Call Transcript: Tickborne Diseases - A Springtime Review of Diagnosis, Treatment and Prevention
Moderators:Leticia R. Davila
Presenters:Christina Nelson, MD, MPH and Naomi Drexler, MPH
Date/Time:April 10, 2014 2:00 pm ET
Welcome and thank you for standing by. All participants will be in a listen-only mode for the duration of today’s call. During this call, we will do a question and answer session. To ask a question please press *1 and record your first and your last name. Once again that’s *1 to record your first and last name. This call is being recorded and if you have any objections you may disconnect at this time. Your host for today’s conference is Miss Leticia Davila. Thank you. You may now begin.
Thank you (Iesha). Good afternoon. I am Leticia Davila and I representing the Clinician Outreach and Communication Activity, COCA with the Healthcare Preparedness Activity at the Centers for Disease Control and Prevention. I am delighted to welcome you to today’s COCA Webinar, Tickborne Diseases: A Springtime Review of Diagnosis, Treatment and Prevention.
We are pleased to have with us today Dr. Christina Nelson and Ms. Naomi Drexler from the CDC. They will describe the signs and symptoms, treatment management and prevention of tickborne diseases in the US, with an emphasis on lyme disease and Rocky Mountain spotted fever. You may participate in today’s presentation by audio only, via Webinar, or you may download the slides if you are unable to access the Webinar.
The PowerPoint slide set and the Webinar link can be found on our COCA Website at emergency.cdc.gov/coca. Click on COCA Calls. The Webinar link and slide set are located under the call-in number and call pass code.
At the conclusion of today’s session the participant will be able to: 1) discuss the geographic distribution of lyme disease, Southern Tick Associated Rash Illness, Rocky Mountain spotted fever, ehrlichiosis and anaplasmosis, 2) explain the signs and symptoms of tickborne diseases, 3) describe the appropriate use of serologic tests for confirming diagnoses of tickborne diseases and 4) state the appropriate use of antibiotics in treatment of these diseases.
In compliance with continuing education requirements, CDC, our planners, presenters and their staffers or partners wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services or commercial supporters. Planners have reviewed the content to ensure there is no bias. The presentation will not include any discussion of an unlabeled use of a product or products under investigational use. CDC does not accept commercial support.
At the end of the presentation you will have the opportunity to ask the presenters questions. On the phone dialing *1 will put you in the queue for questions. You may submit questions through the Webinar system at any time during the presentation by selecting the Q&A tab at the top of the Webinar screen and typing in your question.
Today’s presenter Dr. Christina Nelson is a Medical Epidemiologist in the Bacterial Diseases Branch at the National Center for Emerging and Zoonotic Infectious Diseases at the CDC. She is a subject matter expert for various bacterial vector-borne diseases including Lyme Disease. Dr. Nelson conducts epidemiologic research on Lyme disease, assists with case follow-up and surveillance activities and responds to inquiries from both the public and healthcare providers related to this disease. She has also developed several educational and reference materials related to the treatment, management and prevention of Lyme disease and STARI.
Our second presenter, Ms. Naomi Drexler serves as a Surveillance Officer and Health Communicator for the Rickettsial Zoonosis Branch in the National Center for Emerging and Zoonotic Infectious Diseases as the CDC. She is a subject matter expert on tickborne rickettsial diseases and has developed several educational and reference materials relating to this. Ms. Drexler has an MPH from Emory University in Global Epidemiology and she has published several educational and reference materials on the - on a variety of tickborne diseases. Again the PowerPoint Slide set and the Webinar link are available from our COCA Web page at emergency.cdc.gov/coca. At this time, please welcome Dr. Nelson.
Dr. Christina Nelson:
Hello. Thank you so much for that introduction and thank you all for participating and watching this Webinar. Thank you also to Leticia and the rest of the COCA staff for helping to set this up. So let’s get started.
Today we will discuss some of the leading tickborne diseases in the United States. And these include Lyme disease caused by the spirochete Borrelia burgdorferi, Rocky Mountain spotted fever caused by Rickettsia rickettsii, ehrlichiosis caused by Ehrlichia chaffeensis and other organisms, anaplasmosis caused by Anaplasma phagocytophilum, and Babesiosis caused by Babesia microti. But Babesiosis actually we will not discuss in detail today due to time constraints but the rest of them we will.
There are additional tickborne diseases in the United States. And so it’s helpful if you see this link at the bottom www.cdc.gov/ticks. This is a really great web site. It has all the different tick vectors along with maps of their distributions and information on the diseases that they transmit. So this is a good web site to remember and refer back to for more information on these tickborne diseases and also other ones that we will not cover in this presentation.
So the map, here, shows the distribution of human cases of the four most common tickborne diseases in the United States. The location where these cases are reported is based on county of residence. And there are a couple things to note in this map. So first of all, different diseases are concentrated in different areas as you can see. So Lyme disease and anaplasmosis, the blue and the yellow, are transmitted by the same tick. And they are concentrated in the Northeast and the upper Midwest, primarily Wisconsin and Minnesota.
And then the other diseases, Rocky Mountain spotted fever and ehrlichiosis are concentrated in the Southeast and South Central United States. The second thing to note from this map is that patients with tickborne diseases are found in all states, whether it’s locally acquired or travel related. So as providers there’s a good chance no matter where you are that someone with a tickborne disease will walk through your door at some point in your practice.
So Lyme disease is by far the most common tickborne disease in the United States. And as you can see here in 2012 there were over 30,000 confirmed and probable cases of Lyme disease reported to CDC.
Some of you may have heard that CDC released an estimate recently that we think the actual number is closer to 300,000. And this is consistent with our understanding of underreporting. We know that Lyme disease and basically every other disease that is a part of surveillance is underreported and had expected that the number is much larger than the actual number of cases we get. But based on some studies we have some additional information and estimated that the degree of underreporting is probably ten-fold.
