Februari 21, 2017
>> may i have yourattention please. our network is down again, soour webcast is not yet working. so if anybody's listeningthrough some other mechanism, i hope iptv might be recording. iptv folks, if youcan be recording so we can broadcast our webcastlater, that would be helpful. we're going to go aheadand start timely anyway, and we'll just resumewhen we can. so, sorry about that.
and i hope we get thewebcast going shortly. >> good afternoon. and again, we are havinga little bit of difficulty with our webcast, butwe're going to go ahead and get started withthe presentation. so, good afternoon, goodevening or good morning, depending from when andwhere you are joining us. i'm dr. phoebe thorpe, and it'smy pleasure to welcome you here to the cdc public healthgrand rounds for march, 2017,
emerging tick-borne diseases. we have a very excitingsession, so let's get started. but first, a fewhousekeeping slides. we do offer continuingeducation credits for public health grand roundsfor physicians, pharmacists, nurses, veterinarians,health educators and others. please see our website foradditional information. this is the disclosureslide for this session. we are also available
on all your favoritesocial media websites. please send yourcomments and questions to the grand round's emailbox at grandrounds@cdc.gov. we also have a featured videosegment called beyond the data. this month's segment features myinterview with dr. bobbi pritt. it'll be posted about aweek after the session. we have also partnered withthe cdc public health library to feature scientific articlesrelated to tick-borne diseases. the full listing is availableat cdc.gov/scienceclips.
here is a preview of our upcoming publichealth grand rounds sessions. please join us live or onthe web at your convenience. in addition to ouroutstanding featured speakers, i'd like to take a moment to acknowledge theimportant contributions of the individuals listed here. thank you. and now, for a few words
from cdc's actingdirector, dr. schuchat. >> thank you. well thanks so much. it's actually liberating knowingthat we're not webcasting yet. millions of americans seek care for a tick bite each yearin the united states. and despite that, veryfew of us are equipped to answer the questionsfrom friends and relatives that are in that category.
today you will be hearingthat the reported cases of tick-borne diseasesare increasing. that the range of ticks thatcan carry diseases is expanding. that the number oftick-borne diseases that we are awareof is increasing. and that the laboratoryapproaches to figure out what they areis also increasing. if that list is makingyou feel full, wait until you see thepictures of the ticks
who have been feedingduring this lecture. i believe it is themost memorable part of the slides you'll be seeing. we're in for a treat, becausei think for the four speakers and the slides thatthey've prepared, most of us will be betterequipped to handle that tick that you might find onyourself or a loved one and to help the nationbe more prepared. thanks.
>> thank you dr. schuchat. and now for our firstspeaker, dr. eisen. >> thank you for theintroduction, phoebe. good afternoon. i'm going to start withsome background information. all known tick-borne infectiousdiseases are zoonosis. ticks can maintain thepathogens through transmissions to their offspring or acquireinfection through feeding on an infectious host.
importantly, humansare incidental hosts that are infected throughthe bite of infected ticks, but they do not serveas a significant source for infecting other ticks or perpetuating thepathogen's lifecycle. ticks are unique amongarthropods in the diversity of pathogens they transmit. among the 18 tick-bornedisease agents described to-date in the united states,14 are bacterial
and are transmittedby five tick genera. however, at least three uniquetick-borne viruses transmitted by three tick genera, and at least one tick-borneprotozoa have been shown to cause human disease. in the following slidesi'll present data to show that the majority ofvector-borne diseases in the us are tick-borne. that in recent decades,
the number of tick-bornedisease cases has increased. the geographic range over whichtick-borne disease cases have been reported has expanded. and a growing number of tick-borne diseaseagents have been recognized among the nearly 50,000cases of locally acquired, nationally notifiablevector-borne diseases of humans reported annuallyto the cdc from states and the district of columbia,
approximately 95% aretransmitted by ticks. notably, lyme diseaseaccounts for the majority of reported vector-bornedisease cases with over 30,000 casesreported annually. without denying thesignificance of lyme disease, the focus of thisgrand rounds will be on other human pathogenstransmitted by ticks. of the more than 84 tick speciesdescribed in the united states, roughly a dozen are frequenthuman biters that are capable
of transmitting human pathogens. human-biting ticks are present across the contiguous unitedstates, however, for simplicity, here i'll show thegeneralized distribution of only three human-bitingticks that are responsible for the majority of reportedtick-borne disease cases. ixodes scapularis,the blacklegged tick, is primarily awoodland-associated tick that's distributed across most ofthe eastern united states,
