of diseases where gamma globulin has been suggested without benefit, the use in Sydenham's chorea and this pediatric autoimmune neuropsychiatric disorder associated with streptococcus. People have used IVIG but without firm evidence that it is of any benefit.
In viral diseases immune globulin has a long role in the prevention and treatment. This patient has hepatitis and hepatitis A was the original reason why immune globulin was licensed back in 1943, as Dr. Scott showed and it was used particularly to prevent hepatitis A among travelers. It is very effective if given before prevention and even after exposure it is somewhat beneficial but it doesn't prevent the illness. It prevents icteric hepatitis and in the old days before hepatitis A vaccine and we were going abroad that was the biggest use of immune globulin.
It is also occasionally used in infants if the mother has hepatitis A at the time of delivery.
Hepatitis B immune globulin was the first, I think the first high-titered intramuscular gamma globulin and the biggest use for hepatitis B immune globulin is not to prevent hepatitis B in newborns but in liver transplantation.
Hepatitis B is of course indicated for exposed susceptibles such as newborns, needle sticks, lab ingestions, sexual exposure and in newborns we now give all newborns that are exposed because the mother has hepatitis B antigen positivity, they get both the vaccine and hepatitis B immune globulin.
Hepatitis B immune globulin following liver transplantation is necessary because even if the liver, the donor liver is hepatitis B negative there is enough hepatitis B in the body that the new liver will become infected and so it is used immediately after liver transplantation for a prolonged period of time. It is interesting it is given intravenously very often because the hepatitis B immune globulin from one company is a 5 percent product and even though it is not licensed for intravenous use the liver transplant people use it all the time intravenously and nowadays the hepatitis B immune globulin is used in conjunction with antiviral agents and the hope is that some of these patients can get off hepatitis B immune globulin eventually but it is an enormous use and as it perhaps doubles the cost of liver transplantation in a hepatitis B positive individual.
There is also a product out there called hepatitis C immune globulin that they hope will work in the same fashion. In preliminary studies it does not seem to prevent hepatitis C in the new liver.
This is the subject for today. This is for us old timers. We remember how a patient thought we were wonderful diagnosticians because we used to say, "This child is going to come down with measles in a day or two because of the spots and this is the baby with the rash."
Patients who are exposed to measles and should not get it perhaps for malignancy do get measles immune globulin and the dosage is based on the previous titers of antibody.
VZIG is indicated in all exposed susceptible immunocompromised patients in all prematures or term infants or seronegative mothers who have chickenpox already. So, this product used to be made by the Massachusetts Department of Public Health. There is a new vaccine manufacturer and I think it comes from Cangene(?) in Canada but for a while varicella zoster immune globulin was not available but now again it is.
This is a dreaded illness, rabies and here is a little baby that had rabies and is going to die because all but one patient with rabies eventually succumb.
Rabies immune globulin is based on the following clinical observations. In 1954, a big bad wolf came into Teheran and they knew that wolves came into the villages and bit a number of people. So, the treatment up to that time was rabies vaccine determined by Pasteur, but in 1954, the World Health Organization thought that perhaps immune globulin in addition to rabies vaccine would be effective so that this wolf cooperated and bit 17 villagers. Three out of five just were given the vaccine alone. One of seven was given vaccine and one dose of rabies antiserum, and zero out of five given vaccine and two doses of antiserum developed rabies.
So, since that time their use of rabies either antibody or rabies immune globulin is the treatment of choice in exposed individuals.
Nowadays you use half of this vaccine intramuscularly and half locally.
This is vaccinia. It used to be a problem in individuals who had severe combined immunodeficiency that were given smallpox vaccine and of course now, the main use for vaccinia immune globulin is exposure of our patients to a patient who has recently been vaccinated and since the military and certain laboratory workers still continue to get vaccinations for smallpox the threat of this disease has not diminished and furthermore there is a concern that this is a potent bioterrorism illness.
So, we know that vaccinia immune globulin can prevent both vaccinia and can prevent smallpox and Jenner of course showed that if you are immune to cowpox it will also prevent smallpox and vaccinia immune globulin will prevent the serious complications such as vaccinia encephalitis.
Vaccinia immune globulin is indicated for accidental vaccination, autoinoculation, eczema vaccinatum, progressive vaccinia and vaccinia necrosum.
So, in summary for this portion prevention with immunoglobulin or antitoxin can prevent a lot of diseases such as tetanus, diphtheria, hepatitis, measles, RSV, varicella and it is used in the treatment plus antimicrobials in toxin-mediated diseases such as diphtheria, tetanus, botulism and toxic shock due to staff and strep.
Antibodies may also be adjunctive to antimicrobials and CMV infections and RSV infections in newborns and ICU patients with sepsis, and a few illnesses, notably infant botulism, parvovirus B19, progressive vaccinia and Ebola can only be treated with antibodies.
Now, let me just spend the last few minutes talking about the meeting we had about 2 years ago where we were looking for surrogate markers for IVIG licensure as a way to accelerate and simplify the process of allowing more immunoglobulin to be brought into the market and these were some of the surrogate markers that were proposed at that time which include antibody and immunoglobulin levels, x-rays of the chest or sinuses or inflammatory markers and then the one that we tended to focus on was antibody titers and that is what our subject is for today.
So, which antibodies should be measured? How should they be measured? What is the protective level? How often should they be measured? Are serologic titers equivalent to functional activities?
What antibodies are in the donor pool? What are the most important illnesses to prevent? What are the most important pathogens? What less common antibodies should also be measured?
So, that requires knowing what illnesses are common in immunodeficiency and these include pneumococci, H. influenzae. We, also, have to protect these patients that don't make any antibody to measles, tetanus, diphtheria, polio, hepatitis A and B and chickenpox and then there are certain unavoidable illnesses out there, CMV, Epstein-Barr virus and parvovirus which it is useful to protect against.
So,we are going to hear more later on today about what are the important bacteria and viruses that affect our patients and here is a list of the common pathogens that we see including ones that aren't typically bacterial or viral including Mycoplasma, ureaplasma(?) Cryptosporidium pneumocystis and Giardia infections and we know, however, that there are variable amounts of antibodies particularly for less common pathogens in IVIG and so several years ago I made this list of pathogens that might be useful to measure as surrogate markers for patients that are treated with intravenous gamma globulin and these were the semifinalists, Staph aureus, Staph epidermidis, E. coli, Pseudomonas, herpes simple I and II, Coxsackie, echovirus and parvovirus but they didn't make the cut. The ones that made the cut included H. influenzae, several strains of pneumococci, diphtheria and tetanus, hepatitis B, measles, varicella zoster and CMV and many of these are in the FDA requirements. Poliovirus seems like it is part of the antibody panel but it seems less important to have protective levels in this product,
So, for today should the FDA require additional antibody tests on IG products? Should FDA require labeling of antibody content? If so, what assay should be used and what would be the effect of the cost if we had to do all of these antibodies on the product?
Finally I want to tell you some new events from the FDA. If immunoglobulin doesn't work the FDA has the answer for you. They have just approved the sale of prescription placebo and it is called Sucrosa(?). It is the evaporated juice of Saccharum officenarium. It is a white crystalline substance with a sandy consistency, molecular weight of 676, rapidly and completely absorbed, non-toxic doses of 1 to 40,000. Astra Zeneca will market it as a triangular green pill 50 and 100 milligrams or a good-tasting liquid at 10 milligrams per ml, wide application, minimal side effects. The indications are run(?) PDD, random occasional non-specific pain and discomfort disorder, pediatric board exam anxiety disorder, bipolar disorder, chronic fatigue syndrome, erectile dysfunction and seasonal affective disorder.
