Tuesday, May 24, 2011

4 The FDA Vault: Dr. Vijay Sikand On Lyme Disease & Lymerix

You know how I've said you can never guess what you're going to come across when you surf the net looking for other things?

Well, I came across this FDA transcript for a discussion on the Lymerix vaccine back in 1998. The original transcript contains an endorsement for the vaccine from the founder of Lyme Disease Foundation (LDF, not to be confused with the ADLF), who later determined the vaccine needed to be pulled from the shelves based on adverse reaction reports.

I'm setting aside any discussion of the Lymerix vaccine for now and just posting this statement from Dr. Vijay Sikand, an MD who practiced in Lyme, Connecticut... (items of interest are in bold)

UNITED STATES OF AMERICA 

DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
VACCINES AND RELATED BIOLOGICAL PRODUCTS ADVISORY COMMITTEE MEETING
Tuesday, May 26, 1998 

  
The meeting took place in Versailles Rooms I and II, Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland at 9:00 a.m., Patricia L. Ferrieri, M.D., Chair, presiding.  


VIJAY SIKAND, M.D., Sponsor Rep
:

"...As I was just saying, I included research in Lyme disease as part of a primary care practice for a number of years. In early 1995, 1,200 volunteers came to my office to enroll in the SmithKline Beecham vaccine trial which we are discussing today. Almost three and a half years later now, greater than 92 percent of those patients are still providing me with clinical follow-up.
        
Why do we need a vaccine for Lyme disease? It has been almost a quarter century since Lyme disease was first described as an emerging infection in this country. During these years a number of factors, epidemiologic factors and clinical factors, have resulted in considerable morbidity in burgeoning numbers of patients.This burgeoning load of disease as well as the increasing number of patients thus set the stage for prevention of this disease with a vaccine.Today, I will present to you some of the factors in a brief synopsis illustrating the need for a vaccine for Lyme disease.The illustrations which I will present to you, some of them are from my private practice and some of them are from the vaccine study.

The first factor is an epidemiologic factor,and this has already been discussed by Dr. Schoen. And that is that there is indeed a progressive increase in incidence of Lyme disease. The second factor also epidemiologic is the relentless geographic spread of this disease. There are new endemic areas being created annually and the disease burden is indeed growing.
        
The ineffectiveness of preventive measures which we attempt to practice is another important factor. We have tried various chemical and other means. Why have preventive measures, which are indeed important, not been effective in preventing an increase in cases of Lyme disease?  And before I answer that question, let me underline the fact that I indeed believe it is important that we continue to practice preventive measures because of co-infection with other illnesses besides Lyme disease. 

One obvious reason is that it is very impractical to practice certain protective measures.  This individual in the Lyme, Connecticut area desires to do some outdoor work and does not want to be bitten by a tick. But the point is it is very difficult to ask children or anybody else for that matter to tuck pants into socks, et cetera, in the middle of July and August when the ticks are questing. We can certainly check our pets, but checking one's dog is indeed a Sisyphean task when the dog goes in and out of the house all day long. Probably the best protective measure, I think, in preventing Lyme disease is checking for ticks.  Unfortunately, kids will only allow you to do this up to a certain age. And of course one must be vigilant with oneself.

More specifically, I think one of the important reasons to consider when thinking about why protective measures are difficult to utilize and be effective in preventing this disease is simply the nature of the Ixodid tick bite itself. The bite of this tick when it is infected transmits not only saliva infected with Borrelia burgdorferi, but the saliva also contains certain anti-inflammatory substances which have an anesthetic effect.The end result of that is that tick bites in general are not noticed. In one study, over 80 percent of the patients who presented with definite Lyme disease did not remember a tick bite. It is therefore very hard to correlate the incidence of definite Lyme disease cases with preceding tick bites, and this is well known.

Furthermore, as has been eluded to earlier, the recurrence of disease in individuals is also well known. Unfortunately, in the majority of patients, the vast majority of patients, natural infection with Borrelia burgdorferi does not confer protective immunity. 

Difficulties in clinical diagnosis of this disease are also well known, and it is not my place today to give you an overview or detailed presentation of the clinical aspects of Lyme disease.However, a couple of issues that do spring up and which I would like to address are as follows. In particular, the specter of asymptomatic infection is something that troubles me a great deal and troubles a great number of my colleagues who need to treat Lyme disease. The obvious analogy with syphilis infection with Treponema pallidus is there to consider. It is well known that Borrelia burgdorferi indeed after asymptomatic infection can lurk or secrete itself in certain areas of the body, perhaps the central nervous system or perhaps the joint spaces, only to reappear months or maybe years later in the form of late stages of illness which are harder to diagnosis and treat.

