Transcript
Lucille Packard Children's Hospital (Stanford Medical School)
Grand Rounds Presentation Transcript
September 24, 2004
About 50-60 pediatricians, residents, and other MDs were in attendance. It was open to the public.
Lyme Disease: The Truth About Ticks
Eugene Shapiro, MD
Prof. Pediatrics, Epidemiology and Investigative Medicine
Yale University School of Medicine
This is a picture of the tick that transmits Lyme disease [giant photo of a tick under an electron microscopic]. This is another picture of the same tick [photo of very small tick on a blade of grass]. And the difference between this one and this one is simply perspective.
And one of the problems about Lyme disease is that many people have really lost perspective about this illness. And hopefully today we can bring a little perspective to it.
Today I'm going to talk a little about the etiology of it. You'll probably learn more than you'll ever want to know about ticks. About the clinical features of Lyme disease. Quite a bit about diagnosis, which is one of the one big bugaboos. And I may or may not get to much about prevention.
So Lyme disease is caused by a spirochetal bacteria, called Borrelia burgdorferi. (Bb). In the Northeast and upper Midwest, where most Lyme disease occurs, the vector is always Ixodes scapularis, the black-legged tick. It's also called the deer tick, for reasons I'll explain later. On the Pacific Coast, Ixodes pacificus tick, which looks the same, called the Western Black-legged tick, is the vector for Lyme disease. You can sometimes find the spirochete in a few other ticks, but those ticks cannot transmit it to humans.
But the natural reservoir for Bb is really small mammals, like the white-footed mouse in the Northeast and Upper Midwest. And other small mammals may serve as reservoirs. Birds may contribute to spread to new areas when the ticks attach to them and the birds migrate. Deer are not competent hosts for the bacteria. So bacteria don't live in the deer. But the deer are important for the lifecycle of the tick, at least in the East. Less so, probably in the West.
On the Pacific Coast, lizards are the main hosts for Ixodes pacificus, and lizards not only have a low rate of infection, but – I was reading about this in preparation for this talk – but as I'll show you, they actually seem to kill the bacteria in the ticks that feed on the lizards. The wood and kangaroo rats, which are present here in California, as well as white-footed mice, do serve as a reservoir for Bb on the West Coast.
[Slide of 4 stages of tick development]
So here is a picture of the different stages of the life cycle of the tick. The larvae -- and the larvae are born uninfected, as you'll see – the nymph, which is the stage that is most likely to transmit it. You'll notice it has 8 legs. These are actually arachnids, related to spiders. The adult male and adult female, if you forget, I do have the life cycle on my tie. And you can see the red color of the tick of the adult female is actually the adult female color before they've fed. But here's the real culprit – this is a little mouse – and you can see the ticks that are attached to the mice.
[Picture of a mouse with dozens of nymph ticks on its ear.]
And the mice serve as reservoirs, and the ticks become infected by feeding on these mice. And it doesn't have to be a mouse that's limping across the field. These mice can be spirochetemic for long periods of time, and at the same time asymptomatic. In fact, there's evidence that there's a chemo-attractant between the mouth parts of the tick and the bacteria in the bloodstream of the mice.
[Picture of Bb lifecycle: mouse-tick-deer circle]
So this is a picture of the lifecycle of the Western Black-Legged tick. It's a two-year lifecycle. The female tick lays its eggs, and the larvae are born uninfected. And they feed once at each stage of their cycle. And they "quest" – they get on blades of grass and they have little sense organs under their legs and they glomp onto a host when it comes by. And it takes hours for the mouth parts to implant. It's not like the bite of a mosquito or something. They also elaborate enzymes that break down mediators of inflammation like Bradykininases. So the bites are painless. You don't feel them. So the larvae will feed. And it might feed on a mouse. And it might become infected. Or it could feed on a lizard, and the lizards aren't infected, so that it might not become infected. So then it molts, and emerges.
The larvae are usually born in the late summer or mid summer. After they feed, they spend the winter somewhere in the ground and they emerge in early spring as nymphal stage ticks. And the nymphs, again, may feed on any of these hosts or they feed on a human, and if it became infected at an early stage of its lifecycle, it might transmit it to humans. They drop off and molt and become adults usually in the fall and winter. And again in the winter they feed on any of these hosts. They particularly like deer. They like large deer hosts, and that's why it's called the deer tick in the East. Hunters back in the East find lots of these attached. And again they may feed on humans. Then they die and the two year life cycle begins again.
LYME DISEASE: Proportion of Ticks Infected with B. burgdorferi
Tick
Nymphs
Adults
Ixodes scapularis
20-25%
40-50%
Ixodes pacificus
3-8%
1-2%
But what's important to realize, is that there's a huge difference in infection rates from the East and Midwest and the West Coast. So with scapularis on the East Coast, about 20-25% of the nymphal ticks are infected, whereas with Ixodes pacificus, it's 3%, maybe 8% infected. You might find in some areas 10% or 12%, but many areas it's fewer than that. And the adult ticks in the East they can become infected in each stage of the life cycle, so of course the adults have a higher rate of infection.
It turns out, interestingly enough, on the West coast, the Ixodes pacificus adults have a lower rate of infection, and the reason for that is that when they feed on these Western Fence lizards and other lizards, it seems to kill the bacteria in the gut. So very few of the adult ticks are infected because they actually feed on lizards that seems to kill those that are infected at an earlier stage of development.