Some people actually did misinterpret this as a reported increase. It has been slowly increasing over the past ten years or so but it did not increase ten-fold within a year. But, we do know that it causes significant disease burden.
The other diseases listed here are less common but more likely to cause death or severe morbidity. And all of these have actually been trending up in the last ten years. This slide shows the selected tick vectors that we will be talking about in this slide. So the black-legged tick (Ixodes scapularis) can transmit Lyme disease, anaplasmosis, babesiosis, and also Powassan disease.
And also recent discoveries Ehrlichia muris-like agent and Borrelia miyamotoi. I didn’t list them all here but this tick can transmit a number of diseases. Both the nymphs and the adults can transmit disease. But the nymph tends to transmit disease more commonly because it’s so small and hard to find and hard for people to find and remove.
One mnemonic that I use to remember and encourage other people to use the three main diseases transmitted by the black-legged tick are Lyme disease, anaplasmosis, and babesiosis. So LAB is the mnemonic to remember those primary ones.
The Lone star tick Amblyomma americanum transmits ehrlichiosis, STARI, and tularemia. It is a very aggressive human biter. And we’ll show you the maps of its distribution. And all of the stages -- this is the larvae stage, the nymph and the adult, all of these cases actually can bite humans. And lastly we have the dog tick Dermacentor variabilis which can transmit Rocky Mountain spotted fever and tularemia.
So different ticks do transmit different diseases. And the location and the risk of various diseases depends on the tick distribution.
And again a reminder about cdc.gov/ticks which has good information on their distribution and diseases and it’s really helpful.
So I’ll talk specifically about Lyme disease now. It’s caused by the spirochete Borrelia burgdorferi. It occurs in areas of North America, Europe and Asia.
In North America it’s just caused by Borrelia burgdorferi. In Europe and Asia additional species can cause it including Borrelia garinii and Borrelia afzelii. There are about 30,000 cases reported annually in the US. And due to underreporting we think that number is actually quite a bit higher. And it’s transmitted in the US by Ixodes ticks.
So Ixodes scapularis as you saw in the previous slide in the Northeast and the Midwest and Ixodes pacificus which is in Western states like California. And Ixodes pacificus is the Western black-legged tick.
So the next slide shows the two-year life cycle of the black-legged tick. And so I think of the first year as the “year of the larvae”. And so basically in the spring, eggs hatch and become larvae that then feed on small rodents and birds.
And that’s typically where they pick up the Borrelia burgdorferi infection. White-footed mice and other rodents have been shown to harbor Borrelia burgdorferi. And that’s where the larvae get infected.
They lie dormant through the winter. And then by the following spring - usually around May or so depending on where you are - they molt and emerge as nymphs. And the nymphs exist through the summer. And by the early fall they transition into adults.
And so like I said both nymphs and adults can be infectious and bite people. And so the peak risk is between May and July but does extend beyond those periods.
You’ll see here many people associate deer with Lyme disease. And the deer are an important part of the ecological cycle. So the deer transport the ticks and the ticks find each other and are able to mate on the deer. But the deer are actually not a part of the infectious cycle. The deer don’t harbor spirochetes and don’t cause the ticks to be infected. They just help them distribute themselves and mate.
So I think that’s all I wanted to say. Oh actually and the peak risk is May through July. But as you’ll see in the next slide people can get infected at any time of the year.
So the next slide that’s coming up is a graph of the cases by month of disease onset. So you’ll see as I mentioned the majority are in the summer months. And that’s when the ticks are most active and people are outdoors. But ticks can be out and active in the fall and winter if the temperature is greater than 50 degrees Fahrenheit.
So the purpose of this slide is just to show you as most of you know there’s a primary risk time for tickborne diseases for Lyme disease. But people can present either with later manifestations that they got infected earlier or they can become infected in the off months as well.
The next slide that’s coming up is a map of Lyme disease cases specifically in the United States. So as I mentioned they are definitely concentrated in the Northeast and then the upper Midwest primarily Wisconsin and Minnesota. And actually 12 states account for over 95% of Lyme disease cases.
And as I mentioned before also reporting (as with other disease surveillance systems) is by county of residence. So for example if a child from New Mexico spends a month with his grandparents in Pennsylvania during the summer and contracts Lyme disease there - even if he is diagnosed and treated in Pennsylvania - that will show up as a dot in New Mexico.
So this does cause some confusion with people about, you know, where Lyme disease is endemic and where it can be acquired because you do see dots all over the United States.
But most of those in the non-endemic areas are travel related but they’ve just been reported from residents.
And so you can see there’s spillover in areas like Florida where people often travel between the two places. And so that’s why you see a lot of dots in areas like those.
So next I’ll talk specifically about the clinical manifestations of Lyme disease. So erythema migrans is the most common sign of Lyme disease. And it occurs in 70% to 80% of cases. It occurs about a week to two weeks after the tick bite. But the range is actually quite variable and can range between one and 30 days after the tick bite.
It has this gradual expansion and so it’s expanding over days very gradually. It’s rarely painful. It can be warm to the touch but usually isn’t particularly itchy.
It can be accompanied by constitutional symptoms and regional lymphadenopathy.
And it’s important to distinguish this from allergic reactions since patients often have questions about this after a tick bite. They may have a sort of local reaction and be worried that it’s an EM rash.
But allergic reactions typically appear within the first 24 hours. They are less than 5 centimeters (or about 2-1/2 inches) in diameter. EM by definition is greater than 5 centimeters.
And those allergic reactions are going to be quite itchy and they won’t have that gradual expansion that you see with erythema migrans.
And it’s important to note also that erythema migrans is actually a local infection. So if you biopsy the area here you can sometimes culture the spirochetes from this area if you take a punch biopsy of the skin or a PCR often will be positive on these samples. But it’s spirochetes infecting locally after the tick bite.
I wanted to highlight some atypical erythema migrans presentations. And they can often be atypical and confuse providers and look like cellulitis or other things.
So this is an erythema migrans rash but as you can see it’s very homogenous. It’s just completely red with a slight lesion in the middle.
