Little Bite, Big Disease: Recognizing and Managing Tickborne Illnesses
Presenter:Christina Nelson MD, MPH; Elizabeth Schiffman, MPH, MA; Naomi Drexler, MPH
Date/Time:May 24, 2016 – 1:00 pm CT
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Thank you Amber. Good afternoon. I’m Will Koehne and I’m representing the Clinician Outreach and Communication Activity, COCA, with the Emergency Risk Communications Branch at the Centers for Disease Control and Prevention.
I’m delighted to welcome you to today’s COCA call, Little Bite, Big Disease Recognizing and Managing Tickborne Illnesses. You may participate in today’s presentation by audio only via webinar or you may download the slides if you’re unable to access the webinar.
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At the conclusions of today’s session, the participants will be able to review the geographic distribution to find the symptoms of, identify the serologic tests and use to diagnose, and describe the appropriate use of antibiotics for Lyme Disease, Southern Tick Associated Rash Illness (STARI), Rocky Mountain Spotted Fever, Ehrlichiosis, Anaplasmosis and other emerging tickborne diseases.
Our first presenter is Christina Nelson, MD MPH. As a medical epidemiologist at CDC since 2012 she is a subject matter expert on various bacterial vector-borne diseases including Lyme disease.
She conducts epidemiological research on Lyme disease, assists with case follow-up and surveillance activities and responds to inquiries from the public and healthcare providers related to this disease. She’s also the author and first author and co-author of several Lyme disease publications.
Our second presenter is Elizabeth Schiffman MPH. Elizabeth is a senior epidemiologist with the vector borne disease program at the Minnesota Department of Health.
Her primary tasks involve coordinating human disease surveillance activities for tickborne and mosquito-borne diseases in Minnesota as well as working on a variety of studies and special projects regarding the ecology and epidemiology of vector borne diseases in the upper Midwest. She has been a coauthor on several reviewed publications on mosquito and tickborne diseases, most recently Borrelia mayonii.
Our third speaker today is Naomi Drexler, MPH. Naomi currently serves as an epidemiologist with the Rickettsial Zoonosises Branch at the Centers for Disease Control and Prevention. In that capacity, she compiles and analyzes national surveillance and other epidemiological data relating to tickborne rickettsiosial diseases in the United States.
As a subject matter expert, she has published materials in peer review literature on the epidemiology, prevention, and control of Spotted Fever Rickettsiosis and other tickborne rickettsiosis in the United States.
At this time please welcome Dr. Christina Nelson.
Dr. Christina Nelson:
Hi. Thank you Will. Hello. Thanks to everyone for attending and thank you also to the COCA staff for organizing this call. I wanted to start off with a list of the most commonly reported tickborne diseases in the United States.
Today we will be discussing all of these except for Babesiosis and also some newly emerging tickborne diseases of interest. I wanted to point out also on this slide for information on these and other diseases, you can go to this Web site highlighted at the bottom, cdc.gov/ticks which has a lot of information about the ticks, the diseases they transmit and also maps of where they can be found.
So different ticks transmit different diseases as you can see. So shown here are some of the key tick vectors found in the United States. The blacklegged tick which is here on the top, as you can see, transmits a number of pathogens. I’ve just listed some of the ones it can transmit.
A good mnemonic to remember for the three most common pathogens it can transmit or diseases that these pathogens can cause are, is LAB, is Lyme disease, anaplasmosis and babesosis. Again, it can transmit more but the most common are these three, and that’s a good way to remember it.
Also here you can see the lone star tick which is an aggressive human biter and also transmits a variety of pathogens and causes different diseases and also the dog tick. Here’s a map of the most common tickborne diseases that occur in the United States.
So the diseases that are transmitted or the pathogens that are transmitted by the blacklegged tick are concentrated heavily in the northeast and the upper Midwest as you can see here. So the purple, green, and orange again are those diseases LAB, Lyme disease, anaplasmosis and babesiosis.
You can also see for Rocky Mountain spotted fever and ehrlichiosis, the red and blue dots, those diseases primarily occur in the central and southern states so it’s very geography dependent where these diseases can occur.
So Lyme disease as many of you know, is caused by the bacterium Borrelia burgdorferi and also the newly discovered Borrelia mayonii which our next speaker, Elizabeth Schiffman will be discussing. It occurs in areas of North America, Europe, and Asia.
There are about 30,000 cases reported annually in the United States but based on a couple of studies that CDC has done, we estimate that actually there are probably about 300,000 infections that occur annually in the United States. And again, it’s transmitted in the U.S. by a blacklegged tick. The blacklegged tick or deer tick in the Northeast and Midwest in the United States, and the Western blacklegged tick in California and parts of Oregon and Washington.
There’s a map specifically of reported Lyme disease cases, so again, you can see that they are concentrated in the Northeast and upper Midwest. I did want to explain that diseases are reported to the CDC by the county of residence so this can cause some confusion, for example, when people see dots here in other places where there’s not known to be a high incidence for Lyme disease or a high risk for contracting Lyme disease.
So one example is, if a child from Texas goes to visit his grandparents in Pennsylvania for the summer and contracts Lyme disease there, even if he’s diagnosed and treated in Pennsylvania, he will still be reported as a case from Texas because that’s his county of residence. So that’s important to remember and it kind of helps understand why there are dots in areas that may not be considered high risk for Lyme disease.