In terms of the variability of Lyme disease, it is indeed a very variable infection, if not a very complex infection.  In its very simplest form, it is erythema migrans, well localized, which we can all recognize and which we can all easily treat and from which most patients can get better. However, erythema migrans is not a single beast. Certainly this is the one which we easily recognize and which I just referred to.Before I continue with further slides, let me point out that the erythema migrans lesions you are about to see are all biopsy lesions which were laboratory proven to be caused by Borrelia burgdorferi.

Sometimes erythema migrans can present as a pustular lesion as is this one in the popliteal fossa inviting the scalpel of a surgeon. Sometimes the lesions are vesicular in nature, inviting a diagnosis perhaps of herpes simplex infection.  Sometimes our round lesion is actually triangular. Sometimes it doesn't even look round or red at all and invites a diagnosis of an intertriginous fungal infection in the groin of this patient who was biopsied and proven to have Lyme disease. Sometimes the lesion is more plaque-like, inviting diagnosis of nummular eczema, psoriasis, or other similar lesions. Sometimes it is in unusual locations. Sometimes it is large like this one. Sometimes it is small with satellite areas. Sometimes it is multiple, appearing almost like urticaria or erythema multiform. Sometimes, as in this individual who was a placebo recipient in the Lyme 008 SmithKline Beecham trial, it presents with other manifestations of early dissemination. This individual came in mainly because he was concerned about his face and it felt kind of funny and it was weak on one side. When I asked him whether he had had any unusual rashes, he said oh do you mean this one, and he showed me his arm with that EM. This is simply to illustrate the infranuclar 7th nerve palsy with which he presented. This patient, by the way, had no history of a tick bite or any unusual antecedent illness which he could remember.

The next slide is the electrocardiographic tracing of a 37-year-old mom from Lyme, Connecticut, mother of three. Generally healthy and no medical problems. Early on the day that this electrocardiogram was taken, she went to her local health club and did her usual work-out, which went fine. However, when she came home that day, she noticed that she had some palpitations, a little shortness of breath, malaise, and things just didn't seem quite right, but she wasn't sure what. When her husband came home, she told him that maybe she had worked out a little bit too hard at the club. A few minutes later, he was reading the newspaper in an armchair and he heard a thump on the floor above. He ran up the stairs to find his wife unconscious briefly on the floor and called 911. On arrival at the emergency department, the patient presented with this tracing, which in retrospect was a superventricular tachycardia representing an escape rhythm

There was fortunately a very vigilant emergency physician who didn't understand quite why a 37-year-old healthy woman had completely passed out, and she had what was a relatively benign rhythm at that point. But he was wise and admitted her to the coronary care unit for further monitoring. Late that night and the early hours of the following morning, the CCU nurse noted that the patient had gone through progressive degrees of AV block culminating in complete atrial ventricular dissociation. A cardiologist was summoned. He inserted a temporary transvenous pacemaker. The patient was started on intravenous antibiotics for about a week in the hospital followed by a few more weeks as an outpatient.This patient also had no history of a tick bite.

Besides the difficulties in clinical diagnosis, we are all aware that quandaries in laboratory diagnosis are rife.We rely pretty much on serologic testing in the United States today to assist us in diagnosing Lyme disease. Unfortunately, serologic testing, as with other infectious diseases, provides only indirect evidence of infection. When we order a serologic test, it just tells us that the patient has been exposed to Borrelia burgdorferi and doesn't tell us whether the infection is active or whether it is a past infection. It is probably worth noting, since I have learned a lot, that we don't have the clinical luxury in private practice that we had in the SmithKline Beecham trial in which we had baseline sera on all the patients who enrolled so that when they presented with symptoms, we could draw acute and convalescent serologies so as to compare them with each other and with baseline to better understand what symptoms they are presenting with. But your average physician in the office just can't do this. A patient comes in with symptoms or signs of Lyme disease and you have to make a clinical diagnosis and it is not always easy and serology doesn't help. The fact that in particular the ELISA creates a great deal of false positive results is also problematic. 

In particular and commonly in infectious mononucleosis and other spirochetal disorders, even healthy people, juvenile rheumatoid arthritis and other autoimmune disease all can produce false positive results. Indeed, even with Western blotting recent reports have shown that infection with the agent of human granulocytic Ehrlichiosis can cause false positive Western immuno-blots.The false negatives that we deal with are generally caused by use of serology testing in patients who have early Lyme disease and in whom the serologic response with immunoglobulin M has not occurred to the extent to which it can be measured.