This one as you can see on this man’s shoulder has a triangular appearance which is not considered typical but this is erythema migrans.
And this man has multiple EM rashes and they’re all homogenous in appearance. And the EM rashes can also have a central induration. They can be vesiculated. They can have little ulcers in the middle or they can have a blue-ish hue. So they can be quite variable.
If left untreated Lyme disease does disseminate through the blood and go to other parts of the body and cause disseminated Llyme disease.
So I didn’t put this on the slide but multiple EM rashes is one of the earlier signs of disseminated Lyme disease.
And next facial palsy. Lyme disease is one of the most common causes of facial palsy. And facial palsy is one of the most common early disseminated forms of Lyme disease. It occurs typically in the summer months and can be bilateral. And patients may or may not have a CSF pleocytosis associated with this.
Arthritis can be intermittent and it can be monoarticular or oligoarticular. And the hallmark of Lyme disease arthritis that’s important to remember is that you see swelling out of proportion to the pain.
So patients have these very swollen joints that are somewhat painful but you’re not going to typically see that exquisite tenderness that you see with a septic joint or other things.
And late-stage neurologic effects if left untreated for months or years can appear. And these include peripheral neuropathy. Encephalopathy has been reported but it’s quite rare.
I also wanted to mention, it’s not on this slide but carditis is a known complication of disseminated Lyme disease. It can typically appear as conduction defects and heart block. AV nodal block is the most common form.
And some of you may have seen a recent MMWR that our group published describing three patients who died suddenly, had sudden cardiac death due to Lyme disease.
And these were young patients in their 20s and 30s who basically were previously healthy and died quite quickly and unexpectedly. So this was pretty tragic and we’re looking more into this phenomenon.
In this graph here you can just see a breakdown of the clinical signs of Lyme disease by manifestation. The percentages add up to more than 100% because people could report more than one manifestation.
But as you can see erythema migrans is by far the most common followed by arthritis and facial palsy. And then the less common forms such meningitis and cardiac manifestation.
We do think there is some reporting bias associated with this. A physician who has seen the fifth case of EM in a month is probably less likely to report that to the health department than someone who’s seen a really interesting case of arthritis. But it does give you a relative sense.
So for testing for Lyme disease, we recommend the two-tiered testing approach. And so the first test is this – it’s sensitive EIA. And it’s a quantitative test. The IFA can also be used but it’s usually the EIA. If that is positive or equivocal then the lab should move on to the second test.
So providers should order this as the two tiered testing if possible. And the second test is a reflex if the first one is positive. If the patient has signs or symptoms less than 30 days, then they will do an IgM. They should do both an IgM and IgG Western Blot.
And the Western Blot is a specific test and it’s a qualitative test. So you can see specific bands against parts of the bacteria.
If the patients has signs or symptoms greater than 30 days only the IgG Western Blot should be done. And that’s because the IgM can be quite cross- reactive with other conditions and can be misleading if it’s positive.
So if you can only order the IgG for the reflex second test that is ideal. Often labs automatically do both. And so just remember if a patient’s been sick for more than a month and you get both of those results back just remember that the IgM is cross-reactive and you should disregard that. And really the IgG is giving your answer.
If the EIA is negative then the Western Blot (the second tier) is not performed. If a patient has been sick for less than a month then they are in that window period of serologic testing. So you can consider obtaining a convalescent serum.
If a patient has been sick for more than a month then that testing is trustworthy and you don’t have to do further testing.
Oh there goes the circle that I meant to (unintelligible).
So the next slide -- there’s a lot of lab testing done for Lyme disease in the United States. And this slide’s a reminder that interpretation of any test results depend on the likelihood of diseases in the population being tested.
So if you can see on the left side here if the disease is common -- so the pretest probability is high -- that test is going to be very accurate.
And so if the disease is common -- if for example it’s common in the entire US or it’s common based on the circumstancesyou have a patient in New York who has a known tick bite -- then if you get a positive it is very likely that that’s a true positive. And a negative is very likely to be a true negative.
On the other hand, on the right side if the disease is rare (and again that’s either overall or based on the circumstances) if you have a patient in Arizona who has non-specific symptoms the pretest probability of Lyme disease is quite low.
So in that circumstance even if you get a positive test that test is more likely to be a false positive than a true positive.
So we encourage providers to keep this in mind when deciding whether to order tests for any infectious disease and specifically for Lyme Disease.
This is just a graph of the sensitivity of the two-tiered serologic testing. So remember this is a serologic test so it’s measuring the immune response to an infection. And so there’s a window period. And this is true for any serologic test for HIV or hepatitis or anything that’s looking for antibodies against the infection.
So early in infection the sensitivity is somewhat low. But later in diseases once the body’s developed detectible antibodies the sensitivity is actually quite good.
So the bottom line is this testing is good. In later stages of disease the sensitivity is actually quite high. And early in disease testing of patients with EM is generally not necessary.
So if a patient has been exposed in an endemic area and has an EM rash it is absolutely appropriate to clinically diagnose them and go ahead and treat without ordering the test.
So I wanted to highlight some additional tests that have not been shown to be useful but are often concerning or confusing to patients and providers:
- Some labs will go straight to the Western Blot without the first step EIA and that is not appropriate.
- Some labs also use their own criteria for interpreting the immunoblots and they say that a certain of bands is positive - and that is not consistent with the CDC guidelines.
- There’s capture assays for antigens in urine, tests for cystic forms which have not been shown to exist in vivo,lymphocyte transformation tests, CD57 assays.
- And also note there’s a new lab in Pennsylvania that offers a novel culture technique. And we have a lot of concerns about this test and analyzed some of their results. And you will hopefully see an MMWR coming out soon regarding this test and recommendations around it.
So just some red flags for alternative labs:
- The tests offered are not often not FDA approved. The lab may be CLIA certified but that just means the lab has undergone some basic quality assessments. But the actual tests often are not FDA approved.