The side effects are slight elevation of blood glucose level, tooth decay if used continuously, sweet taste in the mouth if not swallowed, expensive, 50 cents per pill. Manufacturer says, "We have to recover our research costs which coves years of testing, most extensive drug ever tested and there are many of these placebos in the pipeline. There is Inertia from GlaxoSmithKline, Appeasor from Merck, Pacifiex from Eli Lilly and the FDA says, "All placebos are not the same," and medical watchdog spokesman, Pim Naysayer says, "These placebos shouldn't be introduced to the public until we know more about their mechanism of action."
Thank you.
(Applause.)
DR. BLAESE: Questions for Dr. Stiehm?
Agenda Item: Epidemiology of infections in primary immune deficiency
DR. BLAESE:The first general session of this workshop is entitled Epidemiology of Serious Infections in Primary Immune Deficiency Disease and as we have already heard there are a lot of questions. What organisms are particularly a threat to our patients with primary immune deficiency disease? These diseases represent a broad range of different disorders in the immune system and host defense and as my old teacher made such a good point, these diseases are experiments of nature and have taught us a tremendous amount about what parts of the immune system are responsible for what kinds of protection against what kinds of organisms, and they really were the first insight into the fact that the immune system was compartmentalized as to what it was going to be able to help us with.
You know we are going to be discussion the impact of immunoglobulin replacement, you know which infections are controlled and which ones are not. There was certainly the observation when intramuscular gamma globulin was introduced for our patient population that there was a decrease in the incidence of acute infection, less unanimity of opinion as to whether it was effective in controlling sort of the smoldering persistent infections of the sinopulmonary tree. Then as higher-dose immunoglobulin became available in the intravenous form there was evidence presented that in fact you could control not only acute disease but some of the smoldering infections but there still is an issue I think about do we have enough specificity and what is the effect on all sorts of chronic infections and as another part if the workshop is going to be discussing some of the new tools that are just becoming available that we hope can be exploited to help answer some of the questions that have been very difficult for single institutions or single investigators to acquire enough experience with enough patients to be able to answer and so we are going to be hearing from Bodo Grimbacher who represents the European Society for Immune Deficiency, and he will tell us some things about their experience in setting up a patient registry which now has something in excess of 3000 patients enrolled and I will tell you a little bit about the USIDNET patient registry which has some previous collections about 1500 primary immune deficiency patients in the registry and the online registry should be inaugurated within a few days that will then allow us to try to address some of the questions that are relevant to this particular topic and we would like input from the audience. Both Boda and I would like very much to hear how you think we could us these registries that we will be following in a longitudinal way patients with primary immune deficiency.
What kinds of questions should we be addressing in that registry realizing that we have to balance the accurate collection of data that really gives an answer with imposing a lot of requirements on our submitting physicians and whether they will actually comply with the request to collect this data.
So, we have this balancing issue that we want to discuss.
So, the first speaker this morning in this session is Dr. Charlotte Cunningham-Rundles from Mt. Sinai, New York and she is going to be discussing some of these issues of the epidemiology of serious infections.
Agenda Item: Epidemiology of serious infections in PIDD
DR. CUNNINGHAM-RUNDLES: This is a really daunting title and it is daunting because I think we don't actually know very much about the epidemiology.
So, that is the word that sort of gets me down because we don't have that data, but I will tell you a few things that we do know.
Don't look for a handout. It took me forever to come up with the type of slides and information that I thought would be not off the point. So, going forward if we tried to say, "What do we know?" we are talking today really about antibody deficiency. At least that is the point that I am going to stick onto.
I am not going to be talking about some of the other immune deficiency diseases that you don't treat with immunoglobulin because that is just a little bit of a separate issue right now.
So, if you think which ones do we treat with antibody deficiency and what do we know about the infections that occur in this group of people these are the ailments, of course that we want to kind of contemplate more than any other.
For me you can see this is heavily skewed. Antibody deficiency for me is the biggest population that I see but I know from Dick Stiehm's textbook that of course is going to be about 70 percent of all the people with immunodeficiencies are going to be on gamma globulin and antibody deficiencies are actually the most prominent. So, that is not just how I view the world. I think that really the world of antibody deficiency is a little bit larger than all of the others taken together.
So, there is a little bit of data that we can gather together and this one comes from the prior registry that the Immunodeficiency Foundation put together by Jerry Winkelstein in this case and we say, "What were the infections that were observed in the pure antibody-deficiency diseases?" taking that as the most obvious and worst case scenario for having absolutely no antibody to begin with and so Jerry had collected data on 210 patients and this is the kind of data that you can find and these ar treated and untreated but in the main these are people who were referred and the infections that appeared.
This article appeared last year but as you can see in the main you have the upper respiratory tract infections up here in the top and then the lower respiratory tract infections and other entities as you move on further down.
You have plenty of infections in these patients. Of course it turns out to be at least something like 90 percent of all the people with XLA really are having serious infections even before the time that they are officially given that name and most especially those who were diagnosed in infancy may or may not really have such serious infections due to treatment that is instituted early.
Of course, it is a problem because although you have an infection you don't always know what the bug is. So, out of the 210 there were 125 cases in which the actual organism was really identified and as you can see the numbers here are going to be really totally swayed by the fact that 105 of these cases it wasn't possible to actually know and either that is not reported and in most cases that is the case because paperwork is a problem or in fact it simply wasn't able to culture it.
So, pneumococcus comes out again on top. As Dick Stiehm was saying a moment ago that is one of the organisms that we have to take the most seriously along with Hemophilus and Pseudomonas as a big customer also in patients with XLA and so we know something about that but as you can see with about half of these cases not fully diagnosed we don't exactly know. We just know what was found.
If you talk about encephalitis, meningitis again a good number of those were not known. In this case there were 25 cases. Nine of them were not known but in the other cases it was a more clear-cut answer and Strep pneumoniae again ruled the day followed by echovirus, Coxsackie, polio, adeno and then Hemophilus type B.
So, the viruses actually came out on top as one knows so well from the XLA patients. Mike said moment ago that we are really obviously very much trying to amplify what is known about patients with immune deficiency. We have kind of the beginnings of this taking all the patients from the registry existing and merging those with those for Mt. Sinai, about 400 patients or 350, whatever the number was in the registry now we have close to 700 patients in the USIDNET registry at least those who are perched on the brink to be entered, and this was data that one of our fellows, K. Knight put together and she subsequently moved to Alabama but what can you say about it is that we actually had the beginnings of some information on these patients and as you can see US physicians pretty much agree that these are very, very hypogammaglobulinemic individuals and I think that we would say, "Oh, these people definitely belong in this registry. It is not a case of mildly deficient. These are clearly deficient. The complications, about 90 percent of patients in that particular cohort have infections.
As you can see it is not 100 percent which is something that always makes me give pause because that is why infections are not part of the diagnostic criteria of CVID. If you don't have infections, the chances are that you have either autoimmune disease or you have come in the door with an inflammatory bowel disease. That doesn't change the fact that you actually have the capacity for having some serious infection and as you can see about 90 percent of course do.
What infections are they? Sinusitis is a big one. Everyone would realize that. I have no idea what the organisms always are. In most cases the organisms were not entirely registered or we don't know. It is not possible to culture.
Pneumonia is about 70 percent, bronchitis, otitis, various abscesses, recurring herpes zoster came in at an interesting position here. About 8 percent of patients reported that and sepsis was something like 5 percent, meningitis, cellulitis and osteomyelitis.
So, I think this kind of forms a platform. I can't tell you it is wonderful data as of yet but I think it performs a kind of a beginning stage of what we might get to know about these individuals especially if we could do better in terms of culturing and when it comes down to empyema I think the bug you could go to the racetrack with this one and probably earn some money is nearly always Strep pneumoniae, and you can just make a bet about it. It will create this large empyema that has to be drained. It is a pretty nasty infection usually associated with bacteria as well.
Interestingly enough this is I would say one of the more common ways these patients get to be recognized. This is their first most serious and most major illness.