[Picture of an engorged I. dammini nymph tick, a little bigger in diameter than a head of a pin.]
This gives you an idea of the size of these things. This is an engorged Ixodes pacificus next to the head of a pin. So these are nymphal stage ticks. So these nymphs are quite small, as you can see, and difficult to detect.
[Picture of engorged and engorged female adult ticks.]
Now this is an adult female tick, engorged and unengorged. So they can become quite large and actually feed. And they can become as large as adult ticks.
But you can notice this little scutum [hard plate on back of tick's neck] that doesn't change in size. You can actually estimate how long the tick has fed based on the weight and the scutum index, which is the ratio of the length of the entire tick to the distance to the scutum.
[CDC US Map of Lyme distribution]
So here's a map of reported cases of Lyme disease by county in the U.S. This happens to be for the year 2000, but it would be virtually identical for any year. And you can see the darker colors have the higher rates. Most ld occurs in Southern NE and the Eastern Midatlantic states. And there's a little pocket in Wisconsin and Minnesota. A little bit in Michigan.
[Pointing to Death Valley on the CDC Lyme surveillance map]
California. This is ridiculous. This is the desert here. But if some nut reports a case of Lyme disease, it gets included. But most of the disease in California is up in this area (Medicino County) on the West Coast. But there really isn't much.
Notice, here's Colorado. I don't think there were any cases reported this year.
O.K. What are the clinical manifestations of Lyme disease? They can be divided into 3 categories:
In early localized disease, it's simply erythema migrans (EM), which by the way may be completely asymptomatic. It may be associated with headache or fever. It may itch and occasionally it may be painful, rarely.
[Picture of erythema migrans rash]
And what you hear … This is someone's back. It's actually called erythema migrans. It actually starts out as a macule at the site of the tick bite. Then it enlarges or migrates. And without treatment it will continue to enlarge for a week. And people talk about central clearing and the bullseye clearance, and this is an example of this on somebody's back. But really more commonly it really uniformly erythemitis. So don't think that since it's not cleared in the center that it can't be Lyme disease. It can be.
The other thing I point out is that it's not perfectly round. It's often somewhat eccentric in its shape. But this again is someone's back.
[Picture of submarine-shaped rash, ½ way around a midriff, solid red.]
Here's another one. This is one on a child's abdomen. You can see if a kid comes in with a fever, you might think it's cellulitis very easily.
[Erythema migrans rash with rough edges and necropathy in center]
And this is actually on the leg of a teenager. I happened to be attending in the ER the night this kid showed up some years ago. Chief complaint was fever, headache, and by the way I have a rash.
[Pointing to dark center of erythema migrans rash]
These are vesicles, and they thought the kid had shingles. And indeed if you just saw these [vesicles] you'd think that. But look at these large area of erythema around it. That would never happen with shingles. What this is vesicular erythema migrans and occasionally you may have vesicles or some small necrotic area in the center of the rash where the center of the rash, where presumably where the bacteria are injected by the tick. This child subsequently developed Bells Palsy and seroconverted, actually.
DIFFERENTIAL DX of ERYTHEMA MIGRANS
So the differential diagnosis of erythema migrans. The main things that it gets confused with is Eczema (nummular) and ringworm. Ringworm tends to be scaly and raised on the edge, which erythema migrans is not.
Cellulitis. Granuloma annulare. Spider bites and other bites. And if you have multiple erythema migrans, it can be confused as erythema multiforme.
So if you have someone who you think might have erythema migrans, but you're not certain, there's no harm in waiting and watching for a couple days. If it's erythema migrans and untreated, it's going to be there for awhile. If it's gone in a day or two, it isn't erythema migrans.
This is a picture of multiple erythema migrans. Sometimes the primary lesion will be larger than others and then you'll see smaller ones. Here's another one with the child with multiple erythema migrans. Again, you'll notice that they're not perfectly round. And what this represents is a spirochetemic spread of the bacteria to multiple sites in the skin. If you biopsy and culture these, you might grow bacteria, and you might even grow bacteria in some of the apparently uninfected skin. And typically when you have multiple erythema migrans, these kids are mostly going to have fever, and flu-like symptoms and be ill. And this is the common manifestation of disseminated Lyme disease in the U.S., and I'll show you the percentages later on.
LYME DISEASE: Early Disseminated Disease
Now can a flu-like illness alone be caused by the manifestation of Lyme disease? Yes, it probably can, but in my opinion, that's not a diagnosable condition. Because, if you send Lyme titers for every person with a flu-like illness, for everyone that you accurately diagnose, there are going to be thousands that you're going to call Lyme disease that don't really have it. So, I never try to diagnose Lyme disease with a flu-like illness, because there are too many false positive tests. And we'll talk about that in a moment.
But I think it's quite uncommon, and if you don't treat them either, they'll spontaneously get better or they'll develop arthritis or some later manifestation. And you'll treat them then, and they'll be fine. Other manifestations of early disseminated Lyme are aseptic meningitis, neuritis, and particularly the 7th nerve palsy, and carditis, which is quite rare. And that usually manifests itself as some degree of heart block.