and it serves as a vector of theagents that cause anaplasmosis, babesiosis, borrelia miyamotoidisease, ehrlichiosis, lyme disease andpowassan encephalitis. notably, an individual ixodesscapularis can carry multiple disease agents, thus stressingthe importance of coinfections for diagnostics and prevention of ixodes scapularis-bornediseases. the lone star tick,amblyomma americanum, has a similar distributionto ixodes scapularis
but has a more southerlydistribution. it's also primarilywoodland-associated and serves as a vector of the agents thatcause ehrlichiosis, tularemia and heartland virus disease. the american dog tick,dermacentor variabilis, is among the most broadlydistributed human-biting ticks in the us. found primarily ingrasslands, its range spans across the eastern us andalong the pacific coast,
primarily in california. it's a vector of the agents that cause rocky mountainspotted fever and tularemia. when looking at maps of nationally notifiabletick-borne diseases shown by location of residents. there are obvious regionaldifferences that are explained, in part, by tick distributions. notably, although ixodesscapularis is present
across the eastern us, reportable ixodesscapularis-borne diseases, such as lyme disease,anaplasmosis, and babesiosis clustered inthe northeast, the mid-atlantic and the upper midwest where humans encounterthe tick more frequently than in other partsof the tick's range. in recent decades, the numbers of many notifiabletick-borne diseases have
suddenly increased. for example, the average number of reported lyme diseasecases has roughly tripled from 1992 to 2015. likewise, the number ofreported cases of anaplasmosis, ehrlichiosis and spottedfever group, rickettsiosis, has suddenly increasedfrom 2000 to 2015. in addition to increasingcase counts, the geographic distribution
of several tick-bornediseases is expanding. to illustrate this point, the map on the leftshows the distribution of reported lyme diseasecases in 2001 compared with 2015, shown on the right. although less prevalent,the geographic distributions of other ixodes scapularis-bornediseases mirror the distribution of lyme disease cases. tick-borne organisms areincreasingly being recognized
as human disease agents. this timeline shows when tick-borne pathogenswere recognized as causes of human disease. over the first 60 yearsof the last century, seven tick-bornepathogens were recognized common colors on the timelinerepresent a common tick genus that serves as the vector. in more recent decades, the rate
of pathogen discoveryhas accelerated, with 11 additionalpathogens described to cause human diseasesince 1960. notably, more than half of thosewere discovered after 2000, and the majority were associated with blacklegged ticks,ixodes scapularis. there are several explanationsfor why tick-borne diseases and tick-borne diseaseagents are increasingly being recognized and why case countsare increasing in number
and are being reported acrossbroader geographic extents. improved diagnosticsand clinical recognition of tick-borne disease agents and tick-borne diseaseswill be discussed in subsequent presentations. here i'm going todiscuss the importance of expanding geographicdistributions of vectors and a lack of effectiveprevention strategies. the accelerated discovery
of ixodes scapularis-bornepathogens may be attributable to an increased focuson this vector after lyme disease wasdiscovered in the early 1980s. in addition though,the geographic range of this tick hasexpanded considerably over the last two decades. from 1996 to 2015,the number of counties in which ixodes scapularisis considered to be established hasmore than doubled.
the expanding range ofixodes scapularis also helps to explain the expandingdistribution of counties classified as highincidents for lyme disease. over the last two decades, both have expanded followingsimilar spatial patterns. another contributing factor tothe increase in reported numbers of tick-borne diseases isincreasing human contact with ticks that comeswith landscape changes. there are no human vaccinescurrently on the market
in the united states toprevent tick-borne diseases. although we have severaloptions for prevention, we lack a single effective,widely accepted method for preventing tick-bornediseases. current prevention strategiesfall into three broad areas, personal protection, environmental modificationor tick suppression. personal protection strategiesfocus on avoiding tick habitat and use of repellantsspecifically 20 to 30% deet
on exposed skin and wearingpermethrin-treated clothing. daily tick checks and removal and to remove the ticks beforepathogen transmission occurs. to accomplish this, cdcrecommends bathing or showering as soon as possible after comingindoors, checking yourself, your children, your pets andyour outdoor gear for ticks and removing them promptlyand tumble drying dry clothing on high heat to kill any ticksthat remain on the clothing. other strategies aim tomodify the environment
to make it less suitablefor ticks. human contacts ofticks may be reduced by using strategiclandscaping techniques. tick abundance is reducedthrough the use of acaricides and biological agents. other strategies aimed to reducethe abundance of important hosts for ticks in areas where humansare likely encounter the ticks or to reduce the number ofticks on hosts through the use of acaricide appliedto the host.