- The lab may claim to specialize in Lyme or other tickborne disease testing. That can be a red flag. And they often don’t accept insurance. And so the patient is paying quite a bit of money out of pocket.
- And these can be very misleading to patients and providers because they come with very official reports and they look official. And unless you know that alternative labs and invalidated tests are out there it can be misleading.
So treatment in adults, I’ll just highlight real quickly, tick bite prophylaxis consists of one 200 milligram dose of doxycycline. And that is appropriate in certain circumstances when doxycycline is not contra-indicated, if the tick’s been attached for at least 36 hours based on history of exposure or whether it’s engorged, the patient’s coming from an endemic area, and you can give the prophylaxis within 72 hours.
And so, this is for people who can use doxycycline so not for children under 8 in this circumstance.
Treatment of erythema migrans: you can use doxycycline, amoxicillin, cefuroxime. Patients with some other manifestations can be treated with the same oral regimen. Treatment for carditis can be oral or IV. Nervous system disease is typically treated with IV antibiotics.
Patients with recurrent arthritis can be retreated with oral antibiotics or IV antibiotics. And that is the one case where it is appropriate to go back and retreat a patient for a month or so.
And this is just a summary so if you want details please go to the IDSA Website. They have the full guidelines. And for children the Red Book has very good - a very good chart and information on treatment of children.
So the prognosis, most patients treated with antibiotics recover completely. Patients who have persistent or recurrent joint swelling may need a second four week course as I mentioned.
And going back to the first bullet most patients recover completely but it’s important to counsel your patients that it can take some time.
They’ve had a systemic infection and patients can be fatigued or, you know, have non-specific symptoms for some time after recovering from the infection. It doesn’t necessarily mean they need more treatment. Their body just needs time to recover. So counseling them about that can help.
Some patients -- and that’s particularly those who have been diagnosed in the later stages -- can have persistent symptoms of fatigue or muscle aches or reduced concentration. And the preferred term for this is Post-Treatment Lyme Disease Syndrome.
It has not been shown that long-term antibiotic treatment is beneficial for these patients. We think the PTLDS may be due to residual damage or an autoimmune process or pieces of the bacteria left behind.
Lastly on this slide I’ll mention chronic Lyme disease. And that is a poorly defined term. Patients with non-specific symptoms sometimes are told that they have chronic Lyme disease and are treated with antibiotics even if they have no outward physical signs of disease or laboratory evidence of infection.
And I think I’m going over in time a little bit but I should wrap up pretty soon. I wanted to mention that as you all know antibiotics have risks and that long term antibiotic treatment has not been shown to be effective and they do have risks.
So this is a report of a 30 year old woman who received 27 months (over two years) of IV ceftriaxone through a catheter for purported chronic Lyme disease.
She had the catheter in so long that she developed a Candida growth at the tip of the catheter which broke off and embolized to her heart and she died, a 30-year-old woman.
And medical record review actually showed that she had no evidence of ever having Lyme disease. So in this picture you can see here’s the tip of the catheter and here’s this enormous Candida growth that embolized to her heart.
And in addition this there have been reports of severe C. diff infections, neutropenia, anaphylaxis. And in addition to the medical side effects many patients have cashed in their retirement savings or had severe financial strain to pay for these treatments that have not been shown to be effective.
So lastly I’ll just mention STARI which can complicate the diagnosis of Lyme disease because it presents with a rash that’s indistinguishable from the EM you see in Lyme disease.
It can be accompanied by constitutional symptoms and it follows the bite of the lonestar tick. It’s also known as Masters’ disease and the cause is actually not known.
They have looked for various infectious agents including Borrelia lonestari, viruses -- and no organism despite extensive study has been found to date.
There are theories that perhaps it’s an allergic reaction or autoimmune or toxin related. And those are being investigated.
lone star ticks have not been shown to be able to transmit Borrelia burgdorferi. And actually their saliva kills Borrelia burgdorferi. So this is definitely not thought to be Lyme disease.
This next slide is just a map of the distribution of the lone star tick and the actual tick. And so one way to distinguish Lyme disease versus STARI is to identify the tick.
And so the adult female has a very distinct white spot on its back. The adult male has some other distinct markings on its back. So if you can identify that and that’s what bit the patient who has an EM then they likely have STARI.
And also the location can help you distinguish. But as you can see the lone star tick range is actually quite extensive and overlaps quite a bit with some of the range for patients with Lyme disease or range of risk for lyme disease.
So the treatments are actually not known -- whether antibiotic treatment is necessary or beneficial for patients with STARI. And there are areas of overlap.
STARI has not been linked to long-term sequelae such as arthritis, neurologic disease or chronic symptoms. But because it resembles early Lyme disease, physicians will often treat patients with oral antibiotics and that is okay especially in areas where the distribution overlaps -- for example in Virginia where both ticks are present and unless the patient brings in the tick you don’t know early on what the patient has. So it’s okay to treat as if it were Lyme disease.
Paul Lantos and others actually did publish a model that showed based on the benefits vs. risk in places where Lyme disease is rare (in the Southeast for example) if a patient comes in with EM the preferred strategy is to observe the patient and not treat right away. In places where Lyme disease is common the best option is to go ahead and treat.
So lastly just a quick plug for prevention and providers can play an important role in communication about prevention.
So it’s important to avoid tick habitat. Of course we want people out there exercising and enjoying nature. But if they can try and walk in the middle of the trail then avoid exposure to the real forested or grassy areas that’s helpful.
DEET is very effective if you use at least 20% on your exposed skin. And you can put it on most types of clothing as well.
DEET can be used in children at least 2 months of age. And the AAP actually has good guidelines on its web site for application and for use in children, so definitely check that out.
And permethrin is great for treating clothing. You can buy it and treat your own clothing or buy pre-treated clothing. And it lasts through -- depending on the method of application -- it lasts 30 to 70 washes. And so people can have a dedicated pair of hiking pants for example that are permethrin treated.
Showering after being outdoors washes away the nymphs, gets people taking their clothes off and checking for ticks.