What do we have in the way of direct testing to try to see if the organism itself is actually there or evidence of it? Well, culture and PCR are what are out there right now.  However, these are unreliable and impractical. Culture and PCR are certainly not warranted for the diagnosis of erythema migrans. The polymerase chain reaction is indeed sensitive in joint fluid. However, the diagnosis of Lyme arthritis does not require PCR testing since serology is almost invariably positive at that stage. Clinical conditions such as complex neurological conditions when a test like sensitive PCR would be useful, unfortunately cannot be diagnosed that way because PCR and indeed culture are not sensitive for cerebrospinal fluid, nor are they sensitive for urine, blood, and other body tissues when later in the disease one might care to employ these techniques.

Finally, there are indeed many dilemmas in therapy. In particular, untreated or inadequately treated Lyme disease may lead to the chronic morbidity with which we are very familiar. Most commonly arthritis and the not common but complex neurological syndromes are what often result and which confront the primary care physician in the office diagnostically and therapeutically.These particular outcomes result in much more intensive, long-term expensive therapy, often in the form of long-term intravenous antibiotics. These are the patients who often are refractory to treatment. Indeed, these are the patients in whom symptoms seem to persist despite what we have given in terms of adequate antibiotic therapy by any known measure.

            In conclusion, we need a vaccine for Lyme disease because it is increasing in incidence and geographic spread.We need a vaccine for Lyme disease because there are problems in clinical diagnosis, its laboratory evaluation, and its treatment. We need a vaccine for Lyme disease because preventive measures are unfortunately ineffective. Lyme disease is indeed vaccine preventable. Availability of this vaccine would lead to a significant reduction in chronic sequelae and substantive morbidity.  Lyme vaccine is thus a critical new public health approach to the primary prevention of Lyme disease in the United States. Thank you very much."

Dr. Sikand and Dr. Steere were at the same meeting. It's obvious Sikand knew Lyme disease could lead to serious late stage Lyme disease and chronic persistent symptoms of infection. If it could be easily resolved with 2-3 weeks of antibiotics, would they have spent this much time, effort, and money on developing a vaccine and running clinical trials?

Everyone at this meeting - including Lyme disease patient advocates - wanted a vaccine. That it would lead to adverse events in some patients and be pulled from the market later was not what everyone thought at first - at first it was welcomed as a solution to preventing the worst of what Lyme disease could do to a person because it was hard to diagnose and treat.

1998. Thirteen years ago.

How much have things changed since then?

Why are we still looking at the same problems and issues?

4 comments:

  1. Progress has obviously been slow...too slow, but I have witnessed some progress in awareness in the past three years.

    For example, when I first started questioning whether I possibly had contracted Lyme's Disease, most people including my doctors believed LD was endemic only in the northeast even though I knew of a man disabled by Lyme in north central Minnesota.

    A year or so later people I talked to about Lyme still knew very little about the disease, but they more often knew it had spread to the Midwest.

    Another year passes and I notice people having conversations about Lyme's Disease. Most people even know someone who has been infected, and the talk is more about symptoms, treatments, or Plum Island even.

    Now, if my Lyme's diagnosis is mentioned, I frequently hear questions like: "Did you get treatment right away?", "Is your Lyme's early or late stage?", or "Where did you have to go to get treated?"

    In the last three years I have noticed public awareness of Lyme's Disease go from almost non-existent to fairly widespread. That is really quite encouraging when you consider it has happened without the aid of the mainstream medical establishment, or the mainstream media.

    ReplyDelete
  2. CO,

    Dr. Sikand's remarks reflect the reality that many people with tick-borne illnesses have come to discover through our own experiences, reading books and spending time on the internet.

    By reading "The Widening Circle", I'm learning even more about the early history of Lyme disease. It really is rather shocking how the shared enthusiasm and spirit of cooperation between patients and certain doctors in the 1970's has deteriorated so much since then. It's also disheartening to learn that many European doctors were "oh so close and yet so far away" when it came to putting together some key puzzle pieces in the last century.

    A multi-disciplinary and computer-assisted approach to solving medical mysteries is a model that needs to at least be considered in dealing with complex illnesses. With an evergrowing number of sick people, maybe the time has come for computer-assisted medicine -- not to be confused with the other CAM (i.e. complementary and alternative medicine).