We don't expect to ever see that again when the patient is on gamma globulin.
The second largest one or another very large one; I am not going to tell you it is the second largest but it probably comes in third place and that is Mycoplasma. Again, there is kind of a secret handshake deal between people who are immune deficient with antibody lack and then having a Mycoplasma infection. We don't understand this very well because Mycoplasma is not really supposed to be an extracellular organism exactly.
On the other hand, antibody seems to be pretty crucial. Hemophilus, I probably should have put this slide first, hemophilus is our biggest consideration probably.
So, if you look at this particular paper by Samuelson I think it is a large amount of very nice data because they have really gone after this bug in a very concerted way. It is 117 patients followed with antibody deficiency for 5 years. They were either IgA subclass or CVID and the non-typable hemophilus was the sole respiratory pathogen for more than half of those people and it was mostly the CVIDs that were really concentrating this particular bug and many of the patients that have had many positive cultures and they are colonized really with the same strain for many, many months on end. So, it is something that we actually have an incredibly difficult time actually eliminating from our patients. Whether they are on gamma globulin or they are not to me this is our single worst organism currently.
I think this is responsible for the little redness of the eye that you often seen in patients with CVID who haven't had their antibody for a while.
You know Bob Good used to say that you could always tell when they needed their gamma globulin because they get this little pink eye and I think that is true.
If you culture it is always going to be hemophilus and it would be non-typable and between you and me I don't know how we can get rid of it because of course non-typable means no capsule, and no capsule means antibody doesn't help a whole lot and of course many of the are on many courses of antibiotics and as you can see the isolates don't seem to be any different that were isolated from other normal immunocompetent people. So, there is something not so special about the bug as far as I know. It is just this is the open door for these patients as far as I can tell.
In the Finnish population a large amount of data has been done just to try to figure out what is responsible for the chronic lung disease that we see in these patients and in this particular case 14 patients were given a bronchoscopy at a time when they were not knowingly ill but they had some bronchial findings and in this case 11 had CVID and 3 had XLA and as you can see they really isolated quite a bit of the same bugs we have been talking about, hemophilus here but then a few viruses also are creeping in.
I think this is what we don't know very much about though, the viral part of this because it is hard for me actually to culture this.
I am sure it is hard for everyone here to actually know when that particular bug is present. Returning to Mycoplasma that is the secret organism again commonly found in the chronic arthritis and this was a study by Franz in the British Journal of Rheumatology who concluded that they really had a really bad problem with the chronic arthritis. As you know that has been described for some time. So, it is again an organism that isn't necessarily in the lung. It may be elsewhere and some have CVID. Some have XLA but it is obviously a very big or bad problem potentially with the chronic arthritis seen in these patients.
Now, how much do we know about viruses? Actually not very much to be honest with you and I don't actually think about viruses very much when it comes down to antibody deficiency aside from those that I have touched on and the echovirus and XLA, but there is an interesting paper that the Webster group published last year in Clinical Experimental Immunology that sort of opens that thought again saying, "You haven;t resolved it," and what is the point of the slide is that 50 percent of the CVID patients in their peripheral blood had circulating CDA T cells that were positive for CMV and/or EBV and then specific gamma interferon cytokine producing cells were also found in good number in the CVID patients as well.
So, it seems too say that perhaps they are a little bit more challenged with these viruses than I have ever thought about very much. So, although we don't talk about viruses very much with antibody deficiency, at least I know I don't give it a lot of thought, I have to say that that door is not closed in my mind.
There may be more to say about that that we haven't been really looking for and the other one which I know that most of the people here would be aware is that Jack Rudis is also very interested in the role of HHV8. Does it have one? Does it not have one and what might it do to the lymphoid overgrowth and the granulomatous formations which occur and this is from his paper in JEM last year, or 2 years ago and it shows a lot of lana(?) positive cells in the lungs of CVID patients with granulomatous lymphoid interstitial infiltrates. I don't know how I feel about this. I have sent him two samples of blood of patients of mine with this sort of ailment. They have not been positive. I think we need to find that out. Is it true or not true and of course Jack is continuing to work on that, but it says that there are still things we don't know, that we put on the shelf and said, "We will think about that another day," but it could be that viruses are more of an issue than we know.
Okay, what do we know? Well, this was a study from Iran. It is a follow-up of 221 patient years and in this case it says that when you are diagnosed and then treated then the number and incidence of infections clearly diminishes. This is the number of patient years of follow-up down here in this lower part of the slide and what is the point of the slide is that pneumonia and diarrhea, sinusitis, otitis and everything else that is really the high rollers here of these infections here are definitely going to diminish after treatment is started. The number of follow-up years is in this case not very long but it gives you kind of a picture that what we see in the United States is actually very similar to what is seen elsewhere in an entirely different culture and an entirely different environment. It is the same organisms really and the same issues.
Taking 50 of our most recently referred patients, Paula Busse then did a study to say, "Well, does the gamma globulin really cut down the incidence of pneumonia?" and obviously it does. It is P .01 but as you can see we still have pneumonias left over. It has not completely gone away. I mean we have to conclude that a good number of those people have lung damage and so having pneumonia is one of those things that is an anatomic fact of life almost because the airway clearance is no longer entirely normal and these patients of course had been in the hospital at least once in many cases and some of them had so many episodes of pneumonia that they actually lost count and that could be more in this group.
Pneumonia is not eliminated by IVIG. It is one of the things that we might like to just contemplate for a moment.
So, I am just going to touch on one other thing which is the relevant antibody titers in patients receiving IVIG and so I took four patients who don't have any antibody of their own. I guess it is five and with a commercial laboratory simply sent their serum out at a trough level to say, "Okay, fine, how much antibody do you have to these organisms?"
To be honest with you I don't care that much what is in the bottle. I care what is in the patient. So, to me I think trough levels of the patients although I have never given them much thought before, it actually rounds out the discussion here according to me because if you have a patient who is colonized then it could be that you actually have higher titer than you think you do. So, I am rather interested in knowing what the patient ends up with who is on a steady dose, who is not ill, who has got no particular problems and these individuals don't, and I simply chose them because they had nothing to start with. So, everything you see was a result of the gamma globulin.
Now, I very arbitrarily drew this red line over here, 1 microgram per ml because that is what has been stipulated by many to be the so-called "protective level."
It is actually I think as far as I know either a microgram or 1.3 micrograms per ml that is often used as the cut off there for protection and for no colonization.
So, how does this stack up? Well, our RC down here didn't do very well, this particular one and some of the others actually have more as you can see.
Now, they are on different products and this is not very much data. I acknowledge it. Personally I think a study of this sort would be very useful to just gather a lot of data about what the patients end up actually having as their protective level. Some levels are higher than others and some are lower as you can see. I think that was the point.
The other thing, what about hemophilus because that is another organism that I am very interested in. This little red box is what has been stipulated by laboratories as being protective and the patients as you can see, these four patients here are much better than the so-called "protective levels."
This is again a microgram per ml. So, I have often been worried that they didn't have enough hemophilus antibody available in their blood but if you look at this data you would say, "Well, going by anything that we know however bad that is and however insecure we feel about assigning protective, on the other hand they fall above that level of what we have assigned as protective."
This is to viruses because we are going to talk a little bit about measles, mumps and rubella. So, called "protective is the pink box here. So, these are three patients that again have no antibody of their own whatsoever and as you can see it looks to me as if everybody is falling above that level with rubella being somewhat higher.
So, this is something that we want to fold into the discussion somewhere. I am not sure where we need to fold it in but I think that would be another way to look at what our patients have going for them.
So, infections with bacteria and certain viruses are really quite characteristic and they are not completely reduced, these infections by IVIG replacement. We still have infections. I won't say it is common but we certainly have them .