The hallmark of early Lyme disease is the erythema migrans rash. It occurs in 70 to 80% of cases and usually appears about one to two weeks after the tick bite, but there is a range. It can range from three to thirty days.
It expands gradually over several days, and it’s rarely painful. And there are some key features that can help distinguish this from an allergic reaction, which of course is important to distinguish for treatment ramifications. Allergic reactions typically appear sooner, within the first 24 hours, and this is an allergy to the tick bite or the tick saliva. They’re usually very itchy and they’re usually smaller, less than two inches in diameter whereas the erythema migrans rash, as you can see on this slide, it expands gradually. It often has a bull’s-eye appearance, not always. And it’s usually not particularly itchy and it’s usually larger than two inches in diameter.
So it’s important to note that erythema migrans, while the hallmark is a bull’s-eye appearance, that doesn’t always occur, and it can cause some confusion among providers. So here you can see this EM rash has a very homogenous appearance. The one in the middle here has a triangular shape. And here you can see multiple EM rashes on the right that also have a homogenous appearance.
The EM rash can also be bluish in color. It can have central vesiculations or ulcerations. So it’s important to have a high index of suspicion for Lyme disease, even when the rash doesn’t look exactly like a bull’s-eye that one would expect.
So if left untreated, the bacteria can disseminate to other parts of the body. The bacteria is trophic to nerve, joint, and cardiac tissues, so it can cause infections in these locations. So it can cause facial palsy, meningitis, arthritis, carditis and also late stage neurologic effects such as peripheral neuropathy.
I wanted to mention briefly the standard recommended testing for Lyme disease. So serologic testing for Lyme disease follows a two-step process. So the first test is usually an enzyme immunoassay that, if positive or equivocal, should be followed-up by a Western blot. If a patient has symptoms for less than a month, then the Western blot should be interpreted for both the IgM and the IgG aspects of the western blot.
If a patient has had signs and symptoms for more than 30 days, then the IgG Western blot is sufficient for diagnosis. It’s important to follow the two-step process and not go straight to the Western blot. The two step process was decided upon by experts as the best balance of sensitivity and specificity. So following this process helps follow the recommendations and helps get the most accurate results possible.
So because it’s a serologic test, you’re looking for an immune response to the infection. So that takes time for the body to develop. And so as with other serologic tests that are used for HIV and hepatitis and other things, there’s a window period during which there’s early infection, the body’s immune response is still developing, and the sensitivity is actually low.
So as you can see here the sensitivity here again is low during early infection when the EM rash or other manifestations may be there but then during later infection, once the bacteria has disseminated and the body’s immune response is really mounting, the sensitivity is actually quite good.
Sometimes people may say, you may hear that the test misses 50% of cases or other quotes but unfortunately that is an over-simplification. It’s really lumping all of these together without understanding the nuance of the window period and sensitivity during early versus late infection.
So the bottom line for this test, the sensitivity is good in later stages of the disease and testing of patients in this early stage, if they have an erythema migrans rash and history of exposure in area that is endemic or high incidence for Lyme disease, in these cases testing is generally not necessary.
It is absolutely appropriate to diagnosis and treat these patients based on clinical presentation. The patients with later manifestations such as facial palsy or arthritis or other manifestations, these are more non-specific and so the diagnosis really should be supported by testing as well.
We, CDC and others, are trying to develop tests that are, have a higher sensitivity in early disease, which would be helpful as an adjunct.
So just a brief cautionary note, some labs offer an additional tests that have not been clinically validated. Here’s just a list of some of these tests and these tests have, like I said, have not been clinically validated and they are not recommended. And unfortunately they can be very misleading to patients. Because of this issue a couple of years ago, we put out a publication warning about these tests and also explaining the difference between CLIA certification and FDA clearance for tests.
There, many of, most of these labs, if a lab offers the clinical test they must be CLIA approved, which evaluates the laboratory and various aspects and it’s important for clinical laboratories and it’s necessary but not sufficient for proving that a test is clinically accurate and clinically validated.
They look at the lab but they don’t actually look at the individual test and the clinical validation and the evidence behind the tests. So this is a good resource for explaining to others. We kind of go through CLIA certification versus the FDA clearance and what tests, where to find more information. And some tests that should not used.
So the prognosis for Lyme disease, most patients treated with antibiotics recover completely although it can take some time. Patients can be fatigued and have other symptoms, perhaps joint pain for quite some time before they feel back to normal. In patients with persistent or recurrent joint swelling, retreatment with a second four-week course may be needed and that is recommended.
Some patients, particularly those with later stages of the disease, may have persistent symptoms of fatigue, muscle aches, reduced concentration. If those symptoms last for more than six months, the preferred term is Post-treatment Lyme disease syndrome. There have been a number of placebo controlled trials that have not shown a sustained benefit of extended antibiotic treatment in these cases.
Another study from Europe was recently published that looked at this again and still found no sustained benefit. And of course there are definite risks to prolonged antibiotic treatment, so at this point it’s not recommended.
I wanted to mention prevention of Lyme disease which of course is very important. Avoiding tick habitats so of course we want people to get out there and enjoy the outdoors. But if people can try to walk in the center of trails away from the brush where the ticks will be questing, that’s helpful to avoid getting bitten by a tick.