finally, developing technologiesfocus on delivering vaccines or antibiotics to rodents toreduce the infection rates in the host and ultimatelyin the ticks. each of the preventionstrategies i've described variant efficacy andan acceptability. despite the large numberof intervention strategies, looking to the future,it's likely that advances in molecular pathogendetection and bioinformatics, coupled with a sustainedinterest
in tick-borne diseaseswill lead to the discovery of more tick-borne diseasesand tick-borne disease agents. reforestation, increasingabundance of deer, which are important hostsfor many tick species, and changing climatic conditionshave led to the expansion of several vector species. models suggests that sometick species ranges are likely to continue to expand overtime, and this may lead to tick-borne diseasecases being reported
from new locations. a single tick species or evenan individual tick can carry multiple diseaseagents, therefore, coinfections will continue tobe important for diagnosing and preventing tick-borneillnesses. finally, there's a need todevelop effective approaches to preventing tick-bornediseases. but perhaps an evenbigger challenge is how to deliver effective preventionstrategies to large numbers
of people and ultimatelyreduce the trend of increasing tick-bornediseases. it's now my pleasure tointroduce dr. paddock. [ applause ] thanks becky. in the next few minutesi'll be touching on a few things mentionedpreviously in dr. eisen's talk, using two rickettsialdiseases as examples. the beautiful place in the leftpanel is the bitterroot valley,
located in the farwestern part of montana. it's not particularly large,only about 120 miles long and ten miles acrossat its widest point. but at the turn of the20th century, a deadly and previously undescribeddisease emerged in this remote and sparsely populated valley. it was associated with a veryhigh fever and a petechial rash that covered most of the body. and it killed the majority ofpersons who became infected,
generally within thefirst eight to ten days. of the 343 cases identified inwestern montana between 1880 and 1909, 62% ended in death. this case fatality raterivals or exceeds some of the worst infectiousdiseases. investigators soonlearned that the disease, which was given the namerocky mountain spotted fever, was transmitted by ticks and became the firstrecognized tick-borne disease
of humans in the united states. the severity of rocky mountainspotted fever is linked to the tropism of the causativeagent, rickettsia rickettsii, to cells known as endothelium which line the small bloodvessels of every major organ and tissue of the body. this is represented by thehistologic image on the left which shows rickettsiiwithin the endothelial cells of a patient who died fromrocky mountain spotted fever.
this disease progressesrapidly to involve blood vessels in the skin, as shown by thepetechial rash in the center, as well as those in all ofthe major organs of the body. the damaged blood vesselscaused by these bacteria result in extreme vascularpermeability, which can lead to death when it involvesthe lungs and the brain. the panel on the right is ahistologic section from the lung of a patient with fatalrocky mountain spotted fever that shows diffusedpulmonary edema caused
by leaky alveolar capillaries. fortunately, tetracycline classantibiotics can cure the disease if administered ina timely manner. discovered in the mid-1940s, tetracycline drugs considerablyreduce the case fatality rates to contemporary estimatesof approximately 5 to 10%. doxycycline is consideredthe drug of choice for all tick-bornerickettsioses, but to achieve themost favorable outcome,
it should be administered earlyin the course of the illness to prevent irreversibleorgan damage. today, the majority cases of rocky mountain spotted feverreported from a belt of states in the central andsoutheastern us that extend from oklahoma eastward to northcarolina, the principle vector of rocky mountain spotted fever in this region isdermacenter variabilis, also known as theamerican dog tick.
but i also want to drawyour attention to a region of eastern arizonawhich reports some of the highest incidentsrates in the country and where there areno dermacenter ticks. beginning in 2003,epidemic levels of rocky mountain spottedfever were recorded from several american indiancommunities in eastern arizona where the incidents ratesapproached 150 times the national average.
cdc investigators, workingclosely with tribal partners and the indian healthservice, soon determined that the brown dog tick,rhipicephalus sanguineus, was responsible forthese outbreaks. enormous populations of browndog ticks had proliferated among free-roaming dogs inthese communities. because dogs serveas an amplifying host for rickettsia rickettsii, and because rhipicephalussanguineus is an efficient
vector, this createda perfect storm for peridomestic transmission. this also represented a paradigmshift, not only in the magnitude of case numbers, butalso the involvement of a tick vector notpreviously considered relevant in the epidemiology of thisdisease in the united states. through a collaborative endeavorinvolving multiple groups, a community-basedintervention was undertaken in a highly-impacted community.
the yards of 550 homes weretreated with an acaricide spray, and tick collars impregnated with a long-lasting acaricidewere placed on over 1,000 dogs. these efforts resulted ina marked reduction in on and off host tick numbersand, most importantly, a 43% reduction inthe number of cases of rocky mountain spotted fever. so, for more than 100 years, rocky mountain spotted fever wasconsidered the only tick-borne
rickettsiosis inthe united states. however, scientists were awareof other tick-borne rickettsii, like the one reported in 1939from the gulf coast tick, also known as amblyommamaculatum. sixty-five yearslater, this rickettsia, known as rickettsiaparkeri, was isolated from an ill patient in virginia. during the subsequent ten years, approximately 35additional cases
of rickettsia parkeririckettsiosis were identified across nine states inthe southeastern us. at first glance,it's not difficult to see how some patients with rickettsia parkeririckettsiosis might be mistaken as cases of rockymountain spotted fever. the distinction betweenthe rashes, particularly duringthe early stages of the disease, can be subtle.
both are maculopapular,but the rash caused by rickettsii parkeri isgenerally more sparse, and often associated with smallvesicles or pustules as seen in the lower right-hand panel. nonetheless, almost all patients with rickettsii parkeririckettsiosis have the distinctive lesionknown as an eschar, which is a scabbed necrotic areaof about a centimeter across, which represents the site
where an infected tickinoculated rickettsia parkeri to the skin. for reasons thatare still unclear, an inoculation escharoccurs only very rarely with rocky mountainspotted fever. so, as you can see, these diseases showseveral clinical features, such as fever, headacheand rash. where they differ is inthe frequency of an eschar,
but most importantly,in severity and outcome. to reiterate, rockymountain spotted fever is a life-threatening illness with contemporary casefatality rates about 8%. whereas rickettsia parkeririckettsiosis is a far milder disease with no known deaths. so how much spotted fever inthe united states is caused by the respected agents? we currently don't have agood answer to that question.