Levels of the antibody in blood are variable but so-called "protective levels" were found in the serum of patients with no antibody of their own but not in every case and that is my last slide.
(Applause.)
DR. BERGER: Mel Berger, Cleveland. Charlotte, I totally agree with you that the trough titers are really important in the patients receiving gamma globulin and there are some physicians, for example, Ralph Shapiro in Minnesota actually follows a lot of his patients that have lung disease with trough levels of antipneumococcal antibodies, not just the total IgG level and of course your patients may be on different doses also, right?
DR. CUNNINGHAM-RUNDLES: Is that a question?
DR. BERGER: Yes.
DR. CUNNINGHAM-RUNDLES: Oh, okay. They are pretty much all on 450 milligrams per kilogram. They are not on different doses but the products may be different but that is the kind of data that would be useful to gather and these were two on one product and two on another as I recall.
DR. BERGER: But this may be one reason why the studies, every study that has been done in patients with chronic lung disease where they compared 800 milligrams per kilogram or a quote, unquote high dose with a quote, unquote low dose, every study including the original British studies showed that the higher dose is more effective and particularly in those patients and so maybe instead of just taking an arbitrary trough level like our practice parameters specify 500, I don't really know what data that is based on other than the opinion of the panel who wrote that article but maybe we should be calibrating our doses and our dosing intervals by trough levels of pertinent pathogens for that patient.
DR. CUNNINGHAM-RUNDLES: I never thought it was much worth repeating those titers so often as I have seen some physicians who send me their massive charts because it is incredibly expensive but I think we need more data like that and we certainly need it for those who are not getting any better or not doing all that well.
DR. GOLDING: You mentioned that Mycoplasma which I think is very interesting and maybe we need to pay more attention to that, the patients who are on IGIV do you see an improvement or a decrease in Mycoplasma infection?
DR. CUNNINGHAM-RUNDLES: I have almost not seen Mycoplasma at all in the treated patients, I think with one exception over a very long period of time but A, my culture is not good. I am not going to tell you we are very good at it and I don't know if it is indolently progressing in the lung where I can't find it and can't culture it very well, but as far as objectively obviously present, no, not in those who were given good standard amounts of treatment with nice trough levels.
DR. GOLDING: May I just make one quick comment which is a little bit outside the scope of this meeting and that is it is interesting to me that you look at CD8 positive T cells and obviously in common variables some of these people have reasonable T cell function and I wonder if we shouldn't think about that in another context in terms of stimulating that type of immunity to protect those people against viral infections, Mycoplasma and other agents that are --
DR. CUNNINGHAM-RUNDLES: I think viral infections are still kind of the thing we haven't paid a lot of attention to because the bacterial has been so important but it could be the virus is really kind of the underbelly that we don't think about a lot. So, I can't close the door on it.
DR. BALLOW: Mark Ballow, Buffalo. Charlotte, you were talking about total IgG levels with regard to pneumococcal antibody titers. Do you have a feel for whether we should even be looking further than that perhaps at you know the different subclasses of the antibody against a particular pathogen? Might they function differently as far as protecting the host?
DR. CUNNINGHAM-RUNDLES: You know if we talk about pneumococcal titers at any national meeting of any sort or function or subclasses it is a way to have a nice civil war because we don't actually know very much what is protective, what is not.
I mean yes, I think it would be great to know more about that but I know that people don't even really quite agree on the ground rules on that. Different individuals measure it differently. I like to measure 23 serotypes when I can. Some physicians get away with four. I know in Europe they do it entirely differently. They don't do it our way at all. I think it is something that somehow we need to settle but most importantly I think we need to sort of stick to what we are going to look for in the patients and in the bottle and then compare.
It could be that if you are colonized, too, that you are actually just absorbing out. So, RC up there on that slide, we had a couple of admissions to the hospital in the past year which I don't expect for the CVID patient who is well treated. I suspect that she has actually got a very high utilization rate and actually we haven't talked about that part of things yet.
You know, is she using up the antibodies that I am so merrily infusing?
DR. STIEHM: I would like to reiterate that last point. I wonder if the patient is colonized with say, type 4, will that titer to that particular pneumococcus be diminished and that is really very relevant to recurrent infection.
DR. CUNNINGHAM-RUNDLES: Especially since according to me and I think Dorothy Scott's paper which she is going to talk about later type 4 actually was in the minority as far as the number of serotypes that were actually in the mix and for me, too, there is not that much type 4 present.
So, it could be if you are colonized with that that sinks you below the relative level.
DR. OCHS: One of the issues that we have to face is not only how much gamma globulin a patient gets per month but how often this is being given and if you ask patients who do self-infusion IVIG, they come and say, "I feel best if I do it every 2 weeks." They probably would feel better if they did it every week, and that gives you a much better base and trough level in antibodies that are not so highly present in IVIG and if you give it subcutaneous these patients seem to do much better because I give it once a week and some of them actually inject it once a day and so if we want to think about the best optimal treatment for these patients apart from what the differences in antibody titers are from one brand to the next or from one batch to the next it is how often they give it and so that is very important to consider when we do these studies, how much do they get; how often do they get it infused and what is actually the titer in the preparation and that makes it very, very difficult to follow these patients with specific markers and so we have to come up with some surrogate markers which Dick has set and which ones are we selecting and what patients do we select for these studies and how often do they get the gamma globulin infused.
DR. CUNNINGHAM-RUNDLES: I mean it could be that we need to get data on patients who were given subcutaneous treatment. I have actually, maybe it exists; maybe I just didn't see it. I would like to see antibody titers in the patients who get subcutaneous treatment because actually I am not terribly interested in what is going in. I mean yes, we have to know that it has got good stuff but you actually want to know what you end up with at your trough point.
PARTICIPANT: During that clinical trial from CLB Berring(?) they collected the data but I don't think they actually measured but they have the serum available. So, they could measure anything in these patients.
DR. CUNNINGHAM-RUNDLES: I think the data is out there. It is just that we as a group have not collected that and visualized that ourselves perhaps.
PARTICIPANT: It is expensive to do but it is also very important data to figure it out.
DR. CUNNINGHAM-RUNDLES: No doubt about it and I think something like measles or mumps which is not a ubiquitous antigen or hepatitis B or something like that you know would have to be compared to something which is quite ubiquitous with the patients such as the pneumococcal or perhaps hemophilus.
DR. BLAESE: Thanks very much, Charlotte. Our next speaker is Dr. Rebecca Buckley from Duke University. Charlotte gave us the perspective from the department of internal medicine and now we are going to get a perspective from the department of pediatrics.
DR. BUCKLEY: Thank you very much. The subject that Charlotte and I were given to speak is not an easy one to address and I think that I will just start off with my part of the presentation here talking about sort of the spectrum of what we are dealing with.
As you heard earlier from Dr. Scott until Ogden Bruden described gammaglobulinemia in 1951, we didn't know about any of these diseases and now there are at least 150 different immunodeficiency syndromes that have been described and we know the molecular basis of about three-quarters of these defects but the sad part about it is that these are usually recognized only when the person develops an infection or in the case of the common variables when they develop autoimmune disease but even when they develop an infection they still don't get recognized and the consequence of this is that you can end up with bronchiectasis which probably accounts for why people who have common variables who are on IVIG still get pneumonia because they have bronchiectasis or they have pansinusitis and so the cost of late diagnosis is really very high, and this is a slide I always show to the residents when I am rounding with them. I don't know why there are dollar signs here but I think it was a different PowerPoint program,but I think the most convenient thing about this slide is to think about these defects as to whether they are B cell defects, T cell defects, phagocytic cell defects or complement deficiencies and for the purpose of our discussion here today and tomorrow the patients who had B cell and T cell defects are the ones who are going to need the intravenous immunoglobulin.