Doing tick checks every day and removing attached ticks as soon as possible is important. Treating pets for ticks and also encourage your patients to call if they develop a fever or rash. So that’s all I have. Now I’ll pass the presentation on to Naomi. Thank you.
Thanks Christina. I’m just going to go right into the tickborne rickettsial diseases here. I’m going to be mainly talking about Rocky Mountain spotted fever, but I will also mention ehrlichiosis and anaplasmosis.
These diseases are a little different from what you’ve been hearing about from Christina earlier. They’re very rapidly progressing. And unfortunately early presentations are very non-specific so it can really difficult to diagnose in the early stages but it can rapidly fatal in - severe and potentially fatal in previously healthy individuals.
So we want to make sure we’re aware of the potential risk factors and early clinical manifestations so we can treat early.
The nice thing about tickborne rickettsial diseases is that they’re all treated with the same antibiotic Doxycycline. And the testing schemes are similar. So you don’t have to figure out which rickettsial infection it is just necessarily identifying if it could be a rickettsial infection.
So I know Christina went over some of the distribution of Rocky Mountain spotted fever and here’s a picture of just RMSF on its own, cases reported in 2012. Again, these are where the patient lived, not necessarily where they were exposed.
But what you can see is that we have the majority of our cases are located in Southeast and South Central United States. In fact 60% of our cases of RMSF come from North Carolina, Oklahoma, Arkansas, Tennessee and Missouri. So clinicians in that area are I’m sure very well aware of the risks of Rocky Mountain spotted fever.
So Christina went over the seasonal distribution of lyme disease. Rocky Mountain spotted fever, ehrlichiosis and anaplasmosis all have a similar seasonal distribution. We have the majority of our cases reported in June and July.
However as Christina mentioned, we have for lyme disease the same for all other rickettsial diseases that there is - there are cases reported in every month of the year. So there is no no-risk time of the year. And it’s important to keep rickettsial infections on the differential no matter the time of year.
The off seasons are actually some of the more difficult times and when cases are missed most - more frequently.
So I know Christina mentioned the common tick factors earlier in her presentation. I’m just going to briefly go over the primary (RMSF) tick vectors. We have Dermacentor variabilis which is mostly located east of the Rocky Mountains, Dermacentor andersoni which is mostly located in the Rocky Mountain region, some in the Pacific Northwest on down into Northern Arizona and Utah areas.
The last one is Rhipicephalus sanguineus. And this is a newly identified vector of Rocky Mountain spotted fever in 2004. This tick vector is actually present throughout the world. It’s a very common tick.
But we’ve only noticed that it’s carrying Rocky Mountain spotted fever transmitting Rocky Mountain spotted fever in the Southwest and parts of Mexico. So it’s a tick that’s everywhere but it may not be causing Rocky Mountain spotted fever everywhere.
So what is Rocky Mountain spotted fever? This is a tickborne rickettsial disease caused by an intercellular bacterium called Rickettsia rickettsii. This bacterium typically likes to live inside the endothelial cells and can cause wide-spread vasculitis. And this can be really difficult to when looking at diagnosis because it can cause an array of symptoms depending on where it’s located. So it’s very non-specific. It can look like a respiratory infection. It can look like an acute abdominal infection, appendicitis, (Cholecystitis). And it’s notoriously difficult to diagnose.
When left untreated it can cause wide-spread vascular damage ultimately leading to multisystem organ failure and death if left untreated.
One thing I do want to mention is that there is no classic RMSF presentation. This is something we’re trying to steer away from based on newer information about Rocky Mountain spotted fever.
What we used to think of as being the classic presentation would have been a fever, rash and a tick bite, history of tick bites. And those are still, you know, common symptoms for Rocky Mountain spotted fever but we’ve - what we found is that only 20% of patients actually report having this trifecta all at once in their first presentation.
And if you wait for the trifecta you’re often waiting until it’s too late to treat. And you will have allowed for severe sequella to have erupted.
So the rash in particular may appear later in disease presentation. And we never want to wait for a rash to be present in order to treat or suspect Rocky Mountain spotted fever.
So another thing about RMSF is that it is rapidly fatal. And this is why it’s so difficult and we have to treat so aggressively so early is because the median time to death is only eight days. And that’s in previously healthy individuals. So it’s a very short turnaround time unfortunately.
So what I’d like to do is I’d like to break RMSF clinical presentation up into early - to two groups -- early presentation and late presentation.
Early presentation is where the majority of you will be interacting with your patients. They typically come in fairly early on on day one, day two of symptoms because they are feeling very ill.
They may come in several times if they are still having progressing symptoms and have not received proper treatment yet.
So early symptoms again are very non-specific. We see that they’re having fever, headache myalgia. Some of them may have gastrointestinal signs, nausea, vomiting, diarrhea. And some may also have more respiratory like signs which make you think of community acquired pneumonia or viral syndromes.
The maculopapular rash is one that we typically think of as being early in the disease presentation. Unfortunately this may not occur in everybody and my not occur until later in disease progression. So again I’d like to say never wait for a rash to be present to suspect Rocky Mountain spotted fever.
Some of the laboratory indicators may start to erupt after this time, the thrombocytopenia, the hyponatremia, elevated liver enzymes. But what we found is these are generally very mild in early clinical presentations.
So the second category is the late clinical presentation. And this is usually marked around day five. We see a rapid, drastic shift towards severe clinical manifestations around day five of symptoms and in untreated individuals.
And this may unfortunately if you reach this period of time and have not treated the patient may result in permanent disability such as digital necrosis, loss of the tips of the fingers or neurological devistation and sometimes even death.
So their clinical manifestations you may see - be seeing at this time, worsening systemic illness, septicemia, onset of neurological signs to the mentaled alter status, altered medical status, excuse me and the Petechial rash is one of the classic late-stage signs of Rocky Mountain spotted fever.