Using DEET and wearing permethrin-treated clothing are also very important. These are both very effective repellents and the permethrin treatment for clothing is a great option because it lasts multiple washes and people can have a dedicated, for example, pair of pants that they wear when they’re hiking or gardening that they can know that it has been impregnated with a repellent which can be really helpful.
After being outdoors, I wanted to highlight this new finding that we just published a study on this. Tumbling clothes in the dryer on high heat for five to ten minutes can kill blacklegged ticks that are on the clothing. So CDC used to recommend tumbling clothes for one hour on high heat but that was based on one study that washed the clothes and then put them in the dryer for an hour and found that all the ticks died after that.
But we had some anecdotal evidence that actually if you put dried clothes in the dryer it takes much less time to kill the ticks. So we arranged to do some studies on this for blacklegged ticks and found that within six minutes, all of the ticks can be killed when you put dry clothes in the dryer.
So we are now recommending this. This was only studied for blacklegged ticks so to be on the safe side we are actually recommending ten minutes on high heat because lone star ticks and others may be more resistant to the heat.
But we think this can be an easily implemented and effective way for people to kill those ticks that are on the clothes and also help them to remember to get their clothes off, to do a tick check, and also shower within two hours of being outdoors.
I wanted to mention briefly antibiotic prophylaxis there is some confusion about this. So a single dose of doxcycline to prevent Lyme disease is indicated when all of the following conditions are met. If it’s a highly endemic area, the tick is identified as a blacklegged tick, it’s been attached for at least 36 hours based on the history of when the person likely acquired the tick or whether it’s engorged.
Prophylaxis can be started within 72 hours of removing the tick and of course the doxycycline treatment is not contra-indicated. The does is 200 milligrams once for adults. There is some confusion about the duration, but again, it is one single dose of 200 milligrams and this prophylaxis is only for Lyme disease.
For other disease, it either hasn’t been studied extensively or there may be some indication that it may either mask the symptoms or just delay the symptoms. So it’s only for prevention of Lyme disease.
The last thing I wanted to mention, a couple of emerging tickborne diseases. First of all STARI, Southern Tick Associated Rash Illness, causes of rash that is actually indistinguishable from the erythema migrans that’s caused by Lyme disease. It can be accompanied by constitutional symptoms such as fatigue, headache, fever, muscle and joint pain. And this occurs actually after the bite of a different tick, the lone star tick.
It’s also knows as Masters disease and the cause is actually unknown. There have been many studies looking for viruses, bacteria, other pathogens, infectious pathogens that can cause this, and none have actually been found. So the current thinking is that it’s possibly some sort of immune reaction or something else going on after that bite.
Historically it occurs in the southern U.S. but range is expanding northward. You can see here in this map the range of the lone star tick and so it can cause some confusion because especially in areas of middle America and the Atlantic states where both, and the Northeast where both this tick and the blacklegged tick occur, people can come in with a bull’s-eye rash and it’s hard to determine whether it STARI or Lyme disease.
So for treatment, it’s not known whether antibiotic treatment is necessary or beneficial. Like I said, no pathogen has been identified so antibiotics are most likely unnecessary. And STARI has not been linked to long-term sequelae. Nevertheless because STARI resembles early Lyme disease, physicians often treat patients with oral antibiotics.
And in places where Lyme disease, there’s a high incidence of Lyme disease, this is appropriate if the physician or other clinicians choose to do this. We don’t take a hard stance on it but a good reference here is actually an analysis that (Paul Lantos) and some other researches did, of a risk benefit analysis. Where Lyme disease is rare, they found that observation is most like the best strategy. So if you’d like more information on that please refer to this paper and other information from our website.
So lastly I wanted to mention Borrelia miyamotoi. This is a relapsing fever spirochete. It was first identified in Japan, hence the name. It was named after a scientist who helped identify them.
It was first detected in ticks in the United States in Connecticut in 2001 and the first report of human infection related to this was from Russia in 2011. They had a series of 46 patients with flu-like illness who were PCR positive for this pathogen.
The first report of human infection in the U.S. was in 2013 and until recently we only had case reports and small case series about this. And entomologic studies have shown that about 2% but up to 10.5% of blacklegged ticks in the U.S. can carry this pathogen.
I wanted to mention a study that was published fairly recently by Malloy et al. They, I won’t go into the details but they tested a large number of samples from patients with flu-like illness for this pathogen, and they found 97 patients who are positive for it. And described clinical data on 51 patients for whom they could get information on.
So the bottom line for this study, and again feel free to go find it and go look it up, if you want more information. It had a lot of very good information in it. One of the bottom lines is that the patients, many of them, had very severe illness. They often seemed very sick or often described as toxic or even septic appearing.
And many had severe headaches so much so that they were evaluated for meningitis or other central nervous system infections. Another important point that came from this is that some of the patients reacted on Lyme disease serology but not all of them.
And they were tested by PCR for a particular gene called the glpQ gene. That’s G-L-Y-P-Q. And that, they also did serology for glpQ. The PCR for glpQ appeared to be much better than the serology and some companies do offer that test.
So if you’re worried about Borrelia miyamotoi, the PCR for it and particularly for that glpQ gene, would be the best way to diagnosis these patients. But there’s still a lot of research that needs to be done and still a lot that we’re learning about.