Now, the other point to bring out is that while these patients all have increased susceptibility to infection the other thing to remember is that we live in an antibiotic era and so because the data that Charlotte presented from Jerry Wickelstein's survey showed that many of the infectious agents were not identified this is because rarely are cultures done and many patients just automatically get an antibiotic. Many of these infections re probably viral infections but nevertheless the textbook picture presentation of primary immune deficiency is usually masked by the frequent use of antibiotics and the other point from this slide is that these patients appear outwardly normal. They don't look any different from anybody else and so if they have an ordinary infection and I will show you a slide later that they usually do have ordinary infections then somebody has got to have a high index of suspicion in order to make these diagnoses and so again the characteristic infection that you see in the different types here for B cell defects, the ones you have already heard about, pneumococcus, staph, H. flu, strep and Mycoplasma, enteroviral encephalitic, Giardia is another problem but dominantly the infections are respiratory in these patients.
Now, patients who have T cell defects who by definition also have B cell defects because we know T cell function you can't have normal B cell function, but they also in addition to having these will have problems with herpes family viruses and they will also have problems with candida, pneumocystis and then the infections will be severe and persistent.
There are many other serious infections that occur in patients with immunodeficiency, granulocytic defects, monocytic defects or complement and there are characteristic organisms that you see in each of these types of infection, but discussing the problem of enteroviral meningoencephalitis I agree with Dick Stiehm that we rarely see this anymore but just last fall we had a new patient who presented with what was called aseptic meningitis, underwent an extensive infectious disease work up with many antibody titers to many different agents and then finally someone a month later thought of agammaglobulinemia and this child had almost no immunoglobulin. He persistently had elevated cells in his central nervous system and fevers every day and despite PCRs for every know virus he still has a persistent meningoencephalitis. So, I am sure there are other viruses out there that can cause this syndrome.
Echovirus 11 is the one that has most commonly done this. We found polio in some of the CNS samples from our patients who had this and if there is a delay in diagnosis then these people are much more likely to get this and it can occur also in CVID patients and the series that Ross McKenney developed from Duke there were four or five patients with common variables who also had echovirus meningoencephalitis.
The other organisms to consider in pneumococcal infections are most B and T cell defects but now we know you can have that in many different of these genetic types of immune deficiency.
You can certainly see it in most B and T cell defects. You can see it in T2 deficiency. You can see it in congenital asplenia. You can see it in a condition called NEMO, ectodermal dysplasia with immunodeficiency and then in IRAK4 deficiency. So, pneumococcal infection is something that occurs frequently in many different types of primary immune deficiency diseases and conceivably could all be helped by intravenous immunoglobulin.
Mycobacteria and salmonella would be suggestive more of a defect and monocyte macrophage immunity and this was a suggested defect in one of the either interferon gamma receptors or IL-12 or IL-12 receptor defect or STAT-1 deficiency and then Cryptosporidium is a real problem in X-linked hyper IgM and Pneumocystis jeroveci and also in many other types of T cell defects.
So, there are a lot of changing concepts. It was thought that a patient with chronic granulomatous disease which is a neutrophil defect would have problems primarily with staph and Serratia, but we now know that the leading cause of death in this condition really is fungal infection with aspergillus leading the list but there are now other types of fungal infections that have caused demise in these patients including Trichosporon pullulans and Penicillium.
So, what are the new threats for primary immune deficiency? West Nile virus, I think this is something that we need to talk about but as far as we know the patients who have died from West Nile infection have not really been investigated fully to find out whether or not they may have had some underlying host defect.
Also, we don't know much about titers of antibodies to West Nile virus and the various preparations of intravenous immunoglobulin.
A new threat would be as someone mentioned earlier bioterrorism with smallpox or with anthrax and then in my view a new threat to primary immune deficiency is this new live Rotavirus vaccine, Rototeq which is now being mandated as part of the routine immunizations of all babies at 2 months, 4 months and 6 months and contains five different strains of live Rotovirus agent in the vaccine.
Then another threat to our patient population is community-acquired infections such as MRSA, VRE and legionnaires' disease.
So, how many patients are there out there with these diseases? We really don't know because there is no screening for these defects and if you use live vaccines early in life such as BCG in third world countries or during infancy in the United States such as Rototeq or Varivax then this will make death almost certain for those who have genetic defects in T cell function.
I have already mentioned the problem with widespread overuse of antibiotics masking the presentation of these patients.
There was a survey done by the Immune Deficiency Foundation that showed that the average time from the first infection to diagnosis was 9.2 years and just to bring home the point again the most common infections that these patients have really are the ones that are most common for everybody, in other words sinusitis, pneumonia, ear infections, diarrhea and bronchitis.
This was a survey of patients who belong to the Immune Deficiency Foundation and they were asked, "What types of infections do you have?"
So, they don't always have strange infections. They often had very common infections. It is just that they have more of them.
So, since there is no screening for any of these defects this is a major problem in third world countries where all infants are immunized with live BCG vaccine on day 1 of life and these infants will die if they don't have normal T cell function.
So, there are screening methods that are available and could easily be implemented if screening for these defects were accepted as a standard of care but the main obstacle to this is to overcome the general impression that these defects are so rare that the screening would not be cost effective.
Recently the Immune Deficiency Foundation conducted another survey. This was a random telephone call to 10,000 households in the United States and it was learned from that that within those households there were approximately 250,000 persons. The percentage gleaned from that survey would suggest that there are at least 250,000 persons or 1 in 1200 people in the US who are afflicted by these defects and that these are much more common than diseases that people currently screen for.
However, we really won't ever know what the incidence or prevalence will be until there is population screening. So, the cost is a big question and to address this issue half of all persons with primary immune deficiency are not diagnosed until they are adolescents or older.
So, the cost of a late diagnosis is a heavy burden of disease on the patient and causes early demise. The majority of patients report two or more hospitalizations before diagnosis. So, the cost of hospitalization of these patients far exceeds what it would cost to screen for the defect and to implement the therapeutic for preventive measures and this is a pie chart showing from one of the Immune Deficiency Foundation surveys which shows that a majority of patients who are later diagnosed with primary immune deficiency had been hospitalized at least two times and 21 percent of them had been hospitalized five or more times before someone thought of this diagnosis.
So, getting back to the types of infections that you think of in patients with primary immune deficiency I wanted to talk just a little bit about the patients I care for most of the time, and these are patients with severe combined immune deficiency.
At our institution we have transplanted now 158 babies with SCID over the last 25 years and we have been able to fortunately transplant 45 of these patients in the first 3-1/2 months of life, and you can see from this Kaplan Meier plot we have only lost two babies and one of these was from EBV and the other from CMV.
The other 113 patients that we transplanted which the transplants occurred after the first 3-1/2 months of life you can see the mortality is much higher.
Most of these deaths occurred in the first 5 years after transplant. We have had one late death which was in an ADA deficient SCID but the cause of these deaths you can see on this slide right here and so the big offenders for infants who have T cell defect really are viruses, CMV, adenovirus, EBV, enterovirus, rotavirus, parainfluenza 3, varicella. We have had three patients present to us who had chickenpox from the Varivax vaccine and then herpes simplex and RSV are other offenders.
So, one of the things that we have been very much interested in and lobbying for screening for these defects is would it be cost effective and so we went back and looked at data on 74 of our transplants that could be provided to us by the administrators at Duke and we found that if you could do a transplant in the first 3-1/2 months of life that the mean cost overall is around $100,000 including the clinic visit, the rental apartment, the car to come to the hospital and so on whereas if you look at the babies who were transplanted after 3-1/2 months the mean cost was around $450,000 but we had several that were million dollar or 2 million dollar babies and the main cause for this really is infection.
So, despite treating these patients with high doses of intravenous immunoglobin all the antibiotics that were available we still had a very high mortality from viruses in this patient population and the cost of just containment of infection really is the major cost.