Just a word about meningitis. It's quite uncommon. Clinically it presents like meningitis, but it tends to be of much longer duration. So in the summer in the Northeast, enteralviral (sp?) meningitis is far more common than Lyme disease. So I don't start looking for Lyme disease on every kid who comes in with aseptic meningitis, but when it's lasted for a week or 10 days, or longer, without any improvement, then you start thinking about Lyme Disease. Or if they happen to have the erythema migrans or come in covered with ticks.
LYME DISEASE: Early Disseminated Disease
The other thing that is rather common, for reasons that aren't clear with Lyme is papillodema. Nearly 20-30% of children with meningitis will have papillodema. Then I'd start thinking about Lyme.
LYME DISEASE: Early Disseminated Disease
7th nerve palsy is relatively common. It's unaffected by treatment. So we don't treat children with palsy due to Lyme disease to make the palsy get better faster or more completely. The reason we treat it is to treat late Lyme disease. Do not use corticosteroids. It certainly doesn't help, and there are some early studies, mostly in adults, that 3 or 4 adults who didn't do as well happened to get corticosteroids.
Clearly it's not beneficial. Complete resolution is the usual outcome with seventh-nerve palsy due to Lyme disease. Once in awhile there might be some residual and very, very rarely some residual. And usually it gets better with or without treatment.
LATE LYME DISEASE
Late Lyme disease. I used to have late neurological Lyme on this slide, but I took it off because I've never seen a child with late neurological Lyme. It has been described in adults, mostly in more elderly adults who had objective evidence of Lyme disease but were not treated for many, many years. And those people – it's extremely, extremely rare. It does respond to treatment but, it's not something we see in kids, so I took it off [the slide].
But we certainly do see arthritis. In Lyme arthritis, the knee is affected more than 90% of the time. Why that is, I don't think anybody knows. It's a mono or pauci-articular arthritis, the duration is variable. It may come and go away without treatment. I saw one kid who had a swollen knee for six months before he came to the doctor.
So it's usually sub acute, and often they'll think, "Oh, he fell off his bicycle or a treat branch whacked his knee while we were out walking. And that's the cause of it. But it can be very sub acute. Occasionally it can present like an acute bacterial arthritis. But, in any case, the arthritis usually resolves completely with treatment of orally administered antibiotic, thought occasionally it may reoccur. There is a chronic recurrent arthritis that seems to be an autoimmune phenomenon triggered by an infection that isn't treated promptly, and it occurs only with patients with certain DR4 and DR2 allotypes. It's very rare in kids. We've seen it in adults, but very clearly it's rare. But that recurrence of arthritis seems to be an autoimmune phenomena. It's not that the antibiotics could not adequately eradicate the bacteria.
[Timeline of Lyme disease ]
Week 1-2: Flu
Week 2: Cardiac, secondary skin, early neurological
Week 3-12: Arthritis, late neurological
This is a time course of Lyme disease. So erythema migrans flu-like symptoms usually occur in the first month, typically 7 to 14 days after the bite. It could be up to a month afterwards. Early disseminated disease occurs anywhere from 3 weeks to 2, 2 and a half months afterwards. And late Lyme disease – I should've crossed out the "late neurological" – can go from anywhere 6 to 8 weeks. So we'll see kids in March who were obviously infected sometime in the previous summer or fall.
[Newspaper ad]
Recurring Symptoms Getting Worse?
Muscle or joint pain
Chronic fatigue
Upset stomach
Disturbed sleep
Dizziness
Fevers, chills sweats
Sever headache
Stiff neck
Memory loss
Mood swings
You may have Lyme disease, a debilitating but treatable bacterial infection transmitted by the deer tick. You can pick up a tick in a wooded area and shore areas, even from your cat or dog. Lyme disease symptoms mimic lifestyle problems and other illnesses, which complicate diagnosis. Our center is a complete Lyme disease resource. Skilled registered nurses will provide you with information or direct you to a physician in your area specializing in Lyme Disease and a support group. You can be helped. Call now.
The Lyme Care Center
1-800-TICK-BITE
[End of newspaper ad]
So here's an ad that appeared one day in the New Haven Register. It occurred on the obituary page, by the way. [laughter] It says, symptoms getting worse, muscles or joint pains, chronic fatigue, mood swings. You may have Lyme disease, a debilitating but treatable bacterial infection. Lyme disease symptoms mimic lifestyle problems. You can be helped, call now.
And you can call and they list Madison, CT as the location, which is a suburb of New Haven. But it turns out if you call this number you get connected to someone that is sitting in an office in NJ that's supported by a home IV infusion company, and no matter what your symptoms, they'll refer you to the local doctor that happens to be Dr. Jones in the New Haven area, who … Dr. Jones by the way once diagnosed a teenage who attacked a cat with an ax, diagnosed this as chronic Lyme disease over the telephone. I kid you not. I was involved with the court case. And they will refer you to the operator who will undoubtedly tell you that you need treatment. Probably long term treatment, and they'll help arrange for the IV therapy.
Here's another ad: "Do you have unexplained symptoms. Have you had the following? –and they list every symptom known to man. [laughter]
Wait a second. Look at this: a Lyme disease support group in Colorado. Remember how many Lyme cases we had in Colorado every year? It's probably one case a year, and they probably vacationed on the Cape.