So next I will pass to (Elizabeth Schiffman). Thank you all again very much.
All right. Thanks Christina. So I’m going to be talking to everybody today about Borrelia mayonii which is an emerging tickborne pathogen. And so as we’ve already talked about, Lyme disease is a disease that’s caused by bacteria that are part of the Borrelia burgdorferi sensu lato species complex.
And so in the United States this means, you know, that Lyme disease is caused by Borrelia burgdorferi sensu stricto. And in Europe it is Borrelia afzelii, Borrelia garinii and also Borrelia bugdorferi.
And it’s important to note that this species complex does not include the relapsing fever group of Borrelia. So Borrelia miyamotoi, as Christina was just talking about or the most well known, Borrelia hermsii, they’re in a different grouping of Borrelia.
And so we’ve already touched on this as well, but Lyme disease diagnosis is based on clinical presentation, particularly in cases when patients have that characteristic EM, rash as well as a history of exposure to blacklegged ticks in an area where Lyme disease is endemic.
Serologic testing can be used to help support this diagnosis and as was mentioned, a two tiered approach is what’s recommended. Serology is not necessary for diagnosing early Lyme disease if people do have that characteristic EM rash, but it is really important in diagnosing disseminated infections or illnesses in people without that characteristic rash.
The other test that is available for Lyme disease is a PCR test and there are commercial assays that are available that can test blood, cerebralspinal fluid, synovial fluid, and tissue. But it is considered to be more of an adjunct test rather one that’s used for routine diagnostics.
As with any PCR test it has the advantage of being able to directly detect bacteria in a patient with acute illness. You don’t need to wait for the antibody response the way you do when you’re relying on serology. But the major disadvantage of this test for Lyme disease is that it’s not very sensitive.
Blood is only positive in about 50% of patients who have acute illness with EM and CSS is only positive in about a third of patients who have early neurologic signs of Lyme disease. So our story of Borrelia mayonii starts in June 2013 with a ten-year-old male patient from northwestern Minnesota.
And he presented with fever, headache, neck pain, myalgia, nausea, vomiting, and a diffuse rash that was not a typical EM rash. But he’s from an area of Minnesota where tickborne disease are endemic and he had spent the week prior to his illness in northwestern Wisconsin, which is also an endemic area for tickborne diseases.
And so the providers, you know, given his symptom presentation, were highly suspicious for tickborne diseases. He was pretty sick though. He was hospitalized for four days but was treated with kind of standard Lyme disease drugs recommend for the treatment of Lyme disease. So ceftriaxone. And then a course of amoxicillin. So he did recover completely.
So these pictures just show his rash. They’re a little hard to see but you can definitely tell that these are not your typical EM rashes. These pictures look really different from the pictures that Christina presented in her earlier presentation. And so a PCR test was ordered for this patient along with serology and the results were a little bit interesting.
So the peak that you see there–this is a melting temperature analysis of samples. And the peak for that is labelled as peak A, is what you would expected if the patient was infected with Borrelia afzelii. The C peak is what you would see in Borrelia burgdorferi sensu stricto.
And then this patient’s blood had a melting temperature peak that was at, labelled as B which is different, it doesn’t fit in with what you would expect to see based on known species. And this unique pattern was also seen in a few other cases. So there were a few other PCR whole blood samples that were positive with this same abnormal melting temperature pattern.
One was an eleven–year-old male from Wisconsin, that was identified in July of 2013. A retrospective review of samples at Mayo also identified a 65-year-old male who was from North Dakota but had been exposed in Minnesota from the previous year, from 2012.
And then there was also a synovial fluid specimen that had this same pattern. This was from the Mayo Clinic, Eau Claire in Wisconsin and that was a 21-year-old woman. And that one was also identified in June of 2013. And then in 2014, two additional cases had this same, had this same unusual melting temperature pattern.
So this of course prompted some further analysis, so some sequencing analysis was done of one of the genes from those blood samples, the oppA1 gene. And you can see here that all the patient samples and then a few tick samples are included in this which were tested as well but they all clustered together and you can clearly see that they are not clustered with other known Borrelia species.
So it was further evidence that maybe this was something that was different than what we had seen before. And so some of the specimens were able to be analyzed using dark field microscopy and culture. And so specimens were sent to CDC.
And you can see by the red arrow on the picture on the left there that they were actually able to visualize the spirochete in a whole blood specimen, which is pretty unusual because Lyme disease is one of the kind of characteristic things about it is that people only have spirochetes circulating in their systems for a pretty short time.
And then the photo on the right, is actually spirochetes that were cultured from one of the blood samples which is also an interesting thing because Borrelia is notoriously difficult to culture.
So some further phylogenetic analysis was done and I’m going to skip to the next slide to talk about it and come back to this one. So they did a multilocus sequence analysis that looked at eight housekeeping genes. And it’s a technique that’s been used before for defining genospecies in the Borrelia burgdorferi sensu lato complex.
And the highest similarity of these patient specimens was to Borrelia burgdorferi. But it was only about 95% similar which did not meet the threshold for it being just kind of a weird sample. But still Borrelia burgdorferi was enough for the researchers at Mayo.
And people at CDC, they concluded that this was in fact a novel genospecies and the proposed name for this organism is Borrelia mayonii. And so if we go back to the phylogenetic tree you can see sort of the red box on the top shows kind of all the Borrelia burgdorferis clustering together and then the blue box a little further down is where you can see the patient specimens from this novel species.