So, one other point I wanted to make in closing is that we have developed some guidelines. The Medical Advisory Committee for the Immune Deficiency Foundation has developed some guidelines which are posted on the IDF web site and these guidelines are written so that patients themselves as well as their physicians can refer to these guidelines about how to suspect these conditions and how to test for them and the reason we did this is that there is really no stronger advocate for the patient than the patient and his or her family and often the patient can call the attention of these testers to their primary care physician and that way an earlier diagnosis can be made.
I will stop there.
Thank you.
(Applause.)
DR.GOODMAN: You mentioned rotavirus which I found interesting. I was wondering whether you have seen or others in your experience with either PIDD or SCID problems with natural rotavirus infections?
DR. BUCKLEY: Oh, yes.
DR. GOODMAN: And then I was also just going to mention that of course the vaccine viruses are much attenuated and children are going to be naturally exposed to more virulent viruses.
DR. BUCKLEY: We have seen many, many problems with rotavirus among the patients we have cared for who were in the group the past 3-1/2 months where they came in and they had to be inpatients and then we had epidemics of rotavirus infection on the floor and so it was transmitted from room to room. They usually don't get rid of it until they develop T cell function.
So, even though as you say these are attenuated strains they may still have problems and for them they may be just as pathogenic as the other non-attenuated strains are for normal people.
DR. GOODMAN: So for the SCID question what about in antibody deficiency?
DR. BUCKLEY: In antibody deficiency we have not really seen that much of a problem. It has been more Giardia causing diarrhea there.
Agenda Item: PIDD registries and surveillance for infections in patients treated with Immune Globulins
DR. BLAESE: We are going to go out of order. I thought I would make a presentation, the next one and tell you something about this United States Immunodeficiency Research Consortium or USIDNET.
This was a 5-year contract that was awarded by NIAID to develop consortium investigators working to promote the field of primary immune deficiency and there are four programs within this USIDNET operation.
One is to provide research support to help the development of young investigators and so far we are 3-1/2 years into this program. We have given $7.1 million in grant support to 28 different investigators and more than half of those investigators this was the first NIH funding that they had received.
So, part of our mandate is to try to bring in new people into this field because as you can see a number of us are getting fairly old and will be leaving the field fairly shortly and we want to have a sufficient number of people that are expert in the field to carry on.
There is another major part of this which is an education and mentoring component and there are a number of different areas for instance an immunodeficiency summer school for senior fellows, junior faculty from around primarily the Western Hemisphere. There is a visiting scholar program where we can give travel awards to medical students or fellows to go visit another institution if they don't happen to have a program in primary immunodeficiency at their own or if they want to learn a particular technique that is not available at their institution.
There is a cell and DNA repository of primary immune deficiency patient samples that is available on our web site and through Coriel(?).
There are now about 50 samples in that repository of different primary immune deficiency diseases. Sometimes there are many, many samples like ataxia telangiectasia or ADA deficiency and in some cases there are IgG subclass deficiencies and hyper-IgM and Wiskott-Aldrich and XLA. So, if people are interested in studying these disorders because they are rare and if you don't happen to take care of patients you may not have access to these materials and so the USIDNET set up this repository and finally one of the charges of USIDNET was to modernize and expand the existing immunodeficiency patient registry.
Now, the original registry was a chronic granulomatous disease registry that was established again under an NIAID contract with the Immune Deficiency Foundation and that has been going now for about 12 or 14 years. There are 396 patients with CGD in the registry and there have been a number of publications that have come out of that original patient registry.
About 10 years ago NIAID decided to expand the number of registries, the number of patients to eight different groups, a common variable. It now has 362 in the original registry patients and as Dr. Cunningham-Rundles explained we have collected at least another 100 to the new registry and all of these old patients will be converted to the electronic format along with the incorporation of newer patients.
You see we have patients with DiGeorge, with hyper-IgM, with SCID, Wiskott-Aldrich, X-linked agammaglobulinemia. There was also a registry for leukocyte adhesion defect but we have been not able to accumulate andy patients so far with that particular disorder.
In expanding the registry the steering committee decided to work with the European Society for Immune Deficiency. It has already developed an Internet based data entry and review process so that we could have a more standardized way of data entry and a more efficient collection of patient follow-up data.
Most of that initial IDF registry was a static one-time enrollment and there wasn't a mechanism for getting continuous follow-up and updates on the patient's status whereas this new one that is electronic that is web based we will be sending out e-mails to the enrolling physicians on a periodic basis perhaps every 6 months asking them to update the data on a particular patient and at that time ne of the areas that we have asked this audience to consider is what kinds of questions should we be using the power of these registries to help answer as it relates to for instance the use of immunoglobulin and I think we have heard a number of situations where we simply don't know what the appropriate answer is and if we can design a good survey document to help answer those specific questions.
If you visit our web site at www.usidnet.org you can get instructions about how to become a registered user, how to obtain a password and a user name.
We have already sent the protocol off to the Western IRB and gotten approvals along with approvals of informed consent documents.
Some of you will be able to use those Western IRB documents but others at least can use these documents to help establish your own IRB documents.
There is informed consent in both English and Spanish and a tutorial on how to use the registry and we have just recently hired a full-time manager for the registry. It is Beth Garrett who can be contacted at the IDF and you have got her e-mail address there and Beth has been brought on for a number of things, not only to manage the registry but actually to go out to various centers and actually help enroll patients.
One of the things that we learned with the initial registration process in that first registry was that more than half of the patients were submitted by docs who took care of less than five patients with primary immune deficiency which is telling us that the major centers were not participating in proportion to the number of patients that they saw and partly we have learned it is that it was just a burden. There was no one available to do it, and some of the institutions felt that they had enough patients for their own studies. They didn't really to participate in a larger registry.
So, we have been encouraged to develop a way for having an individual go out to the different centers and actually help and Beth will help give the materials to work on getting an institutional review process for everybody that needs to get IRB approval to have registration and as I have said will be willing to come out to institutions.
So, I would encourage people to take advantage of this. Now, our registry has a demo version that will show you exactly what it looks like and it is available at this Internet address with a fairly simple user name and password and I would encourage people to take a look at that. We would like feedback from anybody who might be interested in looking at this to help design it to make it the most effective data collection system available.
What could we use the registry for, and there are a number of issues that we are trying to design it somewhat differently from the previous registries and one is as a surveillance tool and this is just one example. For instance, what is the actual experience in different primary immune deficiency diseases with live agent vaccine?
As you know almost every new live agent that comes out it is recommended that you don't use these in patients with primary immune deficiency and yet from what Dr. Buckley showed you the mean time from onset of infections until diagnosis is 9.1 years for many of these disorders and by that time a huge number of these patients actually have acquired and received live agent vaccine.
So, what we need to discover is what is the appropriate denominator and this is one way of developing that data. So, we can actually figure out for which diseases are these agents a potential threat and for which ones might they be beneficial.
So, this is just a listing of them. This is a very simple one. Was the vaccine given, yes or no? Where there complications from it and if there were complications please describe.
Another way is to try to answer other kinds of questions across a broad range of disorders. This is another question that is being looked at. A number of patients get treated with immunosuppressive agents. They get autoimmune phenomenon. Wiskott-Aldrich is an example that I use all the time. The major problem with Wiskott-Aldrich besides their infections is that they have a severe auto-aggressive disease that ultimately forces us to use immunosuppressive drugs which then gets you into the terrible cycle of immunosuppressive drugs, getting more infections and how do you get them off things like steroids and so we are trying to just get a feeling for which diseases whether it is CVID or Wiskott or others are getting immunosuppressive drug treatment,what do they get and did it cause problems or not, data that we know from just the experience of a number of investigators that they see these problems. We don't have a quantitative number to really nail it down, and finally you can collect very specific data. One of the features of this USIDNET registry is that we are going to be using pull-down menus that give you a whole bunch of choices. For instance if you click on the infections button you will a lot of different abscesses whether it a brain abscess, a colon abscess, a liver abscess that you can check off and we have asked people to grade them. Is it something that was present at the diagnosis? That is one of the things that helped you decide whether the patient had a problem. Was it just observed occasionally in these patients or was it a prominent feature of that particular patient and also addressing in this case the organisms that are involved and we hope we can develop the kinds of data that might be useful for the questions that are being raised by this workshop.