You know, so what's going on? The amount of anxiety and angst over this is incredible. Just let me tell you. You can't believe the stuff I get in my emails. Here's an email that I got one day. You'll notice that it's from RedNeck5. I can't wait to hear from RedNecks one through four. [laughter]
[Redneck Email]
I heard your public comments and they make me mad. You could not handle the pain, because your Yale pansy ass could not handle it.
If there is no such thing as Chronic Lyme, why don't you inject Lyme into your body and see if you're right? And please respond.
[Redneck Email end]
And I can tell you this anxiety gets to not only the patients…But let me show you a picture of me before I got involved with Lyme. [Has a bushy head of hair and beard. (He's bald now.)]
So, what is it about these non-specific symptoms of Lyme?
LYME DISEASE: Nonspecific (Chronic) Symptoms
Never the ONLY manifestation of Lyme disease.
Nonspecific (subjective) symptoms accompany OBJECTIVE signs of Lyme disease
Has anyone in this room had these symptoms in the last three months? How about the last three minutes? Sure. Do people with Lyme disease get these? Sure they do, but it's never the only manifestation of Lyme disease. These non-specifics symptoms accompany OBJECTIVE signs of Lyme disease. So, sure you may have a swollen knee and feel tired, but you may have a headache and erythema migrans. If all you had is a headache or aches and pains, it ain't Lyme disease. And we'll come back to that.
"CHRONIC" Lyme Disease
Clinical Trial of Treatment
The NIH. Some of these Lyme disease support groups really put a lot of pressure on us. And the NIH is really under pressure by lawmakers to do something to study this problem. So there was this problem trial looking at treatment of chronic Lyme disease sponsored by the NIH. It's a double-blind trial of long term treatment of antibiotics. Patients were enrolled with a history of chronic symptoms. Most of these patients had already been treated for an average of something ridiculous, like 4 months. And they were enrolled and stratified into those who were seropositive or seronegative at time of enrollment. And the patients in each of these trials received either ceftriaxone IV for 4 weeks then 8 weeks of doxycycline orally, or placebo IV for 4 weeks, then 8 weeks of placebo PO in a double-blind manner.
"CHRONIC" Lyme Disease
Clinical Trial of Treatment
Now there was an independent data-safety monitoring board that stopped the trial early, before full enrollment had been completed. And the reason was that there was virtually no difference in the proportions of treatment and placebo groups that improved, worsened or unchanged. It's not that the symptoms didn't change. They were actually rather labile. About a third changed, a third worsened, and a third stayed the same. It's just that it didn't matter if you got an antibiotic or a placebo. And they concluded even if they reached full enrollment, the chance of finding an effective treatment was virtually nil, it was something like 3%.
So clearly, these patients were sick. They had problems. It's just that antibiotic deficiency was not one of them. [laughter].
[New Yorker-style cartoon of patient in the hospital with a lime over his head.]
I don't know if you can read this, but, "It's one of the hardest ailments to detect, but I think you have Lyme disease."
LYME DISEASE: Diagnosis
And that's really the big bugaboo with Lyme disease – diagnosis. Now, people will tell you it's a clinical diagnosis. It is. But the CDC have criteria for epidemiological purposes, and it turns out that those criteria are pretty good to use clinically. And those criteria are physician-diagnosed erythema migrans of at least 5 cm. Or One or more clinical manifestations of early disseminated or of late Lyme disease plus a positive serology
Clinical manifestations mean objective findings. And one of the things that people get confused about is that arthralgia is not an objective manifestation. Swollen knee joint – objective evidence of inflammation of the joint – is. But arthralgia is not, and is very common.
Now these are the objective manifestations. And if someone told me that they got bitten, right here, and a week later they developed this rash, and it looks like a erythema migrans rash, but it's only 4cm, I wouldn't say, "Oh, no. It's not Lyme disease." But in general, these are pretty good criteria.
LYME DISEASE: Tests for Antibody
The problem is that if they don't have the rash, we end up having to use the antibody test to make the diagnosis. And tests for antibodies include IFAs assay, which nobody does anymore except for Stanford.
[Someone in the audience, objects]
"Oh, is it an ELISA? Because I thought I saw IFA on the report I just read."
[Clarification from transcriber: Stanford still uses the IFA.]
But most places do an ELISA, which is a quantitative test, followed up with a Western Blot, which is a qualitative test.
PROBLEMS WITH ANTIBODY TESTS
And the ELISA measures a crude mixture of antigens. Basically you grind up the tick and you put it a plate. It sticks to the wells, you pour in the serum, and if people have the antibody, it sticks to the antigens of the bacteria. Then you use a marker system to measure the quantity of antibody that's present. The problem is that it's poorly standardized, especially commercial kits. Reactivity to cross antibodies are quite common.
PROBLEMS WITH ANTIBODY TESTS
The Western immunoblot, on the other hand, measures antibodies to specific antigens. So you take the same crude preparation. You put it on a gel and you put a charge across it. And the proteins move different distances depending on their molecular weight, then pour the patients serum on, and if they have antibodies, they stick, and you use a marker system. And it makes a band if at that site, if the patient has antibody against that specific protein. The problem is the controversy for minimum criteria for positive reactivity. So clearly if you have ten reactions against 10 antibodies, yes, that's a positive test. But what if it's 4 or 5? Generally people say that for IgG, you need 5 positive bands, and ideally some of the more low specific molecular weight.