And unfortunately we never want to get to this stage. If you’ve seen a particularly rash it’s a sign of advancing vasculitis and it’s only indicating what’s going on in the rest of the body and we never want to get to this stage
So we know that the best treatment for Rocky Mountain spotted fever and actually for all rickettsial diseases is Doxycycline. And this is the treatment of choice for adults and children of all ages. It’s recommended by the AAP and the Centers for Disease Control for the treatment of children as well as adults.
And it’s best if you can administer the Doxycycline within the first five days of symptoms to prevent the severe sequella and death.
Because the early clinical treatment, early clinical manifestations are so non-specific, it’s important to rely on exposure history as a guide to whether you think Rocky Mountain spotted fever or any other rickettsial infection could be to blame for your patient’s symptoms.
It may not be that they report a tick bite but you can ask them about their recent history of being in the woods, taking a hike, camping, et cetera where they may have been exposed to ticks.
It’s important to keep in mind that other broad spectrum antibiotics are not effective against Rocky Mountain spotted fever or other rickettsial diseases. And some research has actually shown that antibiotics like sulfas and fluoroquinolones may cause more severe disease and will not prevent fatal outcomes.
Christina mentioned the use of Doxycycline in children. And this is very different from lyme disease because rickettsial infections are so fast-acting. They require a shorter duration of antibiotic therapy.
And it - no studies to date have shown any tetracycline like staining or any staining to date that’s been used from the recommended doses and duration of - for the treatment of rickettsial diseases even when multiple course have been administered.
So keep in mind that this is a different duration and at that dose and duration we haven’t seen any staining present.
And because there are no other effective antibiotics for rickettsial diseases it’s kind of our only option and we highly recommend the use for suscepted rickettsial infections.
Here are the doses and durations again for adults and children. For pregnant women or cases of life-threatening tetracycline allergy we do recommend consulting with an infectious disease physician.
Testing for Rocky Mountain spotted fever is only for surveillance and public health purposes. And of course it’s not going to help you make a clinical decision unfortunately and cannot - no diagnostic test can help you definitely rule in or out Rocky Mountain spotted fever in your acute phases.
So what we do use for diagnosis of RMSF is PCR of - or IHC of whole blood serum and tissue can be done. These are mostly likely to be accurate in the severe stages or late stages of illness.
They are unlikely to be positive in the acute stage because the R. rickettsii are not circulating in large numbers in the blood.
The more common test that we use is the indirect immunoflorescence assay for the detection of antibodies. And this requires two tests, a test in the acute phase and a test in the convalescent phase two to four weeks later.
We use that comparison of baseline and convalescent to show if there’s an increasing titer indicating an acute infection.
So one thing I’ll mention again about the Rhipicephalus, the brown dog tick is this is one vector that we’re finding carrying Rocky Mountain spotted fever in Southwest and in parts of Mexico. This has been associated with a higher case fatality rate and a higher incident of cases unfortunately.
I’m going to speed through Ehrlichiosis and Anaplasmosis. I know most of the information is going to be the same. They’re very non-specific clinical presentations. But they are found in different tick vectors and in different parts of the country.
Here’s an image of the Ehrlichiosis chaffeensis cases from 2012. As you can see most of the cases are localized at the Southeastern and South Central United States except for E. Muris-like cases which are located more often in Minnesota and Wisconsin. So you can see some of those upper Midwestern cases.
Again signs and symptoms of Ehrlichiosis very non-specific. One important difference from Rocky Mountain spotted fever is that rash is less common. We get rash reported in about 60% of children but only in 30% of adults.
And another thing that we have found is that studies have shown that Ehrlichiosis severity may depend on the immuno-competence of patients.
So those who are - have a compromised immunity may have more severe cases than the general population.
Again here are some images of where we find common reports of cases of Anaplasma. You can see it’s mostly localized to the upper Midwest and Northeastern United States where that black-legged tick is more commonly found.
Symptoms are again very non-specific -- fever, headache, myalgia, cough, confusion. The rash is very rarely reported in Anaplasmosis cases.
In fact if you do have a rash presenting on a patient it’s more likely that this is the cause of a co-infection of lyme disease because they are both lyme disease and Anaplasmosis are transmitted from the same tick vector. But it could also mean that it - you may be looking at a case of Rocky Mountain spotted fever instead.
And as with Ehrlichiosis persons with compromised immune systems tend to have a more severe clinical presentation. I’ll just briefly note that there have been reports of organ transplantation and blood transfusion transmitted cases of Rocky Mountain Spotted Fever - not Rocky Mountain spotted fever - of Ehrlichiosis and Anaplasmosis.
Because these bacteria are often infecting the white blood cells and circulating in the blood stream they’re more commonly present - more likely to pose a risk for transfusion transmitted cases. There have been cases reported out of the United States for both Ehrlichiosis and Anaplasmosis transfusion transmitted cases.
Donors may be asymptomatic at the time of their donation. And any patient who received - who develops symptoms of Anaplasmosis and Ehrlichiosis following months after a blood transfusion or a solid organ transplant should be reported to state health organizations for very prompt investigation.
Treatment is again the same as Rocky Mountain spotted fever Doxycycline for children and adults. And the only difference is that for Anaplasmosis if that is suspected we recommend a slightly long duration of ten to 14 days of Doxycycline just in case there’s a co-infection of lyme disease.
Testing is the same. You can use PCR or serology. PCR is actually very- is a very good test for Ehrlichiosis and Anaplasmosis because they are circulating in wide numbers in the blood stream. So even after they - shortly after they receive antibiotics PCR can be the most sensitive test for acute illness.
You can also use the two serologic tests in the acute phase and in the convalescent phase. And again we’re looking for a four-fold drive in the antibody titer for indication of an acute infection.
And I know we’re running over so I’ll just leave it at if you have any more questions we have the MMWR available from 2006 on tickborne rickettsial diseases in the United States. Thank you.
Thank you Dr. Nelson and Ms. Drexler for providing our COCA audience with such a wealth of information. We will now open up the lines for the question and answer session.