but there is someevidence to suggest that there is more rickettsiaparkeri rickettsiosis than we know. for example, we knowof multiple instances of individual clinicianswho are adept at recognizing this disease andhave identified up to five cases in just a few yearsof searching. another clue comes from therelative rates of infection in the tick vectors witheach of these pathogens.
rickettsia rickettsii is rarelyfound in dermacentor ticks in the eastern united states,and current estimates suggest that fewer than 1 in 2,000 ticksactually harbor this pathogen. in contrast, rickettsiaparkeri is commonly found in amblyomma maculatumwith one in about every two to four adult gulf coast ticksinfected with this agent. finishing up, thetake-home points from this segment arethe etiologic spectrum of rickettsiosis in the ushas expanded during the last
15 years. rocky mountain spotted fever and rickettsia parkeririckettsiosis share many clinical features but differconsiderably in severity. and finally, andperhaps most importantly, doxycycline is thedrug of choice for all tick-borne rickettsiosesand in all patients of all ages. therapy needs to beinitiated immediately based on a presumptive diagnosis.
thank you, and at thispoint, i'm going to turn over the podium todr. greg ebel. today, i want to provideyou with some information on tick-borne viruses. most of us think oftick-borne disease as fairly badly neglectedin the current environment. and tick-borne viruses areneglected even among these neglected pathogens. this lack of attentionis somewhat strange,
so i want to take aminute to give you a sense of the wide diversity of viralagents vectored by ticks. these agents belong to a widearray of taxonomic groupings. they also have verydifferent strategies for storing genetic informationand packaging that information into infectious particles. like other arboviruses,outcomes of human infection with tick-borne virusesare variable but may be quitesevere and often fatal.
the other notable point thati'd like to make here is that tick-borne viral diseasesare found all over the world, so tick-borne virusesreally a global problem. so why is it that ticks aresuch great vectors of viruses? if we think aboutthe characteristics that impact the reproductiverate of an arthropod-bornepathogen, ticks have them all. they can be extremely abundantin certain areas and tend to focus their feeding on a veryrestricted set of host animals,
often on a single host species. they also are extremelylong-lived, especially in comparison tomosquitoes, with lifecycles of most taking severalyears to complete. that means that they tend not to die before a virusinfects their salivary glands and is released intotheir salivary secretions. there are also some otherbiological factors that have to do with the way that theirsaliva suppresses host immunity
in order to permit the prolongedfeeding process ticks require, and with the way that theydigest their blood meals that are all critical inmaking them outstanding arbovirus vectors. so in the next few slides i'mgoing to review a few emerging and really interestingtick-borne viral diseases that are of relevanceto us here in the us. and i'm going tostart with the one that in my mind is themost problematic and about
which we know the most andhas the greatest potential for emergence, and that'spowassan virus, also referred to as deer tick virus inportions of the literature. powassan virus ismaintained in nature in at least three fairlydistinct transmission cycles. the first has beenknown since the 1950s and involves woodchucksand a species of tick ixodes cookeithat's generally confined to woodchuck burrows andfeeds almost exclusively
on woodchucks. a second cycle involvessquirrels and a different speciesof ticks, ixodes marxi. this cycle was alsonoted shortly after powassan viruswas discovered. more recently, it's becomeclear that a distinct genotype of powassan can be maintained in a deer tick white-footedmouse cycle alongside the agents of lyme disease,human babesiosis
and human anaplasmosis. the extent to whichviruses spill over from one transmission cycle to another aren't really wellunderstood at this point, but based on virusgenetic studies, it appears that at least thedeer tick-associated cycle is isolated from the others. also notable is that most, ifnot all, recent human cases of powassan virusinfection appear to be linked
to the deer tick-driventransmission cycle. that is part of the reason that powassan virus isconsidered an emerging health threat in the us, and there is in fact some evidenceto support this. the first piece of evidenceis from wildlife studies. this shows that deer collectedin connecticut from 1978 through 2010 had anincreasingly likelihood of carrying antibodiesdirected against powassan virus.