    There are obviously major privacy and security issues involved in computer-assisted medicine -- so the integration of all medical data on a large scale may never be fully realized. Knowing that insurance companies -- even in Canada -- already have access to a central data bank (in Boston at one time) that contains records of most (if not all) hospitalizations in North America might surprise some people. Here's a link for anyone who wants to learn more:

    https://www.privacyrights.org/fs/fs8-med.htm

    C. The Medical Information Bureau (MIB) is a central database of medical information shared by insurance companies. Approximately 15 million Americans and Canadians are on file in the MIB's computers. About 600 insurance firms use the services of the MIB primarily to obtain information about life insurance and individual health insurance policy applicants.When you apply for life or health insurance as an individual, you are likely to be asked to provide information about your health. Sometimes you are required to be examined by a doctor and/or to have your blood and urine tested. If you have medical conditions that insurance companies consider significant, the insurance company will report that information to the MIB.The information contained in a typical MIB record is limited to codes for specific medical conditions and lifestyle choices. Examples include codes to indicate high blood pressure, asthma, diabetes, or depression. A code can signify participation in high-risk sports such as skydiving. A file would also include a code to indicate that the individual smokes cigarettes. The MIB uses 230 such codes. [more details available]

    In theory, the mandatory reporting of some illnesses could be done with a few keystrokes and clicks of a mouse in a doctor's office -- ending up with the CDC and WHO within seconds. On the other hand, I do understand the aversion to "Big Brother" having access to private and personal information. Insurance companies would be the first in line requesting access to any detailed information, and so might pharmaceutical companies for that matter.

    As you can probably tell, I haven't thought this out all that carefully.

    ReplyDelete
  3. Rita,

    Once I contracted Lyme disease, I began getting various diagnoses even though I found an LLMD because the family doctor I kept seeing for other issues (covered by insurance here in the US) would write them down and get me tested for various things. So at this point, any information an insurer can get hold of at this point is probably going to be held against me one way or another. Even if in the future they cannot legally deny insurance to anyone with preexisting conditions, I am certain that insurance premiums will go through the roof for me or I will have to buy in to a state health plan if that's an option by the time I need one. Either that or move to Canada.

    It's not a good situation.

    I think that in order to protect patient privacy in the case of mandatory reporting, it makes more sense to me for a clinic to have its own system - a local area network not connected to the internet that contains patient records doctors can access - and small terminals which are connected to the internet solely for the purpose of reporting anonymous data to a state or national health service. The fact that a specific patient's data has been reported could be marked on the local network without the remainder of their personal data being shared at large. I see this as one way to protect patients' privacy while sharing data for research and surveillance purposes.

    ReplyDelete
  4. CO,

    I can just imagine all the codes (many of them probably inaccurate in retrospect) that are now contained in my MIB file.

    No, it's not a good situation -- and especially when many people don't even realize that current and potential insurers have access to this type of information -- some of which may be inaccurate. Accurate or inaccurate, that information was never intended to help consumers. MIB was clearly set up to minimize risk on the part of insurers.

    You would be an asset to Canada, however moving here might not solve all your problems. There are currently so few medical professionals in Canada willing to treat patients with Lyme disease patients that they are virtually non-existent. On the other hand, naturopathic doctors in B.C. are now authorized to prescribe antibiotics, and NDs in other parts of Canada are likely to be granted that right as well in the coming years. Relying on NDs for healthcare can become very expensive -- especially since they don't have access to all of the diagnostics (covered by provincial health insurance plans) that medical doctors do. The cost of ND visits is usually only partially covered by private insurance -- and even then it's often limited to $20 a visit (depending on one's plan). That doesn't even begin to cover the initial consultation or subsequent visits. Aside from that, I'm still partial to consulting with medical professionals who have trained an additional 4 (and sometimes 8) years to become proficient in their field.

    If you moved to Canada, you would want insurance to cover the cost of prescription medications, as well as dental care, medical devices and some specialized blood tests. There's a good chance you would find wait times for medical services longer in Canada than in most parts of the U.S. The wait to see most specialists -- at least in Toronto -- is between 3 to 6 months. My wait time to see the orthopedic surgeon recommended by my ID specialist (and the one I would have chosen anyway based on his qualifications) is a year and a half. I cannot walk properly only partly due to the loss of cartilage and subsequent bone damage in one joint of my left foot, so that does seems like a rather long wait. Oh well, at least I'm not in Haiti or the Horn of Africa where things are decidedly worse. It helps to put things in perspective once in a while.

    Despite all the security software available, it probably would be a good idea to have a standalone system for providing epidemiological data to state and federal agencies in U.S. I worked with some of Canada's best IT security experts, and most of them didn't recommend the use of internet banking, believe it or not. Hearing about highly secure computer systems all over the world being hacked seems to confirm that was good advice on their part.

    I'm off to consume some of our country's healthcare services ... a privilege I still don't take for granted even they aren't perfect.

    ReplyDelete

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