So it’s pretty clear when you look at that phylogenetic tree that we’re looking at something that’s different from Borrelia burgdorferi. So obviously there was some question as to maybe whether some specimens had been missed in the past that could also be positive for this novel agent.
So Mayo Clinic went back and looked for specimens from going all the way back to 2003 through September of 2014. And they analyzed about 100,000 specimens. And what was kind of interesting is they found that, you know, none of the specimens from prior to 2012, none of those specimens were positive for Borrelia mayonii.
But they did find positive specimens in kind of the more recent ones collected from January 2012 to September 2014. And what was even more interesting is Mayo clinic gets specimens from all, patients from all around the United States although they’re located in Minnesota.
And so when they looked at specimens from 44 states that were not Minnesota, Wisconsin, or North Dakota, they once again found no positives. The only positives that they found were from patients who were residents of Minnesota, Wisconsin, or North Dakota.
And so clinically what did these patients look like? It’s important to remember that we’re dealing with a really small n here of only six patients so, you know, what we find initially may not be what holds true in the longer term if we start to see larger numbers of patients with Lyme disease caused by this bacteria.
But at least in these six patients, you know, we had a wide range of ages ranging from 10 to 67. Four of them were male. Two of them were female. Two patients had a known tick bite but everybody reported exposure to either ticks or tick habitat in Minnesota or Wisconsin.
And this isn’t strange. It isn’t uncommon to have patients who have tickborne diseases but never remember getting a tick bite. That’s a pretty common thing. Five of the six patients presented with an acute febrile illness and three of them had potential neurological involvement. Although neither one of them had meningitis or encephalitis or really severe neurologic outcomes, there were some patients that reported confused speech, profound somnolence, and visual difficulties in one patient.
Four of them did present with a rash but only one of those rashes was suggestive of what you’d think of when you think of a traditional EM rash. And one patient did present with arthralgia rather than that acute febrile presentation. And so outcome wise, two of those six patients were hospitalized which is kind of interesting. Most patients who get infected with Lyme disease do not require hospitalization. All of these patients were treated with antibiotics that are recommended for treatment of Lyme disease. And five of the patients were covered completely, although one did report residual joint pain.
So this map just kind of shows you where patients were exposed and their residence. It’s a little hard to see on this graphic but the triangles indicate locations of possible exposure. And then circles are locations of their county residence, has the circle.
But the map it’s overlaid on is kind of a broader tickborne disease risk map that’s based on incidence of tickborne disease. So that darkest red area are parts of Minnesota and Wisconsin that would be considered highest risk for tickborne infections. And then the lighter colors are lower risk.
So most of the patients that ended up with Borrelia mayonii did have routine serologic testing ordered for them, five of the six patients, actually. And most of the specimens did test positive, by the EIA test in particular. Although if you look at the two columns for the different EIA assays, you can see some differences. It seems the C6 assay performed a little bit better in these patients than did the whole cell assay.
And when you look at the Western blot results that becomes a little less clear. Some of the patient specimens, you know, met criteria for positivity for the IgM. Some of them for IgG and but none of them actually were positive on both IgM and IgG. But what this does tell us is that this indicates some cross-reactivity on the conventional assays between these species of bacteria.
So what about the ticks? We always want to know more about what’s going on with the ticks and we suspected that the likely vector of this would be Ixodes scapularis, or the blacklegged ticks since that’s the vector of most of our endemic diseases here in the upper Midwest.
And so ticks were collected from two sites in Wisconsin and four sites in Minnesota and then PCR testing was performed on those ticks that looked for both Borrelia burgdorferi and Borrelia mayonii. So the ticks from Wisconsin were tested at the Mayo Clinic laboratories and the ticks from Minnesota were tested here at our Health Department’s Public Health lab.
And so what we found, you can see the Minnesota tick results are on the top line. The Wisconsin ticks are on the second line. Borrelia mayonii results are in kind of in the middle columns and then burgdorferi results are in the rightmost column.
And what you can see is that overall, more ticks were positive for Borrelia burgdorferi than for Borelia mayonii, which isn’t surprising since we’re probably dealing with something that’s more recently emerged. And that infection prevalence was higher in adult ticks than in nympal tick which is also not surprising. It’s typically what we see.
Adult ticks have had, you know, another opportunity to take a blood meal and acquire pathogens than nymphs have. And these results are pretty consistent with what we would expect. And so Borrelia mayonii does seem to have some unique features although as I’ve said, we’re dealing with a pretty small n here.
But this disease so far as only been identified in patients from the upper Midwest. So either patients who are residents of Minnesota or Wisconsin or who were exposed in Minnesota and Wisconsin. And it wasn’t detected in, you know, nearly 25,000 blood samples from other parts of the United States.
Based on these initial findings, it seems that more severe, the disease is more severe when it’s caused by Borrelia mayonii than by Borrelia burgdorferi. The rashes are also different. They seem to be more diffuse than that classic EM presentation and the other interesting thing is that this organism has been found primarily whole blood, which is traditionally not a great way to look for Borrelia burgdorferi.
So in conclusion I think there’s still a lot we have to learn about this new species of Borrelia and it’s really unclear at this point about how common of a cause of Lyme disease it really is. But research does indicate that it recently emerged. Like I said they looked at blood specimens from before 2012 and didn’t find any positives. All the positives have come since 2012.