the likely explanationhere is that more ticks in the environment equalsmore tick bites to the deer which equals more transmission,which also equals more risk because generally, human riskis proportional to the intensity of enzootic transmission, which in this case isclearly increasing. there's also good clinicalevidence that the incidence rate of powassan virus in humanbeings is increasing. although this couldpartly be due
to enhanced recognitionand detection. given what's known aboutincreasing enzootic transmission that i showed you about in theprevious slide, it seems prudent to consider the possibility that human infections areindeed becoming more common. this table showingclinical features of a case series collected from2013 to 2015 demonstrates this. also, please note thatthe case fatality rate of approximately 25%and the prevalence
of severe long-termsequelae among survivors, which was about 33%,is consistent with what we thought weknew about the severity of the infection datingback to the earliest studies of powassan virus in humans. since 2006, 68 cases ofpowassan encephalitis have been recognized and reported. because this diseasecan initially look like other illnesses,
it's likely that only themost severe hospitalized cases or deaths are the onesthat are being reported. cases have occurred in thenortheast and upper midwest, which of course, is consistentwith transmission by deer ticks. severe powassan virusdisease occurs due to neurological involvement. these images show thatthis can occur via two distinct mechanisms. the first is due to inflammatorychanges within the perivascular
and parenchymal portions ofthe brain which are shown in panel a. the other mechanism by which powassanvirus causes diseases, direct neuronal injury,which is shown in panel e. in this particular case, nearlyall of the purkinje cells, which among other things controlmotor functions, were targeted by powassan virus and werenearly absent on this biopsy. so both direct infectionof neurons and inappropriate inflammationdue to infection contribute
to pathogenesis in humancases of powassan virus. so we keep learning aboutnew tick-borne viruses. well i want to take amoment to discuss two that are cause for some concern. i'd like to stress thatvery little is known about these viruses. the first is heartland virus, aphlebovirus that was recognized in 2009 due to two casesthat occurred in missouri. the virus is transmittedby the lone star tick,
amblyomma americanum, whichis currently expanding in its distribution. wildlife studies suggestwidespread distribution of the virus in the southernand southeastern united states. another newly discovered virusis bourbon virus, a thogotovirus that is known from asingle case report in 2015. based on its biogenetic positionin in vitro replication studies, it seems highly likely thatthis also is a tick-borne virus. the sole case resultedin a fatal outcome.
again, though, the realpoint is to highlight that we're always finding newpathogenic tick-borne viruses and that there is a widetaxonomic array of agents that can potentially emerge. so these are thingsthat we really need to maintain vigilance about. i want to close bytaking a moment to talk about the state of the field. i mentioned that this is aneglected area, but it's not
because we don'thave interesting, relevant things to work on. it's been clear that much of theemergence of tick-borne diseases in our country is linked to thereforestation of the eastern us, which has led to the broadecological changes we've seen in this region. so where are the knowledgegaps and unmet needs that we should betrying to fill? well, first there'ssome lack of clarity
in the field regardingwhat's required to facilitate virus perpetuationin nature, and by extension, what factors impact whenand how these new tick-borne viruses emerge. what's clear is that manydifferent transmission modalities exist, and that insome cases, many may be required to allow the viruses to survive. a general problem in the fieldis the disconnect that exists between theoretical,experimental
and field-oriented individuals. and this is currentlyhindering progress. a second opportunity exists aswe've experienced an explosion and knowledge about tickfunctional genomics that's arisen due to fundamentalchanges in the way that we collect andanalyze genetic information from arthropod vectorsand their pathogens. the work that's been donerecently builds on years' worth of work that's characterizedthe potent salivary secretions
of ticks, work that's continued to raise severalimportant questions on how tick saliva impactspathogen transmission. those who work on functionalgenomics will appreciate the large amounts of datathat can now be generated incredibly rapidly. i, however, would stressanalysis here, because it turns out that tick genomes areincredibly large, almost as big as the human genomeand that much
of the information theyobtain is duplicated in some way or another. the functions of many tickgenes are not well understood, as you can see from this figure of a paper describingthe transcriptome of the tick, hyalommamarginatum. forty-five percentof the transcripts in this case areclassified as unknown. it's also, of course,become clear
that many importantphenotypes are controlled, not only by the hostgenome, but by the assemblage of other organisms thatinhabit ticks in all of us. clearly, piecing this alltogether is complicated, but new advancesin computational and experimental biologyare already allowing us to make some progressin this area. so we're at a very excitingtime in the history of the field of tick-borne virusdisease research.
we have a broad expertisein the ecology of ticks and their hosts, improvementsin in vitro and in vivo systems to study tick-borneviruses, and new sequencing and computational tools to applyto these important problems. but progress isn't being madeas fast as we would like. there are both technical andenvironmental reasons for this. many tick-borne viruses, as imentioned, are highly pathogenic and require bsl-3, or evenbsl-4 containment for study. here's a picture of myfriend, dennis, trying to work
on tick-borne viruses at bsl-4. and as you can imaginefrom the picture, that might presenta few problems. also, the systems that we'retalking about are complex, as they are for allarthropod-borne disease. but the understandingof ticks lags far behind that of mosquitoes. this is partly because of theprolonged lifecycle of ticks. they live longer than thegrants many of us hope
to obtain to use to study them. so the point is thatour system in the us for funding biomedical research in academia isn't particularlywell-suited to work on ticks and the pathogens they carry. finally, while tick-borneviruses are clearly emerging, they tend to do somuch more slowly than do mosquito-bornearboviral diseases which emerge in these explosive epidemics
that we've seen repeatedlyin recent years. so there aren't manypeople left working on them. so thank you for your attention. i hope that i've convinced you that tick-borne viruses areemerging health concerns, that we have interesting,relevant and tractable questions, andwe have great opportunities to move the field forward. but that we do havesome difficult technical
and environmental barriersthat are impeding our progress. so at this point, i'dlike to turn the podium over to dr. bobbi prittfrom the mayo clinic. >> thank you, greg,for that introduction. so, so far in this programwe've discussed the clinical and epidemiologic features forsome select tick-borne diseases. i'm now going to shiftgears to talk about advances in laboratory detection methods for diagnosing tick-bornediseases.