Will the registry be successful? You know, after 10 or 12 years we had about 1400 patients enrolled in the initial registry and we had a lot of push back as I mentioned from the major institutions that didn't get involved. So, we have a balancing act to do between making the registry easy enough to use and yet comprehensive enough to collect useful data and we are just going to have to see how this works out but a number of the questions how do you actually incentivize a physician to participate? Dr. Grimbacher will tell you about the European experience where they have provided a bounty for each patient that was enrolled of I think 10 euros to encourage individuals to enroll their patients.
As I mentioned there is a balance between the quality and the quantity of the data requested and what level of tolerance the submitting physician may have to answering lots of questions.
One of the ways we are going to be doing it in this country is to have the patients be able to initiate the registration process. If the patients get access to the database, can enroll, put in their own information and then e-mail it to their doc and say, "Finish this," that may be enough of an incentive to get more patients enrolled so we can increase the number of patients in the registry and as I mentioned USIDNET will provide assistance and this database has a capacity for periodically requesting follow ups.
So, with that I would like to introduce Dr. Grimbacher from London. Bodo was involved with the European Society for Immune Deficiency in the establishment of their original database and they have been online now for 2-1/2 years, nearly 3 years collecting data on more than 3000 patients.
DR. GRIMBACHER: Thank you very much for inviting me to this hearing and I am pleased that I am allowed to report on the European efforts to collect data on patients with primary immunodeficiency diseases and this is a project sponsored by PPTA and the European Commission and it started in 2002 when I took over the registry from Leonard Thomas in Stockholm and he had collected more than 10,000 patients sa you did with a one-time registration.
However, the data was not followed up. So, after 10 years we wouldn't know how many of those 10,000 patients would be still alive and how many have deceased and how they are doing on therapy. So, we decided in 2002 that we want to have a new registry, an online-based registry where follow-up data to the patients can be added and so we started out to develop this new online registry for primary immunodeficiency diseases and as you can see as of today we have 66 documenting centers who are agreeing to enter their data and however, only 42 have already started documentation and this is because we require three things to happen prior to documentation.
One is there has to be an agreement signed between the documenting center and ESID and this is basically that everybody knows to what rules we are playing or according to what rules we are playing and that is that the documenting centers know that they have to keep their password secure and things like that.
The second requirement is that all the documenting centers need ethical approval. So, they need to go to their local IRB committee and ask for approval to documenting into that European registry and this is because unfortunately also the European Union does not have a central ethics committee in place.
The third requirement is that every patient who is registered has to sign a written consent form or the parents. A legal representative has to sign such a form and before that we cannot register patients into this registry and so 66 centers want to do that. However, only two-thirds of them have already achieved those three requirements and are documenting patients into the registry and these red dots represent where those 66 centers are located and you can see that some of them are even outside of Europe and this is because those countries also want to participate in the clinical research we are doing, and I also have to explain that some of the countries have national registries. For instance, in France there is one big national registry located in Paris and since France is very centrally organized this national registry has obtained data from more than 1000 primary immunodeficiency patients from all centers across the country.
So, although you see here only one dot it is a representative dot for all the other documenting centers within that country.
There is a national registry in Spain for instance in Majorca. You can see that Maria Matamoras in Majorca collects all the patients in Spain meaning that you have only one dot doesn't necessarily mean that thee is only one documenting center per country.
We started the online registry in 2004, and it was kind of a slow start because of those regulatory issues and because all these documenting centers had to go through ethical approval and collect consent forms.
However, in the more recent month we have seen a huge increase in patients documented. So, this number of 3000 is from a couple of months ago and because just in recent months you know we added additional patients now amounting to 4142 patients in the registry.
I would like to use that slide, also, to mention some of the incentives. For instance at that time point here we decided to give the 10 documenting centers who get the first 50 patients in an additional incentive of 2000 euros. So, this steep increase here is because those centers then decided to enter the first 50 patients and have a student or a documenter sitting there and enter the patients just to get those 2000 euros.
So, yes, there is a financial incentive you can put to the documenting center because some of the centers can actually use actually extra money and for any documenting data set per year the documenting center obtains 10 euros per patient.
So, then it is also interesting to know out of those 4100 patients how frequently are they entered again and again and again. So, of course most of them and I apologize, I should have plotted that in absolute numbers. So, most of the patients have already entered once because most of the entries have only been in the last year. However, you see that a fair amount, one-fifth of the patients have already been entered twice some of them three times. So, three times over the last 3 years and you also see that some of the centers actually chose to document the patients more frequently than only once a year, and what is very interesting here that we have 3 percent. That amounts to approximately 120 patients who have been entered already more than 10 times in the last 4 years and this means that those centers are documenting these patients probably every single time they are coming to their clinic and that generates very important data because this is very close maybe every 3 months documentation of the patients enabling you to look at very dense data and very deep data.
These are the current statistics. Of course, most of the patients suffer of predominantly antibody deficiency disorders, 60 percent of the patients do so and others have well-defined immunodeficiencies like Wiskott-Aldrich syndrome belongs to those 17 percent of the patients. Fourteen percent suffer a phagocytic disorder, neutropenia for instance being one PIDD diagnosis and 6 percent suffer severe T cell disorders, for instance PIDD. Two percent have unclassified immunodeficiencies. There is only 1 percent of complement deficiency so far into the registry.
I think this is mainly because the centers documenting the complement deficiency have not yet embarked to enter the patients and there are some patients with autoinflammatory syndrome and immunedysregulation syndromes in there as well.
These are the different diagnoses. As expected CVID with more than 1000 patients in the registry is the most prevalent. The second most prevalent is XLA due to mutations in BTK, more than 300 patients, IgG subclass deficiency more than 300 patients, selective IgA deficiency more than 250 patients and I have plotted in red the diagnosis where we do use IgE replacement to treat the patients and I have plotted in blue where some of the centers would use the IgE replacement and some of them would not.
So, you see here that a huge amount of patients in the register do receive immunoglobulin treatment. So, this is a clinical online database system accessible by standard Internet browser and the database is hosted in Freiburg in Germany where I worked for the last 6 years before going to London. It is online since August 2004. You can at the documenting center opt to have the pseudonormalized version so work with a number as an alias for the patient but since last year the personalized version that the documenting physician can work with the patient's name on the screen has also been accepted by regulational ethical authorities. So, you can opt whether you want to work with patient names or whether you want to work with patient identifiers.
It covers all 206 primary immunodeficiency diseases as set forth in the IUS table of primary immunodeficiency diseases and in all of those conditions we document a common core data set of 22 data fields.
In addition to this common core data set we offer a disease specific extended one for 29 of the diseases and I am going to show you which those are in the next slide.
We have a continued documentation of patients to obtain follow-up data and we can document the mutation and this mutation documented in the patient is then linked to public mutation databases which then can be accessible by researchers from all over the world and we also have some goodies for the documenting centers like percentile curves. So, the pediatricians actually can see how their patients do and get something out of the registry. So, it is not only feeding into the registry. The documents centers can actually also use this registry and print out reports, send those reports to the referring physicians and monitor the quality of their treatment in the registry.
We have implemented questionnaires for quality of life monitoring. The first one going in there was the SF36 for adults and there will be also questionnaires for the quality of life for children and we have predefined queries. So, as a documenting center you can always compare the patients you have entered to the other patients which are in the registry and as I mentioned this is sponsored by five PPTA member companies and the European Commission.