Both Minnesota and Wisconsin are considered to be high incidence states for Lyme disease and have several endemic tickborne diseases aside from Lyme disease. And the risk for these diseases is highly seasonal here. The highest risk time of year is late spring through midsummer and so tickborne diseases including Borrelia mayonii should probably be in the differential in patients who present with febrile illness after being exposed to the outdoors in the upper Midwest.
And I’d just like to acknowledge all of the other people who worked on this research and made this discovery possible. And with that I will turn it over to Naomi.
Thank you Elizabeth. So I’m going to be discussing some of the other tickborne diseases today including tickborne rickettsial diseases such as Rocky Mountain spotted fever, ehrlichiosis, anaplasmosis, and other emerging tickborne rickettsia.
So I’m going to start off with probably the most well-known, rickettsiosis in the United States, Rocky Mountain spotted fever, which is caused by the bacterium, Rickettsia rickettsii and is a member of the spotted fever group Rickettsia. This is the most pathogenic, of the spotted fever group rickettsiosis disease in the United States, in the U.S. it’s transmitted primarily by Dermacentor variabilis in the Rocky Mountain region, can also be transmitted by Dermacentor andersoni.
And in some parts of the U.S., including Arizona, has recently been reported to be transmitted by Rhipicephalus sanguineus, which is the brown dog tick. This organism infects and destroys endothelial cells and can cause widespread vasculitis leading to multi-system organ failure and, if left untreated, can be highly fatal with a 20% case fatality rate in untreated cases.
So I’m going to skip over the distribution maps in the interest of time so we can have time to discuss questions. But as you can see the majority of spotted fever, spotted fever rickettsiosis cases are being reported out of the central United States, with 60% of the cases reported out of Oklahoma, Arkansas, Tennessee, Missouri, and North Carolina.
But spotted fever rickettsioses are reported in the contiguous United States. So I usually like to describe Rocky Mountain spotted fever clinical manifestations in three stages – the early, the moderate, and the late. Early illness is typically day one or two of illness. And typically patients are presenting with fever, headache–which may be severe–and myalgia.
Around day two to four, we start to see the additional onset of more systemic symptoms, including respiratory symptoms, gastro-intestinal and you may see the occurrence of a slight rash at this time. It’s important to note that most patients do seek care within two to three days of symptoms, meaning that they’re presenting for clinical care at this time when it’s very, you’re seeing nothing but non-specific symptoms.
Nothing here screams “Rocky Mountain spotted fever” and is going to give you a red flag to know to treat presumptively. And for this reason, Rocky Mountain spotted fever is misdiagnosed in about 60 to 85% of patients in their first presentation.
So the initial rash of Rocky Mountain spotted fever, the spotted part of Rocky Mountain spotted fever, comes from the rash that starts to be presented around day three of the illness, or day two to four of the illness. And the early manifestations of rash are typically, as you can see in these images, macular or maculopapular, blanching, and this usually appears as I said, two to four days after onset of fever.
The rash typically starts on the ankles or the forearms and spreads centrally to the body. And it’s important to note that the rash can be atypical, evanescent or absent altogether and that’s really important to keep in mind. So late stage manifestations of Rocky Mountain spotted fever really occur on day five or later, and include worsening systemic illness.
As this disease advances, there’s going to be increased amounts of vascular damage throughout the body and as the bacteria continues unabated, this can be irreversible and death typically occurs after day five. Laboratory abnormalities may also begin to occur at this time or become more prominent. This will include thrombocytopenia, hyponatremia, and elevated liver enzymes.
Also on day five or later is when you start to see the classic Rocky Mountain spotted fever rash. So this is the petechiae present on the palms on the hands and the soles of the feet. And the petechial rash is really representative of the micro-hemorrhages in the dermis.
So as you see those vessels rupturing in the dermis and is presented by petechial rash, you know that this is what’s going on in other organ systems throughout the body. And this is really a late stage of manifestation that we work to prevent. We want to make sure that antibiotic therapy is initiated before these manifestations are shown.
Please excuse the graphic nature of this image but this just underlines the point of the diffuse nature of the vascular damage that can happen in late stage Rocky Mountain spotted fever. It can manifest as respiratory distress, cutaneous necrosis, meningoencephalitis, encephalitis, and other cerebral edema, other manifestations that are very prominent.
And these are often included preceding death and even in patients where they are able to survive this disease, they may have long-term and permanent sequela resulting from this vasculitis, this damage that’s done. We know that children have had permanent cognitive deficits. We know that there’s blindness, hearing loss, brain damage, and these may be irreversible.
One of the risk factors that are associated with fatal outcomes includes advanced or young age, delayed onset of rash, different seasonality of presentation. But the most important thing to remember is that the highest risk factor is delayed in administration of effective antibiotic therapy and in this case we’re talking about doxycycline.
So I want to also mention some of the other spotted fever rickettsiosis in the United States that known to cause human illness. Besides Rocky Mountain spotted fever caused by Rickettsia rickettsii we also have Rickettsia parkeri rickettsiosis, and Rickettisa species 364D.
