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Update on Lyme Disease

Lyme disease was first recognized in this country in 1975 along this rural road in the region of Lyme Connecticut. The most characteristic feature of Lyme disease is the slowly expanding skin lesion, erythema migrans, that usually occurs at the site of the tick bite. This is classic erythema migrans. The most characteristic feature of this lesion is its slow expansion. The recent Smith, Kline, Beecham vaccine trial gave us a better opportunity than weíve had previously to determine the frequency of the various manifestations of Lyme disease. This is because an attempt was made to identify all cases of Lyme disease that occurred in a population of nearly 11,000 people living in endemic areas for Lyme disease in 10 different states. As we see on the slide, in the study it was about 64% of patients had erythema migrans, 23% flu-like illness. Actually presenting with neurologic involvement or arthritis was quite unusual, only about 1% of the total. This is the first time we really had any idea about the frequency of asymptomatic seroconversion and it was 11% of the total population. Of course if these people were to develop another illness but be tested serologically for Lyme disease, that test would be positive and that may cause confusion in diagnosis. But of course we usually donít know who has asymptomatic seroconversion, so if we simply look at the number of symptomatic cases we see that it is about three-quarters presented with erythema migrans and the other quarter with flu-like illness, although that number is somewhat suspect. People who may have had erythema migrans but they didnít see the study physician, it wasnít biopsied, were not counted as a case of erythema migrans and it was roughly eight of these people gave a history of having erythema migrans that were counted in this category. Of course the other point of potential confusion is that there are co-infecting agents that may be transmitted by the same tick, that may also cause flu-like illness. In the case of aleukiosis may also cause a positive test or positive IgM test for the Lime disease spirochete. So I come to think of it that it is in about 80% of people have erythema migrans at the onset of this illness. But one may see a more non-specific, more flu-like illness. Itís often not a very febrile illness. One in which headache, particularly in the back of the head, and neck stiffness are prominent early signs. One may also see migratory musculoskeletal pain.  

I do want to comment on the other infectious agents in the U.S., at any rate, that may be transmitted by the same stage of the same tick. It includes the agent of human granulocytic aleukiosis, so a white cell pathogen, more often symptomatic in the elderly population and may be a cause of high fever. So if a patient presents with erythema migrans and high fever, think about that they may be co-infected with aleukia. Well, what should one do about that? Doing a blood count is a helpful thing in that aleukiosis, unlike Lyme disease, is often accompanied by leukopenia and thrombocytopenia. Now one may try to visualize the agent in white blood cells, but better is a PCR test of blood, and of course not often available. This disease is also treated with doxycycline. The Besia microtia is a red cell parasite that may cause a malaria-like illness. One may also get clues to this from blood testing, in that it is often accompanied by thrombocytopenia; and in severe cases, hemolytic anemia. Again, one may try to visualize the parasite in red blood cells but that is often difficult. PCR testing is the modern way to try to do this.

The final part of my talk, the idea of it is to be a practical summary about the diagnosis and treatment of this disease. This is in your handout but here goes a quick summary. Serologic testing is the major laboratory test that one has available nationally to support the diagnosis of Lyme disease. And these are the national standardized criteria for a positive western blot. The CDC has recommended a two-test approach in which testing is first done with an ELISA assay but positive or indeterminate responses are then tested by western blotting. During the first 30 days of symptoms, the antibody response in this disease often develops somewhat slowly and itís the IgM response that is often more important, in terms of diagnosis, and the criteria are two of these following three IgM bands. If at any time in the illness any five of the following IgG bands are used for diagnosis. The most common mistake that I see is using IgM criteria to support the diagnosis of Lyme disease later in the infection. So, if a patient presents with arthritis and you do serologic testing and the result comes back positive IgM but negative IgG, that is not Lyme arthritis. Lyme arthritis is a hyper-immune syndrome. You see the highest antibody responses that you see in this disease in patients with Lyme arthritis and they have a positive IgG response to therapy, in my experience.  

This is what western blots look like in such patients. This is the IgM response to the IgG response. This is in 25 different patients. We are seeing reactivity often with 12 or more spirochetal polypeptides. In fact, when somebody asks me about the diagnosis of Lyme arthritis and says that the patient only had five bands, I start worrying about whether that is a positive serologic test or not. Whether the laboratory has done the test correctly. The new wrinkle in serologic testing is that patients now have the potential of being vaccinated for Lyme disease. Iíll be saying more about that in a moment. And they are vaccinated which is with outer surface protein A, ironically, because the vaccine is recombinant outer surface protein A. The ELISA test will become positive. One then depends on western blotting as a way of being able to tell if the response is to vaccination as opposed to the natural infection. Well, I can tell the difference. This is what the response looks like in 25 people who were vaccinated, and soon after their third booster injections. So at this point they have very high titer antibody but itís only to outer surface protein A, which is shown here. There are some breakdown products of outer surface protein A that may give positive results in lower molecular weight bands. But again, it just takes some experience in reading blot.