And also you - also remember you can submit questions through the Webinar system at any time. Operator?
At this time we’ll begin the question and answer session. If you’d like to ask a question please press *1 to record your first and your last name. Once again that’s *1 for your first and last name. One moment while we wait for our first question.
And we do have a question that comes from the Webinar system. And it states what would be a good test to diagnose lyme meningitis?
Dr. Christina Nelson:
So for diagnosing Lyme meningitis typically it’s the clinical picture. And so you’re going to have the signs of meningitis along with a potential exposure in an endemic area.
And so you see a lymphocytic meningitis with this. And so that’s - and then you can do the two tier serologic testing. That’s - meningitis is considered the early disseminated phase. So there’s a good likelyhood we heard that the two tier testing would be positive.
You can - there are CFS tests for Lyme disease. If you want to run them you can do an - a CFS to CRM antibody ratio. And so you can talk to the lab or get in touch with us about the specifics of doing that. And you can also do a Western Blot to look at specific bands within the CFS.
Sometimes the antibody expression is slightly different in the CFS versus the blood. And so if you do see bands and compare them to the IgG bands that you’re seeing the blood that can helpful for diagnosing an infection. But typically it’s by the clinical picture exposure history and serologic testing.
Thank you. Operator?
My apologies. I was getting the participants’ names. Your first question comes from (Pat Gormerly). Your line is now open.
Hi. I wondered what had you said about the actual causes of death for the cases of spotty - ah, Rocky Mountain Spotted Fever? What actually causes the death?
That’s a great question (Pat). For the most part these are ending up in cases of multi-system organ failure unfortunately. So patients become very septicemic and succumb to widespread bacterial septicemia. There have been more neurologic like illnesses as well, neurologic presentations, some stroke-like symptoms and meningitis like symptoms. But for the most part it’s the widespread bacteremia.
No additional questions from the phone lines at this time.
We do have a couple that have come through the Webinar system. I have heard that there may be a new lyme disease vaccine in the works. Is this true? And if so could you comment on this?
Dr. Christine Nelson:
Yes that’s a good question. So many of you recall that there was a lyme disease vaccine available. Back in 1998 Lymerix was released on the market. And it did have fairly good efficacy against lyme disease.
But there were some opposition groups and questions about the safety. Some people claimed that it cause arthritis symptoms and they - the demand due to these claims and some other things was low and so it got pulled from the market in 2002.
I will mention that they did an analysis of over 1.4 million doses of distributed vaccine through the Vaccine Adverse Events Reporting System and actually did not find an association. But that was kind of too late. The vaccine had already been pulled.
So just my personal opinion, a vaccine would actually be very helpful. The preventative measures that I mentioned are all helpful but they require a time commitment and remembering to do them every day. And for public health, you know, it’s nicer if you can provide people with more consistent protection that they don’t need to go out and do something every day.
So a vaccine would be helpful. Baxter has actually been studying a lyme disease vaccine. And they recently published results of a phase one and phase two trial in Europe. And that was published in Lancet Infectious Diseases.
And they had good results from the phase one and two trial. The main outcomes were adverse reactions and also antibody responses.
The vaccine is actually comprised as the same with - from the same protein that was in the early vaccine. It’s the outer surface A protein (OP A). And that’s expressed by the bacteria.
But due to those concerns that were raised with the first vaccine they actually took out even though they were unsubstantiated they actually took out that epitope from the current vaccine formulation. So hopefully that will assuage some concerns about that.
So anyway we’ll see where it goes. I believe that or hope that phase three trials are in the works. And it may be on the market sometime in the next five years or so but to be determined.
Thank you. I also have another question from the Webinar system. For Lyme testing is the C6 peptide ELISA considered useful and if so when to use?
Dr. Christina Nelson:
Oh I am so glad that person brought that up. That’s a very good question.
I didn’t mention C6 due to time constraints on this call but yes the C6 so usually the ELISA is done with a whole cell sonacate, so the whole bacteria.
C6 is a certain surface peptide on the bacteria and it seems to be more immunogenic. And so C6 by some labs can be substituted and that is an FDA approved test for the first year test instead of the whole cell ELISA.
C6 is useful. It seems to become positive a little bit earlier than the regular ELISA. And so if a patient’s earlier infection sometimes the C6 can be helpful.
It’s also tends to be positive more often in patients who have the European strains of lyme disease. So if you have a patient who returned from a trip and there’s a question of European lyme disease then the C6 can be helpful in those situations.
And lastly the C6 antibodies tend to fade a little bit faster. It’s still on the orders of years but more like one to three years versus the typical antibodies that we look for stayed within five to ten or more years.
And so in questions of reinfection that hasn’t been studied extensively but there is the thought that the C6 test could be helpful in questions of reinfection. So I’m glad you brought that up. And it is an approved test and it’s a trusted test.
Thank you. Operator?
Yes once again if you’d like to ask a question please do so by pressing *1 on your touch-tone phone and recording your first and last name. Again that’s *1 and your first and last name. At this time there are no questions pending.
Okay I have another one coming from the Webinar system. Could you speculate about what causes the bulls eye appearance of the EM rash in Lymes for STARI?
In particular are there any thoughts about the histology of the central cleaning - clearing?
Dr. Christina Nelson:
Central clearing I think?
Yes central clearing?
Dr. Christina Nelson:
Yes the bulls-eye, we think what’s happening are the spirochetes are replicating and expanding in the skin. And so as they’re expanding they’re kind of leaving behind the skin that probably becomes uninfected as they’re advancing. And so that’s why for lyme disease we think there’s that bulls-eye appearance.
For STARI it’s really hard to say. Since we don’t know what causes it we don’t know what causes the various manifestations either. And so, you know, if it is a reaction to the saliva or the autoimmune process I guess there’s ways you could explain why that would cause a bull’s-eye appearance but it’s hard to speculate at this point.
Thank you. Operator?
Once again there are no questions from the audio.