so let's first start with anoverview of the primary methods for diagnosis fortick-borne diseases that we have available to us. and i'd like to actually start by emphasizing the clinicalevaluation of the patient that occurs by membersof the healthcare team. this is essential at this point that tick-borne diseasesbe considered in the differential diagnosis.
and this is not just so thatthe crack laboratory test can be ordered but also that empiricalantimicrobial therapy can be begun if indicated. and as we heard fromdr. paddock, this is especially importantif rickettsiosis is expected or ehrlichiosis or anaplasmosis. because some of theseinfections can be rapidly fatal, and they need tobe treated quickly, often before the testresults are available.
so, now let's move on tospecifically laboratory methods. and these can be furtherdivided into indirect and direct laboratory methods. indirect methods, as i'mcovering on this slide, don't detect the organism itself but rather the host immuneresponse to infection. and typically, thisinvolves detection of igm or igg class antibodies inserum or other specimen types. now serology is themethod of choice
for diagnosing manytick-borne diseases. that's especially true forinfection with rickettsia, ehrlichia and anaplasma species, and there are commerciallyavailable options for these tests. now tick-borne virus serologyis a little bit more challenging because there aren't anycommercially available tests. instead, these methods uslaboratory-developed tests, and these are availableprimarily
through the state publichealth laboratories or the cdc. i also want to mention that serology is not theprimary diagnostic method for babesiosis. instead, blood smearshould be used. now one important,very important, caveat about serology isthat the sensitivity varies by the time the specimen isobtained during the course of illness.
and i want to illustratethat here on this chart. so this graph shows thegeneral patterns of igm and igg antibodiesfollowing infection. and if we consider day oneto be the onset of infection, then you can see that igmantibodies start to rise in the first few days. they're usually detectibleby seven days. and then titer eventuallydrop off after several months. then, production ofigg develops after igm,
and levels will continue to rise and then can remaindetectible for years. so as you can seewith this graph, there's this first week lag where serology is aninsensitive method for detecting tick-bornediseases. but by the second or third week, sensitivity increasessignificantly. so, now in comparisonto indirect methods,
let's talk about direct methods. these detect the organism itself or some componentof the organism. so for example, microscopycan be used to detect bacterial clustersof anaplasma phagocytophilum, relapsing fever borreliaspirochetes in peripheral bladdercsf, or babesia parasites within red blood cells. also nucleic acidamplification tests are a method
for directly detectingthe organism's dna or rna. and then culture isalso a direct method. it's not routinely usedtoday except for detection of francisella tularensis, thecausative agent of tularemia, but it is an importantresearch tool. so let's go back to our graphnow to look at the utility of direct laboratory methods. in comparison to antibodies,which the curves here show, dna or rna can almostalways be detected earlier
on in the patient. this is just a generalization. you can see different curveswith different organisms. now the onset of symptomsis also quite important when you're consideringmolecular testing since this will stillinfluence when patients present with treatment or fortreatment by their physician. so for many tick-borne viruses,as i've highlighted here in this yellow-orangecolor, you can see the onset
of symptoms occur, doesnot significantly overlap with the period of time thatthe patient has detectible dna or rna in their blood. so by the time thepatient presents to a healthcare providerfor evaluation, nucleic acid may no longerbe detectible in the body. so, in general, this explainswhy nucleic acid amplification methods can be one of ourearliest detection methods for some organisms, yet canalso be an insensitive method
for other organisms. they do happen to beour most sensitive tool for detecting anaplasmaphagocytophilum, ehrlichius species andbabesius species, particularly in whole blood, because the dna of these organismsis present usually in high amounts during the stagethat patients are symptomatic. now there are a variety of nucleic acid amplificationmethods available.
unfortunately, none arecurrently fda cleared or approved for in vitrodiagnostic use at this time. now let's discussspecifically one aspect of nucleic acid amplificationmethods. that's called real-timepolymerase chain reaction, or commonly known as pcr. by using one of severaldifferent types of probes, dna is detected asit is amplified. and when designed well,pcr allows for sensitive
and specific detection. the greater amount ofnucleic acid that's present in the specimen, the fasterit's detected, and therefore, real-time pcr alsoprovides some measure for how much dna ispresent in the specimen. we can get even more informationout of the test reaction by incorporating a step calledmelting temperature analysis. this can use eithernonspecific dna-binding dyes or specific probes.
this occurs after amplification, and melting curveanalysis can alert the user if there are anymutations present. this could be a simple mutation, or it could represent anentirely new organism. and i want to showyou an example of that on this next slide. in my laboratory at mayo clinic,we have a real-time pcr test that targets growel, that's the gene
that encodes the heat shockoperand of ehrlichia species. now we designed theprimers to amplify a region of the gene that's conservedin all ehrlichia species, and then we differentiate thetwo human pathogens ehrlichia ewingii and ehrlichiachaffeensis, by melting temperature. and you can see themelting peaks here. this is possiblebecause we chose probes that target the regions of dna
where there are twobase pair differences. so you get two distinctdiscriminating peaks for each of the organisms. now, what this was reallyinteresting for this assay, as we were using itfor several years, we then noticed this peakright here in the middle. now this peak indicated anew organism that was clearly within outside of the range of ehrlichia ewingiiand chaffeensis.