Laboratories are also working with this problem, creating tests that use recombinant proteins or OSP-A list strains of the spirochete. Still most laboratories are using this approach. Itís still whole sonicated spirochetes in which vaccination will interfere with the ELISA test but the result by western blot looks different. The Infectious Diseases Society of America is about to release recommendations for antibiotic treatment of this infection and this is what these recommendations look like: in most people, Lyme disease is not hard to treat. For early disease usually oral agents with doxycycline or amoxicillin for 20 to 30 days works well. Of course one does not use doxycycline in young children or pregnant women. In case of allergy, cefuroxime axetil, which is Ceftin, is a suitable alternative. Erythromycin may be used but it really is a fourth choice and does not work as well as the other antibiotics and thatís true of if congeners as well, such as azithromycin. The hardest manifestation of Lyme disease to treat with antibiotic therapy is that there is neurologic involvement. So acute or chronic neuro-borreliosis - and most people, in this county at any rate are treating those manifestations, which would include meningitis with - ceftriaxone, 2 gm once a day, or cefotaxime a similar drug but it has to be given three times a day, or sodium penicillin usually for 30 days. It may be acceptable to treat patients with facial palsy alone with oral therapy, but one of the most common mistakes I see made is to focus on the facial palsy, which is very obvious, and not realize that the patient has subtle meningitis as well. This is an unusual manifestation of Lyme disease and a patient who has it, most people would admit them, monitor them, start with IV therapy but when the clinical picture improves change and finish the 30 day course with oral therapy.

This is actually the recommendations for the treatment of Lyme arthritis that are in The Infectious Disease Society of America guidelines, but this is how I approach it as well. I generally start with oral treatment, with doxycycline or amoxicillin for 30 days, which in most patients works well. If the joint is still swollen after 30 days I just go ahead and re-treat with oral antibiotic for another month, or some patients would use intravenous ceftriaxone at that point for one month. It is very important to consider whether the patient has concomitant neuro-borreliosis, which can happen and it may be subtle. Again, ones attention may be distracted by the fact that the knee is very swollen and not pay so much attention to neurologic symptoms. If they do have that, I will treat with intravenous antibiotic therapy. If the joint, however, is still swollen after 60 days - and we would do PCR testing at that point too, and show that it is negative - we would change the way we think about this and think that we are treating an autoimmune process in which we would want to use antiinflammatory agents. A combination that we often use is Indocin and Plaquenil. More recently, in some more resistant cases, we have used methotrexate with actually quite dramatic results. And I now think that Iím no longer seeing the natural history of treatment resistant Lyme arthritis. Itís actually been some time since we have done arthroscopic synovectomy but that used to be the way that we dealt with this in someone who still had a swollen joint after 12 months or more.

I do want to make this point. Fibromyalgia or chronic fatigue syndrome may follow Lyme disease. If it does, to me it doesnít seem different than fibromyalgia or chronic fatigue syndrome that one may see due to other reasons. I look at it that this infection is one of the stressful events, or perhaps infection of the nervous system in particular is one of those events, what one may see is a fibromyalgia picture following it. It is usually much more debilitating than the Lyme disease itself, and I do not need to read off this list for the people in this audience. It would be a clinical presentation that you would be very used to seeing. This has really become the other Lyme disease, and in fact Lyme disease is often a diagnosis for fibromyalgia or chronic fatigue syndrome now in which there really is no evidence for Lyme disease. Patients may feel somewhat better while they are on antibiotic therapy, but in my experience and in the experience of most others, it relaxes. In other words, antibiotic therapy is not a cure for this condition and I think the more effective treatments are the treatments that we use regularly for fibromyalgia anyway.  

Finally, vaccination. It is now possible to vaccinate for Lyme disease. A commercially available vaccine was licensed, now 11 months ago. It is a recombinant outer surface protein A and this is the data from the phase III efficacy trial in which patients received three injections of recombinant OSP-A, though the first two injections were given before the first yearís transmission season and the third injection given before the second year. So half received those three injections of vaccine, half received placebo and in definite cases 22 after two injections in year one in the vaccine group, 43 in the placebo, for a point estimate of vaccine efficacy of 49%. After the third injection, third booster injection, 16 cases in the vaccine group, 66 in the placebo group for a point estimate of vaccine efficacy of 76%. The difference in the break-through cases, in the vaccinated break-through cases compared with various comparison groups was that the vaccinated break-through cases had lower titers of OSP-A antibodies. This is a vaccine that takes high titer antibody of OSP-A to be effective. Thatís a very unusual mechanism of action in that it kills the spirochete in the tick during the first 24 hours of feeding. After that point the spirochete down-regulates outer surface protein A. So one has 24 hours roughly for the vaccine to work. In the tick it takes high titer antibody to do that. It may also take rather frequent booster injections to maintain that type of titer. Itís still not really clear, recommendations have not been published, but it may take booster injections as much as every year or every other year in order to maintain high titers of antibody that would be protective.  

Is that a safe thing to do? The major side effect in this study was of soreness at the injection site, in the deltoid, occasionally with redness or swelling at that site or occasionally systemic symptoms as well. Usually mild to moderate in severity. Usually going away within several days. Ironically, itís outer surface protein A thatís the vaccination, thatís used in vaccination, but of course Iíve been standing up here saying that I think the immune response to outer surface protein A in the natural infection is associated with treatment resistant Lyme arthritis. So one asks the question; well is it a problem to vaccinate people with outer surface protein A? I do not think that vaccination causes the sort of picture that one sees in the natural infection. I do think itís important that the spirochete is in the joint. It takes that, it takes recruiting a lot of OSP-A reactive cells within that pro-inflammatory environment before I would postulate that autoimmunity might develop. Itís still, though, something of a concern of mine; if one is boosting people in an endemic area year after year, is it a problem to keep amplifying this group of OSP-A reactive T cells? And under some circumstances, might that not be a problem? I still think that is an unanswered question.