The criteria for IgM positivity I think is extremely liberal. You need only 2 of any 3 bands. And false IgM tests are extremely, extremely common, including Western Blots. And people say that you should never make a diagnosis on Lyme disease based solely on IgM. Especially when someone has had symptoms for more than a month.
And the other problem with this is that the reports of results are often confusing and misinterpreted. So people will look at it and say, "Oh yes. It's a positive band at 41 so and 29 positive bands, so it's positive, but actually it's negative, because you need 5 to be positive. And it's only 2. So it's frequently misinterpreted.
LYME DISEASE: Serologic Tests
There are other problems. Antibodies may be bound in immune complexes early in the course of the illness, so that … Remember I showed you that usually you see the rash 7 to 14 days after the bite? Well, the antibodies usually aren't detectable for 3 to 4 weeks afterwards. So if you get an antibody test from someone with a erythema migrans, and it's negative, that's normal. And most people with a erythema migrans will not have a positive antibody test, so you shouldn't send a test in on someone with a erythema migrans. Furthermore, early treatment with antimicrobials will further ablate the response. So if you treat somebody for erythema migrans, don't get another test in a month to see if they really had Lyme disease, because even if it truly was Lyme disease, it really could be negative.
Once a person's been treated for Lyme disease, it'll remain positive indefinitely.
Now this seems like a simple concept. But people have this misconception that the antibodies are a sign of disease activity.
If you had a headache, nobody would walk into an office and say, "Ah, ha! Your measles antibody is positive. You've got measles." But God forbid you should have a positive antibody for Lyme disease. You know, you walk across the street and say, it's Lyme disease. People are ready to attribute anything to Lyme disease.
LYME DISEASE: Serologic Tests
So the way you… and I often get calls, "Well, I had this child with Lyme arthritis, and I repeated the antibody test, and it's higher than it was. What do I do?"
Well, how's the knee?
"It's all better."
Well, that's how you tell if it's all better. Not by the Lyme titer. And these titers, by the way, are not all that reproducible. I would not ever look at a titer from time A and compare it to time B, and say it's high on time B, so therefore …. Because unless it's run in the same batch, there is a lot of variability from batch to batch. So you never want to do that.
IgM antibodies for Bb, as I said, false positive tests are common. True positive tests may persist even after treatment and cure of disease. That's important to realize. People think that IgM has got to be there early in the disease if it's positive. That isn't true.
First of all, there are lots of false positives. Second, there are well documented cases of people with Lyme arthritis who've had positive IgMs who've been treated and cured. IgM can persist for years.
Western immunoblot does not equal "truth". Sometimes we see people only ordering a Western immunoblot, without giving a qualitative test. It should not be used in place of an ELISA. And false positives, even for Western Blots, are not uncommon.
Really, what's recommend is a two step process. First a quantitative test like an ELISA, then if the test is positive or equivocal, then confirm the specificity of the test with the Western immunoblot.
EVALUATION OF SEROLOGIC TESTS FOR LYME DISEASE
And just to show you some of the problems, the State and Territorial Public Health Laboratory Directors and the Centers for Disease Control did a study – and this was some time ago – where they took seven commercial kits with the best concordance with the CDC's own ELISA test, and then they had 4 state health departments and the CDC itself blindly tested 158 reference serum specimens, known positives and negatives, with the seven kits, and what they found, was the mean agreement between laboratories using Kappa – Kappa is a statistical test of agreement…
EVALUATION OF SEROLOGIC TESTS FOR LYME DISEASE
That takes into account ?, it goes from 0 to 1. So zero is no agreement, one is perfect agreement. And the mean agreement between laboratories, for the same serum sample, the same kit, but different laboratories ranged from 0.35 to 0.61, only fair.
The main agreement between kits, that is, now we're talking about the same laboratory, same serum sample, different kits, ranged from 0.16 to 0.690 (poor to fair). The mean sensitivity was from 26 to 57% . The Mean specificity was 12-60%.
Well, let's give it the benefit of the doubt and say it's 50% sensitive and 50% specific. I have a quarter here in my pocket that we can flip [laughter].
And the conclusion – not my conclusion, but their conclusion, too – that the currently available tests to test for antibodies for Bb are very inaccurate. And the use of these tests will result in a high rate of misdiagnosis.
This was done quite a number of years ago. I think the tests have improved somewhat, but there was a paper… they tried to replicate this in Wisconsin, a few years ago, and they found the same thing.
TEST FOR ANTIBODIES AGAINST B. BURGDORFERI
But here's… And what I'm going to say now is the most important thing… if you remember one thing from this talk, besides my tick tie, is remember this… Let's suppose you have a good test. Let's suppose we have a VERY good test for antibody. Let's suppose the sensitivity 95% and the specificity is 90%. Not a bad test. There aren't too many tests that we do that are better than that. But let's suppose that the prevalence of the disease in the population that we're testing is 1%. The pretest probability, OK?
And I can tell you if you test on people with aches and pains and headaches and fatigue, the percentage of those people in California… or even in Connecticut, too, that have those symptoms due to Lyme disease is going to be way less than 1%. But just for the sake of argument, let's take a population of 10,000 people with 1% prevalence of disease.