This is a screen shot of how the database actually looked like. As I indicated we have a core data set which are the red fields. So, the red fields the core data set represents the characteristic data we feel are necessary to capture primary immunodeficiency disease.
However, this also contains some preliminary data on quality of life and for instance how many days have you been sick or have you been in hospital in the last year and this would be entered into the core data set field and then we have in addition as you can see here for the CVID subregistry a big subregistry to capture additional data sets.
So, this is more than 350 additional data fields, more similar to an electronic patient chart. So, you can enter all types of information into that subregistry.
So, disease specific data sets where you can do a very in-depth study on the patient are available for CVID, for agammaglobulinemia, for selective IgA deficiency, for IgG subclass deficiency, for ataxia telangiectasia and for several other immunodeficiencies which are less prevalent and those types of subregistries are needed to address specific clinical and research questions. Those you would not be able to answer with the common data set of 22 data fields.
This is only to describe the epidemiology of primary immunodeficiency diseases in general but if you want to do disease-specific study you need to develop a subregistry for those diseases as USIDNET has done for eight of the conditions.
This is another screen shot of the registry, what we capture for therapy and adverse events. You can see here the data fields we are capturing and the question mark here always defines what the registry wants to have documented in the field. So, there is always definition of the data field. We have drop-down menus as the USIDNET registry and some of the drop-down menus can be edited because we cannot a priori think of all the systems being involved in primary immunodeficiency diseases.
So, if you are on that system you want to enter here. It is not in the drop-down list. You can add that to the drop-down list and by that expand the drop-down list which then can be selected from all the other documents.
We also have free text and we also have different colors of fields. For instance you see a red color for the core data set, a black color and you also see the blue color and the blue color would indicate that there is a current study going on in that specific disease.
So, the red fields are mandatory anyhow for all of the patients and the blue fields are in that case mandatory for the CVID substudy going on right now.
So, we looked prior to coming here, we looked a little bit into the immunoglobulin therapy which has been entered into the database and the total number of patients immunoglobulin replacement therapy out of those 4100 patients is 1741. All of them receive immunoglobulin replacement, most of them through the intravenous route. However, almost 20 percent already by subcutaneous measures. In 50 percent we don't know what the route of administration is because it has not been documented.
I was surprised to learn that we still have four patients in Europe which have at least in Germany and the UK considered obsolete intramuscular applications and there are six brave patients in Sweden actually which drink your product and I have contacted them and this is because the treating physicians think that by drinking the immunoglobulin product they can get rid of the diarrhea and I would be surprised to learn then what the outcome of this is in future documentation to the registry.
We looked into the infections. We have infections with immunoglobulin replacement and on patients with the same diagnosis without immunoglobulin replacement. So, you se that the immunoglobulin replacement, excuse me, just the other way around. This is without immunoglobulin replacement, the numbers of infections and with immunoglobulin replacement.
So, you see that the immunoglobulin replacement leads to a reduction of the overall numbers of infections in patients with antibody deficiency syndromes.
You also can see and this is similar data which has been already presented here that it leads to a drastic decrease in the numbers of pneumonias. However, the decrease in sinusitis is not that steep and the decrease in bronchitis is quite considerable and this is actually also supported by a paper coming out now from the Rome group. Isabella Quinti, et al will publish in a clinical immunology journal. I don't quite remember which one it is, but the paper is in press and I want to point out that you look out for that publication because she looked in more than 250 CVID patients from Italy and what are the effects of immunoglobulin treatment and she in addition to what has already been presented by Charlotte found that immunoglobulin replacement on the IV route decreases the severeness of the infection. So, it is very potent in treating otitis, in treating pneumonia, in treating sepsis.
However, the incidence of the chronic infections, chronic sinusitis and the chronic deterioration of the mucosal membranes is not very well affected by the treatment and I have to add to what has been said already this morning that that is probably because we are giving IgG and not IgA. So, if we treat all those bacteria which have been mentioned this morning we still need to consider that there is still the IgA component. The body will need to defend itself from those bacteria.
Another analysis and we did, and I have to apologize, we didn't redo it; so this is from 2006 data and so less patients. We looked at patients without hemoglobin replacement, with CVID and patients on immunoglobulin replacement with CVID how frequently they missed days at school or work and you can see here that this is pretty much a well-defined effect of immunoglobulin replacement leading to better performance and quality of life and this has socioeconomic impact as well.
The database and the results of the database have already been published and this is also in your printout so that you don't have to scribble it down. It has been published in Clinical and Experimental Immunology this year and this is the first clinical result of the database and the bioinformatics publication which is the publication on the platform and the IT behind that.
So, in summary in Europe we have an online database suitable to answer clinical and research questions. It has run stably since August 2004. It contains data of more than 4100 patients. It covers all the PID which are known with a common core data set. It has 29 disease-specific extended registries for studies and it offers a continued follow-up of the documentation on single patients. It is ready to address clinical studies including post-licensing surveillance.
So, anybody who comes forward with the data set, they want to capture we can put this data set as a green data set or as a pink or purple data set into the relevant subregistry to capture that data and it can be easily adapted to other diseases because it is meant in XML programming and so this is why it was possible to adapt the ESID registry into the USIDNET registry and accommodating those uses but it can also be used for, this platform can also be used for other diseases. In Freiburg we have a registry for rheumatic diseases and for nephrology diseases and for HIV.
So, this is the contact and I want to finish with thanking the sponsors of this project listed on the bottom of the slide.
Thank you very much.
(Applause.)
DR. GRIMBACHER: Are there any questions?
PARTICIPANT: Yes, thank you, Dr. Grimbacher. Could you clarify your last point? Were you saying that the ESID registry can now integrate data directly from the USIDNET or is there a system in place to merge the two data sources?
DR. GRIMBACHER: From the old USIDNET registry into the new one or between the ESID registry and the USIDNET registry?
PARTICIPANT: Between the two including the new USID electronically?
DR. GRIMBACHER: Yes, so, since the two of us developed the USIDNET registry together we paid a lot of attention to make this the new USIDNET registry as close to the ESID registry as possible.
However, there were many requests by, specific requests by US researchers and documenting centers to add additional fields.
So, yes, the core will be analyzed together but in addition what we analyze in Europe you will have additional data fields specific for the US.
DR. HOLMBERG: Jerry Holmberg. As far as adding the data sets that a researcher may want to incorporate is there a charge for that? Is there a governing board to determine whether these data sets are appropriate? How does that function?
DR. GRIMBACHER: For the ESID registry when an ESID researcher comes and wants to add additional fields that is all covered in the project. Since it is XML programming you can add and delete and change fields really quickly and it doesn't cost a lot and you can just update the registry. So, that is very quick and fast to do and it doesn't cost anything for the ESID researcher. How it will be for the USIDNET registry I am not so sure but --
DR. BLAESE: There is a steering committee for the USIDNET registry and all applications for that kind of a modification or additions to the registry would go through the steering committee and if they believe that it is a scientifically valid thing to do I am sure that they would approve it.
It, also, will depend a little bit on our experience about compliance with actually doing it and we have to keep in consideration it may be just a subgroup of for instance individuals that might be participating and a specific research project could be built in with a certain number of investigators.
DR. HOLMBERG: And how will this affect the IRB approval process if you are adding new data sets?
DR. BLAESE: Every participating physician basically must go to their local IRB and if you are going to add additional questions that is a good point about if it goes to everybody I suspect that everyone would have to potentially modify but we haven't addressed that with instance the western.
DR. GRIMBACHER: How it works in Europe is that the IRBs request an update of what has been changed and then they will come forth and tell us if they are happy or not happy with it.
So, every time we change the data set we will have to submit it to the respective IRBs and by mailing and then they would tell us whether they think