These rickettsial agents cause acute febrile illness that’s similar to Rocky Mountain spotted fever except that they’re often preceded by the appearance of an inoculation eschar which you can see in the image on the lower right. This inoculation eschar here I believe is due to Rickettsia parkeri.
So these illness are typically less severe than Rocky Mountain spotted fever but can have similar clinical presentations including rash and fever. So I’m also going to talk about ehrlichiosis, which is a general name for the members of the ehrlichia family.
In the United States ehrlichiosis, human ehrlichiosis is most frequently caused by Ehrlichia chaffeensis but can also be caused by Ehrlichia muris eauclarensis which is formerly called Ehrlichia muris-like agent. And by Ehrlichia ewingii. Again, here you can see the surveillance data that for Ehrlichia chaffeensis where the majority of our cases occur.
And a little note that those cases in the upper Midwest are likely either cross reactions with anaplasmosis or Ehrlichia muris eauclarensis and are not likely to be Ehrlichia chaffeensis. The clinical presentation of ehrlichiosis is very similar to Rocky Mountain spotted fever. In the early stages it’s non-specific with fever, headache, myalgia, malaise. Gastro-intentional symptoms can be prominent. And rash can occur more frequently among children but is less present in adults.
Rash is even less frequently reported in cases of Ehrlichia ewingii ehrlichiosis and Ehrlichia muris eauclarensis ehrlichiosis. That’s a mouthful. So severe presentations of ehrlichiosis often occur, include multiple system organ failure, shock, respiratory failure and about 20% of patients have central nervous system involvement including meningitis.
Other ehrlichial species as I mentioned are—include Ehrlichia ewingii and muris eauclarensis which was first case was confirmed in 2011. And these are more emerging infections as we define them better. The last disease I want to cover very quickly is anaplasmosis which is caused by Anaplasma phagocytophilum here in the United States and is spread by mostly Ixodes scapularis which is again same vector as Lyme disease and babesiosis.
These cases predominately occur in the upper Midwest and northeastern United States. And the symptoms, as with Rocky Mountain spotted fever and ehrlichiosis, are non-specific including fever, headache and muscle pain. Anaplasmosis is typically less severe than ehrlichiosis and RMSF, but can be severe in some patients, especially those with—who are immune compromised and those with advanced age.
Severe presentations can include respiratory distress, shock or neurological problems. And again, rash is less common in patients with anaplasmosis and may actually be indicative of a co-infection with Lyme disease. The most important thing about rickettsial disease, tickborne rickettsial diseases, is that you have a very small window of time, because they are rapidly progressing, in order to initiate antibiotic therapy.
Doxycycline is the most effective antibiotic treatment for the treatment of rickettsial diseases and should be used in patients for, of patients in all ages. Other, the use of other antibiotics especially sulfa derivatives for the treatment of Rocky Mountain spotted fever may actually be more associated with death.
So this study that was done in 2015 or published in 2015 I just want to point out that it contributes to the evidence saying that doxycycline, when used in short courses meaning about a week, such as those used for the treatment of Rocky Mountain spotted fever, ehrlichiosis and anaplasmosis, these can be used in patients that are under the age of eight years.
There’s historical evidence saying that tetracyclines are contraindicated in children,under that age due to the presence of permanent dental staining and enamel hypoplasia. But the study that we did looked at patients who had received doxycycline for the treatment of RMSF before the age of 8 and looking back, we saw no difference in patients who have received doxy and those who hadn’t in tooth shade or enamel hypoplasia.
So doxy, in short courses, can be safely used for treatment of Rocky Mountain spotted fever and other rickettsial diseases in children. Due to the lack of sensitive diagnostic assays and the rapid progression of some of the rickettsial diseases, it’s most important to keep in mind that when you’re making a diagnosis this is based on your clinical presumption alone, clinical suspicion alone.
The diagnostic tests that are available may not be sensitive in acute phases and will likely not help you make a treatment decision. That being said, I do want to go over some of the treatment options that are available for rickettsia. Amplification of rickettsial DNA by PCR is the most specific diagnostic test available.
And PCR can be used on whole blood, skin, tissue, CSF, vitreous humor. PCR of whole blood is considered very sensitive for the diagnosis of ehrlichiosis and anaplasmosis because they are associated with the leukocytes in whole blood. However it’s not likely to be a sensitive diagnostic assay for Rickettsia rickettsii and other spotted fever group Rickettsia because they are not circulating the whole blood in early stages.
However, PCR of skin punch biopsies when there’s a rash present or an eschar or the swab of an eschar can be very helpful specimens and can contain a lot of spotted fever rickettsiall DNA which can then be tested by PCR. However the global standard really is the indirect immunofluorescence assay for the testing of all rickettsial, tickborne rickettsial diseases including Rickettsia rickettsii, ehrlichiosis, and anaplasmosis.
And of course the correct interpretation really does depend on having the acute phase serum samples which is collected in the first week of illness and the convalescent which is collected two to four weeks later and the comparison of those two samples really directs us to a recent infection by rises and falls in antibody titers.
Other diagnostic, excuse me, diagnostic specimens, diagnostic tests could include immunohistochemistry and peripheral blood smears for Ehrlichia and Anaplasma. In summary, the rickettsial diseases are difficult to diagnosis and really do have the potential to progress very rapidly, which leaves little room for misdiagnosis or not considering Rocky Mountain spotted fever and other rickettsiae in your presumptive diagnosis.