TEST FOR ANTIBODIES AGAINST B. BURGDORFERI
Test
Lyme Disease
No Disease
Total
Positive
95%
990
1,085
Negative
5%
8,910
8,915
Total
100%
9,900
10,000
So there are 10,000 people. 1% of them, or 100 of them have Lyme disease. The test is 95% sensitive. So 95 will have a positive test, 5 will have a negative test. That leaves 9,900 without Lyme disease. 90% specificity. So there are 990 positive tests. So there is a total of 1,085 positive tests, of which 990 or 91% are false positives. That's if it's 1% prevalence. If it's .001%, which is more likely, this is going to be 99% of your tests are going to be false positives.
This is simply Bayes Theorem. This is not specific to Lyme disease. This is for any diagnostic test. But it is something that patients don't understand, and most physicians don't understand.
LYME DISEASE: Clinical Situation
2. Moral: Don't order Lyme titers
So, if you have a clinical situation, where a patient has vague symptoms, not likely to be Lyme disease. Antibody for Bb is negative, not likely to be Lyme disease. Antibody for Bb positive, diagnosis: Not Lyme disease.
The moral of the story is don't order Lyme titers on these patients. I can't tell you how many calls I get every week, where the docs have done this, and they're in this situation.
And I know it's hard because, you know sometimes you have a parent come in who wants the test, because they've been on the Internet. You know that if you don't do it, there're just going to go to someone else. It gets complicated, but …
[Photo: Tick Crossing Sign]
OK. There are some areas of the country where ticks are a problem.
[Photo: Christy Brinkley with pet Guinea Hens]
Do you know who this is? Right, Christy Brinkley. Now Christy Brinkley was deathly afraid, and she lived in a big estate on Long Island. She was deathly afraid of getting Lyme disease. So she employed these guinea hens. Lots of these guinea hens that eat ticks supposedly. They spread out on her property to try and eat the ticks. Supposedly she got Lyme disease anyway, the poor thing. [laughter]
LYME DISEASE: Tick Bites
How should person bitten by a tick be managed?
So, how should a person bitten by a tick be managed?
LYME DISEASE: Tick Bites
i. Infected nymphs: >36-48 hours
ii. Infected adult females: >48-72 hrs
Well, there are a few things. Transmission of Bb is going to depend on the proportion of infected ticks. So, if you're somewhere in California, where 1 or 2 or 3 % of the ticks are infected, the chance of getting infected by this disease is extremely low. But the other thing that's important is duration of attachment. It turns out that there is a lot of evidence that the risk doesn’t become substantial with an infected nymphal stage tick until at least 48 hours or more. Adult ticks, 72hrs or more.
LYME DISEASE: Clinical Trial of Treatment for Ticks Bites
And there was a randomized trial done in Westchester County, NY, which has one of the highest risk of Lyme disease in the world. Much, much, much higher than in California.
What they did is enroll people 11 years of age who had removed an I. scapularis tick within 72hrs. Now the ticks were identified by a medical entomologist. Most of you probably don't have medical entomologists in your office, which is a problem we'll talk about in a minute. There are actually studies of ticks submitted by doctors for identification. About a third of them aren't ticks. [laughter] They're dirt, head lice.
And what they did was treat them with a single dose of doxycycline, 200mg of doxycycline, which is a high dose, double the normal dose. Or placebo in a double-blind manner.
LYME DISEASE: Clinical Trial of Treatment for Ticks Bites
New Infection with B. burgdorferi
Treatment Proportion
Doxycycline 1/235 (0.4%)
Placebo 8/247 (3.2%)
Protective efficacy=87% (P<0.05)
95% CL: 25-98% (lower limit may be 1%)
And what they out was that 1 in 235, or 4% of the patients developed erythema migrans that got doxycycline and 8 of 235, or 3.2% of the placebo group [got a erythema migrans].
Now, the protective efficacy of doxycycline was 87%. And it was statistically significant. But the confidence level around that was very wide. It was not very robust. Because of the small numbers. It could be consistent with 25% or 1, depending on how you calculate the 95% confidence level, even 1% effectiveness.
But there are some interesting things we can learn from this. One thing is that in the placebo group…actually the doxycycline group, too. The only people who got Lyme disease were bitten by nymphal stage ticks. So overall, there was a little over 5% bitten by nymphal ticks got Lyme disease. If they were at all engorged, it was almost 10%. That means 90% bitten by an engorged tick didn't get Lyme disease. And none of 59 who had flat, unfed ticks got it. Among person who were bitten by adult ticks, none of 97 and none of 8 who were bitten by larvae got infected.
Furthermore, remember I told you can estimate how long the ticks have fed by the scutum index? Among the ticks where they could actually estimate how long they've fed, if a nymph fed more than 72 hours, 25% (3 of 12) developed Lyme disease. Whereas, none of 48 developed Lyme disease if the nymph fed for less than 72 hours.
It turns out from studies that most people who recognize that they've been bitten, actually pull the tick off in less than 48 hours. At least 75% who recognize that they've been bitten pull it off in less time.
LYME DISEASE: Clinical Trial of Treatment for Ticks Bites
But there were some problems. There were some high risks of minor adverse side effects. Nausea and vomiting was common, and people were driving off the road and puking. This was in part because they didn't give it with food, so if you ever, for any reason, decide to give it, give it with food.
All infected patients developed EM. There were no asymptomatic seroconverters. So all we're doing is talking about preventing a little rash. This isn't AIDS that we're talking about or preventing, folks.