this prompted us to performsome additional testing, and we recognized that thisis a new organism now called ehrlichia eauclairensis. so now, let's just take a sec and talk a little bit morebeyond single plex pcr. because this is talking aboutjust a single pcr reaction. some of the things thattake us beyond that, one of them would bemultiplex molecular panels. this is when you use acombination of primers
and probes to detectmultiple bacterial, viral and parasiticpathogens in a single test. we already have these fourrespiratory pathogens, gastrointestinal pathogens, and now there are tick-bornepathogens that are also panels that are under development. one aspect that takesus a little bit beyond that even further wouldbe broad range sequencing. unlike a multiplex panel
where you only detectwhat you're looking for, broad range sequencing, you'retargeting a specific gene. you amplify then andthen there's subsequent sequence identification. we have common targets such as16-s, the rrna gene for bacteria and the internal transcribespacer region for fungi. unfortunately, at this point, there is no equivalentfor viruses. so instead, we tendto target groups
of closely related virusessuch as flaviviruses. now the last categoryof emerging technology that i find particularlyexciting is metagenomics. and with this method,amplification of all nucleic acidsthat may be present in a specimen are amplified. that could be bacterial, fungal,viral, parasitic and human. because of the large amount ofnucleic acid that's amplified, you then need to do extensivepre and post processing steps
to target the areas of interest and remove nonrelevantnucleic acid. so, this is currently veryexpensive and time consuming, but i think this is boundto change in the future. so with that, i'd like to close with this last slide showing therecently published guidelines for diagnosis and management oftick-borne rickettsii diseases and thank you foryour attention. >> thank you, bobbi.
we're going to open itup for questions now. in the interest of time,i'd just like to ask you to keep your questions succinctand focused on the scope of the presentationsfrom this grand round. i'm going to start by askingif there are any questions from online or remotesites. >> we actually do have somequestions that came in, and again, our apologies forfuture when this is recorded and posted on thewebsite by friday.
this is a technical difficultywe haven't experienced before, but we did receive acouple of questions. one that i think is a good one. how do you remove a tick? >> carefully. >> i can answer that. well the best way to remove itis using fine-tipped tweezers, or forceps if you have them. and you just grasp the tick asclose as possible to the skin
and then just pull it out slowlyin a smooth, continuous motion. try not to twist it orsquish it, because then that might possiblyinject some of the contents of the tick into the skin. and then you can dispose of it,wash that bite site afterward. >> okay, any questions fromthe audience, we'll take next. >> nobody can accessthis right now. so we're still hoping. >> okay, we'll open it up thento questions from the audience.
>> i think you can hear meright here in the front. in relation to behaviorchange, campaigns related to this particular topic,what are the two, three, four areas that you wouldpoint to when we start looking at employing simplemodifications for folks to start practicing betterhabits as relates to ticks? >> so you're talkingspecifically about prevention of tick-borne diseases? so there are a couple ofstrategies, one includes trying
to avoid tick habitat, whichis often easier said than done. and a lot of times the ticksare in residential areas where you simplycan't avoid them. when that's not possible, werecommend using a repellant, specifically containing 20 to30% deet that you can apply to exposed skin or clothing. or using permethrin-treatedclothing. those are probably the simplestprevention steps you can take. but then it's also recommendedthat after coming indoors
that you bathe anddo a tick check. and any tick that youidentify you remove promptly to prevent the likelihood ofthe tick having the ability to transmit any of thepathogens that it's carrying. you can also tumble dry yourclothing at high heat to try to kill any ticks thatare still on your clothes. but most importantly, make surethat you do the tick checks. check yourself, your children,your outdoor gear, your pets, so that you're notbringing those,
the ticks into yourhome for later exposure. chris is going toadd something else. >> yeah, i just want to followup on that because it relates to the previous questionin terms of tick removal. and as was mentioned previously,that's a very important process where you can reduce therisk of transmission. not all the ticks thatbite people are infected with a pathogen. but, enough of them are sothat getting that tick off you
as quickly as possible reducesthe risk of transmission. and different pathogens takedifferent periods of time to transmit once thetick is attached. but the quicker you can get thattick off, the better you are. and the other thing is,you need to be looking at your kids very,very carefully. and ticks will go to placesthat are hard to find. so you have to do avery thorough tick check when you've been intick-infested areas.