I have a few more questions in the Webinar system. Just give me one second while I pull those up. Okay the question says can you elaborate a bit about what may contribute to the notion that there may be about 300,000 cases of lyme disease annually rather than just 30,000?
Dr. Christina Nelson:
Sure. So in the past there has been some studies of underreporting in specific states and specific circumstances. And so those studies gave us a range of underreporting as anywhere between two and 12. So what they did is they looked at the reported cases and they used various methods to go back and find the actual cases. And the difference was between two and twelve-fold.
So we thought that reporting was somewhere in that range, you know, probably five to - underreporting was five to ten-fold we thought. But there have been some recent studies and just the abstracts have been presented. And so I can’t really go into detail.
But one of them was based on a survey of laboratory testing. And they were able to back calculate using the number of positives to estimate the actual number of infections.
And another one was using a large insurance database to look at coding for lyme disease and distributions of codes and how that compares to the reported cases.
And then another was based on survey of the general public and whether they’ve been diagnosed. And we have some other information to kind of to corroborate that as well.
So that was a preliminary estimate. You know, we made sure to hopefully highlight that it was a preliminary estimate. And we are finalizing our results. But they do seem to point to ten-fold underreporting.
Thank you. I have another question. Can a patient become infected more than once with any of these diseases, i.e., are there antibodies protective at all?
Dr. Christina Nelson:
I’ll answer briefly for Lyme Disease. The answer is yes. But studies have shown that when they’re re-infected it’s with a slightly different strain. And so Borrelia burgdorferi but the genetic, when they look at the genetic composition of the reinfection it’s different from the initial infection.
So infection does provide some immunity but not complete immunity and yes people can be re-infected. And then Naomi?
Yes for rickettsial diseases the best answer I can give you is that we’re not positive. We don’t believe that people can become -we do believe that they can have generated immunity from their first infection. But we’re not positive that it will provide life-long immunity. We have no reports of reinfection of any of the diseases that I presented today but we’re not sure if it’s possible or not.
Thank you. Operator?
Yes our next question comes from (Shanell Shumay) and your line is now open.
Thank you. Hi. I have a question and then possibly a follow-up question.Generally, we’re taught that lyme disease is a northeastern concern and I saw the maps of distribution. In our area in one particular county we have a lot of positive lyme tests. But the suspicion is so low because we’re in North Carolina and we’re not supposed to have lyme. And I just wanted to know what the threshold is for national recognition that lyme is not necessarily a Northeastern phenomenon.
Dr. Christina Nelson:
Right. Yes and we do look into the cases carefully and the state and local health departments do become aware and look into those cases also. So yes the range is definitely expanding both northward and southward for the - ticks who are infected with Borrelia burgdorferi and for the risk for patients where they can acquire it.
And so, there is definitely an understanding that the range is expanding and that we need to keep our eye out for new cases. But at the same time have to remember that sometimes the test can be cross-reactive and should be performed in the appropriate situation.
And so it’s kind of balancing that information and trying to determine whether this case was truly acquired locally and whether this is a true infection.
But we definitely keep tabs on that and try to be aware of where it can be acquired. Did that answer your question?
It does thank you. And then the follow-up somewhat related is a lot of people want to save the ticks or bring them into the office and show it to us. And I just wanted to know your thoughts on that. How important is it to really identify the tick, et cetera?
Dr. Christina Nelson:
Yes that’s a good question. So it is - we do encourage patients and to bring in their ticks just so you know, you know, since ticks transmit such different diseases that really helps you narrow the differential diagnosis if you can identify the actual tick. So we do encourage that.
Tick testing on the other hand usually is not recommended because it does take time. And by the time you get the results back, you know, you should be looking for clinical signs and symptoms anyway.
And also it can give you a false sense of either security if it’s negative. The person could have been bitten by another tick or if it’s positive it doesn’t necessarily mean the patient was infected if they remove the tick in time and stuff like that. So yes if they can bring it in and you can identify it or someone in the office can look at pictures and identify it that’s definitely helpful.
Great. Thank you.
There are no further questions at this time.
We’ll go ahead and take two more questions from the Webinar system. The first question says from the public health department perspective when a person with non-specific symptoms is reported with multiple positive antibody titers for example RMSF, Ehrlichiosis, Anaplasmosis how would you decide which disease to classify the case as?
That’s a great question. If you have antibody results to - both the acute and the convalescent there should be one of those diseases or one of those antibody antigen specific antibody responses that is more - has a higher titer change than another. Oftentimes, you know, our antibody responses can stay elevated for months or years. And each one of these antigens can produce their own specific antibody response.
So why we take the acute and the convalescent is to try and see what is the change, the active change that’s going on in the body. So if there’s a four-fold or greater response in one of the three rickettsial diseases but not out of the other two that would be strongly indicative of that antigen being to blame.
Also you can use some of the geographic indicators too. If the person was exposed in a certain location where maybe Rocky Mountain spotted fever is more prevalent than Ehrlichiosis or Anaplasmosis you can use that in differentiating which disease to report.
Dr. Christina Nelson:
And I’ll just add to that and Naomi can - this is Christina - can correct me if I’m wrong. But if you have a patient with long-standing non-specific symptoms that is not consistent with our current understanding of how these diseases present.
And so if they have low level titers to a number of - especially the IgM which can be more cross reactive and if they have low level titers that is likely an indication, you know, we would take it on a case by case basis. But it’s likely an indication of cross reaction and not necessarily an acute infection with the extra information that Naomi described. So just keep that in mind as well.
That’s absolutely correct. Or it could be an indication of a historical infection. We’re really looking for that change in titer to be able to be a strong indication of an active or recent infection.
Thank you. One last question for today’s call, is the C6 test approved for body fluids or only blood samples?
Dr. Christina Nelson:
I believe it’s only approved for blood samples. I haven’t seen any research on other body fluids.
Okay thank you. On behalf of COCA, I would like to thank everyone for joining us today with a special thank you to Dr. Nelson and Ms. Drexler.
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