It's not a big deal if you get Lyme disease. It's easy to treat and cure.
Nearly 20% of subjects had another tick bite during the six weeks of follow up. So if you're going to give prophylactic antibiotics, you're going to be giving a lot of antibiotics to these people. You can not extrapolate that a single dose of amoxicillin would work for younger children, though probably doxycycline in one dose isn't going to stain the teeth of younger children, anyway.
As I said, although one dose is effective, the results were not very statistically robust and it could have a much lower than 50% ? specificity. As I said the ticks were identified by a medical entomologist. Most people don't have those. And anyway, here [California], the risk of Lyme disease was low. It's only 3%.
The risk is really greater from the tick bite that is not recognized. Where the tick can feed to completion. So if you recognize a tick bite, most people clear it off before it could transmit the disease, even if it is an infected tick.
So watching and waiting is the most reasonable approach.
SUMMARY AND CONCLUSIONS
What about analyzing ticks? Little is known about the accuracy of [testing for] Bb in ticks, either the sensitivity, the specificity, or reproducibility of the assays. And anyway, what we're really interested in is what's the risk in the person that's bitten, not whether the tick is infected, per se. It may be, you know, people do PCR tests on these ticks, and conceivably could detect as little as one spirochete in the tick, and maybe you need 100,000 per cc in tick juice before the risk becomes substantial. So, we don't recommend getting assays to see if the tick is infected.
[Photo: Tweezers grabbing embedded tick by head.]
How do you remove a tick? And you can see there was a letter in the Lancet several years ago, where they said in the Southern hemisphere you should turn it this way, and the Northern hemisphere, turn it that way…[laughter] All you do is grab tick as close to the mouthparts, the skin, as you can and pull it out. Actually a friend of my at Yale who is a acarologist, people who study ticks, let some lab ticks feed on him, then I pulled it out and videotaped it, and made a CD-ROM for the AAP. So if you want to watch somebody doing it, if some of the mouthparts remain in the arm, do not amputate. [laughter]
You know you see some kids come in who are hacked up. It's not going to change your risk of getting Lyme disease. It's just a little foreign body. If there's a little mouthpart in there, it'll get extruded. Don’t worry about it.
LYME DISEASE: Congenital Disease
Prevalence of congenital malformations among offspring of seropositive and seronegative women is similar.
What about congenital Lyme disease? Actually infection of the fetus has been documented but congenital Lyme has not. There is no pattern of congenital malformations related to infection of the mother. And the prevalence of congenital malformations among offspring of seropositive and seronegative women is similar. So I think that either it doesn't exist.
Mike Erber did a survey of all pediatric neurologists in endemic areas, and none of them had ever seen a credible case. So I think it either doesn't exist, or it's so rare as to not be a problem.
LYME DISEASE
Transmission of Lyme disease via breast milk has not been documented.
INITIAL CLINICAL MANIFESTATIONS OF LYME DISEASE
N=201
Single erythema migrans 66%
Multiple erythema migrans 23%
Arthritis 6%
Facial nerve palsy 3%
Aseptic meningitis 2%
Carditis 0.5%
This just shows you – this is a study we did of 201 consecutive cases of Lyme disease in Southeastern Connecticut. And it just shows you. And you can see that in 66% of children had a single erythema migrans, and only 23% had multiple erythema migrans. So about 90% of children who developed Lyme disease had erythema migrans. 6% had Arthritis. 3% had Facial nerve palsy. 2% meningitis and one child, 0.5% had carditis.
LYME DISEASE IN CHILDREN: Outcomes
1. By 4 weeks after initiation of treatment:
a. All symptoms resolved in 97%
b. Non-specific symptoms (arthralgia, fatigue, neck pain) present in 3% (7/201)
c. By 5 months all symptoms had resolved
d. At follow up a median of 2.5 years later NONE had either chronic or recurrent symptoms
By 4 weeks after initiation of treatment, all symptoms resolved in 97%. So, non-specific symptoms, like arthralgia, fatigue, neck pain, were still present in 3%. By six months, all symptoms had resolved, and at follow up, in a meeting 2.5 years later, none had current or chronic symptoms.
LYME DISEASE: Long-term outcomes
A number of studies have found that long-term outcomes of person treated for Lyme disease are excellent. When asked about symptoms of problems with normal activities 5-10 years later, depending on what question you asked, 5-40% reported worsening. Most problems attributed to aging or comorbid illnesses. If you ask me if my memory today is as good as it was 10 years ago, it ain't, but I don't have Lyme disease.
But it turns out that the frequency of complaints are similar among age-matched controls. So there isn't any evidence that Lyme disease is really related to any long term outcome.
LYME DISEASE Coninfections
i. Anaplasmic phagocytophilia
One word about coinfections. Human ehrlichiosis, which is now known to be caused by Anaplasmic phagocytophilia. I think it's changed its name again to phagocytophilim.
And Babesia microti, both of these are transmitted by the same tick, Ixodes scapularis, and there is some in California.
There is no chronic form of HGE. Those kids… it's indistinguishable from a flu or a viral-like infection. Occasionally you'll see someone who's really sick. Those kids typically have lycopenia, thrombolycopenia, and they look pretty ill. And the treatment is doxycycline.