So we just want to encourage you to have a low threshold for considering rickettsiae when the symptoms are consistent and the exposure history for tick bites or tick exposures are consistent. And the diagnostic tests should really be used for retrospective diagnosis and not for a treatment decision.
So I didn’t get a lot of time to go into detail unfortunately but luckily we have a brand new user, updated guideline for the treatment and diagnosis of Rocky Mountain spotted fever, other spotted fever group rickettsioses, ehrlichioses and anaplasmosis. So if you have any questions please look to that document and I think we’ll open it up for questions from the group. Thank you.
Thank you presenters for providing our COCA audience with such a wealth of information. We’ll now open up the lines for the question and answer session. Questions are limited to clinicians who would like information on preventing recognizing and managing tickborne illness.
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Amber, if you can open the phone lines for questions.
Thank you. We’ll now begin the question and answer session. If you would like to ask a question, please press Star 1. You’ll be prompted to record your name. Please be sure to unmute your phone. Once again, if you would like to ask a question, please press Star 1. And one moment for your first question.
We have a couple of questions in the webinar system so far. I have one here, what diagnostic tests are able to distinguish between Rickettsia rickettsii and Rickettsia parkeri?
Thank you Will. This is Naomi. And that’s a great question. Because of the cross reactivity among spotted fever group rickettsioses, antibody tests including the indirect immunofluorescence assays can have, can be difficult to distinguish between those two diseases.
We do have antigen-specific assays for serology here at the Centers for Disease Control and Prevention, however you can also use commercial antibodies to say that there’s a positive spotted fever group rickettsiosis.
However another option is to use PCR. I mentioned that whole blood is not necessarily a sensitive specimen for spotted fever group rickettsial DNA in acute phases of disease. However if there is a skin biopsy that is present or if there is an eschar, those provide good sources of rickettsial DNA which we can then type specifically to the antigen.
Thank you. Amber do we have any questions on the phone lines?
We do have a question on the phone line. This question is Jafar. Please state your organization.
Yes, hi this is (Jafar) from the State Public Health Office in Connecticut. The question, do you guys have any studies or have you done any work to see if there is any drug resistance to doxycycline for treatment purposes?
This is Naomi. As far as I’m aware we haven’t had any reports of direct resistance to rickettsial diseases. Christina, I don’t know if you have any evidence about Lyme disease drug resistance from your experience?
Dr. Christina Nelson:
We haven’t heard reports to that either.
Thank you. We have a question from the webinar system. Based on your statement that doxycycline can be used in short courses for children under eight, would you consider using it for single dose prophylaxis? If so, what ages, and at what does?
This is Naomi again. So it’s important to note as Christina mentioned, Dr. Nelson mentioned earlier in her presentation that prophylaxis may be considered in certain circumstances for the treatment, for the preventative treatment of Lyme disease again meeting those criteria that she mentioned earlier on.
But it’s not actually recommended for prophylactic treatment of rickettisal diseases. As Christina mentioned, there are studies that show that this may just delay the onset of symptoms and will not actually kill the bacteria or reduce your chances of becoming ill.
Thank you. We have time for about one more question. Are there any questions on the phone lines?
Yes, we have a question from Harrison. Your line is open. Please state your organization.
Hello, this is (Harrison) from the Children’s Mercy Hospital in Kansas City. We just got a blast email to our group from bioMerieux claiming that they have a Lyme disease test that will tell you within 27 minutes exactly where it is, if the form of disease is early, mid, late and if it will have a high sensitivity, is higher than Western blot. It’s a one-step test. Do you guys know anything about that?
Dr. Christina Nelson:
Yes, this is Christina. We have heard that test. You know we typically recommend that a test be FDA cleared before we recommend that it be used because as you know, FDA clearance is a very rigorous process of evaluating evidence for both sensitivity and specificity and making sure that that test is clinically validated.
So it’s very interesting the findings and we look forward to seeing more published information. And if and when it’s FDA cleared it could possibly be used as a test.
We’re already getting requests from our local practitioners of where they’re going to get it and how they’re going to get it. I just wanted to make sure I wasn’t missing something. Thank you.
Dr. Christina Nelson:
Yeah, yeah, thank you for the question.
We actually have a little bit more time for one more question. Are there still any questions on the line?
We do have a question from Karen Lopez. Your line is open.
Hi there. This is Karen Lopez from the University of Minnesota. I seem to remember reading perhaps on ProMED about a rickettsial organism that had been showing up positive.
People have been showing up positive on Rocky Mountain spotted fever testing for a rickettsial organism that wasn’t, but they weren’t showing clinical signs. Does this sound familiar that people were being treated for Rocky Mountain spotted fever when they didn’t actually have it because there was some other organism that was causing like an asymptomatic infection?
Yes, thank you for the question. This is Naomi. There are several other spotted fever group rickettsioses in the United States that are asymptomatic in humans. People don’t have any outward symptoms, clinical finds and symptoms of disease but will express an antibody response to spotted fever antigens.
So they will have a positive Rocky Mountain spotted fever test or spotted fever group rickettsiosis antibody test but may not have clinical symptoms. The diseases I discussed today, the Rickettsia parkeri, Rickettsia 364D and Rickettsia rickettsii are all pathogenic meaning that those persons with those illnesses do express symptoms.
Got it. Thank you.
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