Babesia is rarely a problem unless you're immunocompromised or don't have a spleen. There is some evidence that it can cause some minor symptoms. But we usually don't make a diagnosis of these in Connecticut. We don't see it at all. Except EXTREMELY rarely. So it's even less of a problem in California.
I think I'm going to stop right there and entertain some questions. [Couldn't hear all the questions.]
Q: The distribution of Lyme disease in the U.S. – it's been stable all these years?
A: Yes, it has.
Q: How reliable is the testing for Ehrlichiosis and Babesiosis?
A: It depends on which tests you're doing. You can detect these in blood smears if you see them, or a PCR from a reliable laboratory would be pretty good. Most of what's done are antibody tests, which I think are not very good. And again, I frequently see people diagnosed with chronic ehrlichiosis, of which, there is no such thing to start with. But they'll have a positive IgG in their blood, for Ehrlichia. And I don't know what that means, but it certainly isn't a cause of any symptom, and most likely it is a false positive test. Or they were truly infected in the past and they cleared it.
Q: Dogs frequently pick up ticks. Do they get Lyme Disease?
A: Yes, they do get Lyme disease, but as with humans, I think it's grossly overdiagnosed. But they do get it and the vets in our area find Lyme disease to be a lucrative disease.
Q: [Inaudible]
A: There are many physicians, throughout the country. You can go to New Mexico and get IV therapy for Lyme disease, even though we know there is no Lyme disease there. So there are these groups of physicians who will treat for prolonged periods – and I've read the records of these patients, and it's pretty sad, really. And there are a number of kids who've had their gallbladders out because of complications of long term ceftriaxone, and so on.
Q: The question is what is the mechanism for prolonged IgM activity?
A: I don't know what the mechanism is, but it's clearly documented… Not that everyone does it, it's just occasionally people have it. It occurs.
Q: How do you convince people who are committed to the diagnosis of Lyme disease, that Lyme disease is not the cause of their non-specific symptoms, especially after they have the support of their own physician, confirming this diagnosis.
A: I have a whip! [laughter] And this is a very difficult problem, as you right say. I get many, many calls about this. And it varies. There are many people that you can convince, and some that you cannot. What I try to talk about is what we know about Lyme disease. What the cause is. I think some people… One of the stories you often get is that they've been on antibiotics for six months, and the day they stopped, all the symptoms came back. Now, how is that possible? Let's think about how the inflammation caused by bacteria. That just can't be. It really varies, but you see the whole spectrum and some of this is Munchausen's by Proxy. I have had situation where I've had a call into the department of family services to get involved. There are varying degrees, and you just do what you can.
One thing I say, and I didn't get to my slide, but how to prevent it. The best thing to do is order serological tests appropriately to avoid misdiagnosis, because most of Lyme disease is overdiagnosed because of inappropriate ordering of serologic tests. Occasionally if you're backed into a situation where you have to test, then I'd say, do we'll do it but there are lots of false positive tests, and if it's positive, we're going to send it to this other lab, a reference lab at Yale – which I have no relationship with the Yale Lab, or the Univ. of Conn. Or some reference lab. And it's just like any psychological problem -- sometimes you need to get people to talk about what their fears are. And sometimes you can shake it, and sometimes you can't.
Moderator: As a case in point, Gene has agreed to see a patient of ours, a teenage boy. He's reviewed the records. [?required blood cell] It's really an unusual thing. And we don't have an explanation for it. And the patient is seeing another doctor in California, and has been given the diagnosis of Lyme disease. And he's been seen by our ID people, and they have not confirmed that. So we don't have an explanation for it, but it's probably not Lyme disease.
Q: The question is Lyme vaccine, and do I recommend it for anybody?
A; Well, it wouldn't matter whether I recommend it for anybody, because it was taken off the market, not because of any problem with the vaccine, but because it was not profitable. Actually the mechanism by which the vaccine worked was interesting. It was a single protein vaccine and that protein is not expressed in early disease. And by the spirochete, but it is by the tick. So what happens was is that you immunize people, but the tick has to feed awhile before it's transmitted. Because the bacteria live in the gut of the tick and they have to migrate up to the [] so the tick is feeding on the immunized person. It ingests antibody, and antibody dependent killing took place in the tick. But as a consequence of that, people the vaccine, would never get a boost to immunity. So it turns out it was recommended that three doses be given. It was recommend that 3 doses be given, anyway. Back when it was available, the only situation where I'd recommend it was when someone was working out in the fields or utility lines in Lyme, CT. Then it might be reasonable. For most people it wasn't easy for people to get.
Q: If there are so many false positive tests, when can you have confidence that the test is accurate?
A: Again, I think the key point is the point I tried to make about Bayes Theorem. So it doesn’t matter what the test result is in someone who walks in with aches and pains and fatigue for six months. That ain't Lyme disease, whether the test is positive or negative. On the other hand if you have a subacute knee joint – at least in Connecticut – the probability that that's Lyme disease is pretty high. We published a paper using that same algebra that I showed you. If you have 50% prior predictability then the positive predictability is terrific, it's pretty good.
So the key thing is you have objective findings of Lyme disease and you have a positive test, then it's likely to be Lyme disease. If you have a positive test with some non-specific tests that everybody has, or somebody's nose falls off and somebody got a Lyme titer that is positive, probably Lyme disease is not the cause of that problem.
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