but that does minimize risk. >> okay. dr. schuchat. >> one of you showedthat nice origin of the rocky mountainspotted fever in idaho. and in the maps it reallylooks like, you know, the rockies don'thave it anymore. i was wondering if you couldclarify whether we are just seeing emergence of new vectorson the eastern southern area, or has something changedin the western states
to make rocky mountain spottedfever less frequent there. >> well that's a great question. and i think what's reallyimportant to realize is that tick-borne diseases,like any zoonotic disease, they're dynamic processes. these thing changes. there's ebbs and flows interms of the distribution, the prevalence, you know,the frequency of infection. the disease was first discovered
in the bitterroot valleyof western montana. but it existed in theeastern united states. it just wasn't diagnosed. it turned out that there was anepidemic in this small valley, and it was so dramaticthat scientists from around the unitedstates came to that valley to investigate, much the wayscientists do now from cdc. so that's where itwas discovered, and that's why it got the namerocky mountain spotted fever.
it's really a misnomerbecause actually we now know that infection with rickettsiarickettsii occurs all throughout the americas. we know that it exists in braziland argentina and columbia, as well as all thestates in the us. and actually, most ofthe disease that we hear about now comes fromthe eastern us where dermacentorvariabilis is the vector. what was very interesting isthe emergence of this disease
in eastern arizona associatedwith the novel tick vector. and that, i don'thave enough time to go into the details of that. but that was a veryintriguing process. and again, kind ofthe whole concept that these diseases change overtime and new things emerge. we always have to be, youknow, prepared for new vectors, new pathogens and newareas of emergence. >> so, over here.
thanks all. just to follow up on chris'point, not a tough question, but what is your thoughtson the next emerging virus or bacteria from ticks? can you predict anything, whatare you expecting to happen? >> sure. i think, you know,there's a couple of ways to answer the question. if by so, if we say, whatvirus is going to emerge and give us the largest numberof cases in the shortest amount
of time, something thatwe know about already. i think in my mind, that's pretty clearlypowassan virus and its allies. and the reason forthat is that it is in exactly the same transmissioncycle that's driven the emergence of lymedisease, human babesiosis, anaplasmosis and so forth. so, the question, i mean there'sa lot of interesting questions around that why have wenot had a gigantic epidemic
of powassan virus encephalitis,and so in a way, that's almost as interesting ofa question as is that one really going to emerge. all of the kind of ecologicalfactors that could drive that sort of an epidemicare there. beyond that, are we likely to see more bourbon virus,more heartland virus. i don't know that i have a greatanswer for that or the things that we don't know about
yet because we're not doing aparticularly great job of going out and surveyingticks for viruses. some of that work is being done. but it makes it hard to kind of predict what'sgoing to come next. >> so interesting, we'verecently seen two fatal cases of powassan virus in our, whichis not common by any means. but that's a good prediction. >> and.. ithink part of the answer
to that question is theavailability of assays to actually pick it up. so if you don't look forit, you don't find it. and i think one thingthat's very apparent is that we haven't discoveredall the tick-borne diseases that are yet to be discovered. as bobbi mentioned,more than half of them have been discoveredin the last couple decades. so, with the advancement of, youknow, technological diagnostics
that bobbi mentioned, i thinkwe're going to find more. and then the other thing is, you've got to figurethere's not just two or three viral diseases,tick-borne viral diseases or two or three rickettsia diseases. it's very likely that every oneof these ticks has its own suite of pathogens, whetherthey're viral or rickettsia or protozoal. and we found themost serious ones,
those declare themselvesusually pretty quickly like rocky mountain spottedfever is very dramatic. so, it's not surprise thatwas sort of the first one. it's the most lethal. but i think there are a lot of other probably moresubtle diseases out there that remain to be discovered. >> do we have any morequestions from online? i don't want to completelyneglect them.
>> yeah we do, but let'sget other people in the room since we're not webcasting. >> okay. >> thanks for thegreat presentations. i noticed on some of yourincidents maps there's a state-shaped hole oflower incidents surrounded by areas of higher incidents. so could you just describesurveillance systems for these types of diseases?
>> so, most of the data,or almost all of the data that we have for theseincidents maps are based on passive surveillance. and so, you have allthe limitations inherent in passive surveillance systems. so you may have some verydiligent people reporting from a particular county inflorida or oklahoma or texas. and then people in othercounties in other states that, you know, aren'tnecessarily looking
or considering tick-bornediseases on their radar. so, i think that's part of it. it's hard, when you look at amap like that, it's hard to sort of say, this county hasit, this county doesn't. or this county has this highincidence, this county doesn't. i think it's better tolook at it as a continuum. and also just a general pattern. and that's why onthe incidents map for spotted fever rickettsiosis,what i really wanted
to emphasize is sort of theoverall pattern, which was sort of a band that extended fromoklahoma to north carolina. i didn't want to say oh lookat this county in tennessee. it's got huge incidents, andthe county next to it doesn't. the other thing is, theseare arthropod-borne diseases. ticks don't fly. the infections can bevery focal, you know, where you find a cluster ofcases in a particular area. and then, you know,100 yards away,
there aren't any infected ticks. so, it's tricky. i hope that answersyour question, brian. >> it does, thanks. >> thanks. >> next question. >> it sounds likeprevention is a continuing and difficult challenge, tryingto get folks to repeat something that needs to happen regularly.
given the success apparentlythat you had in the southwest with the experience with dogtick collars, i'm struck. and i'm wondering if i'mgoing to get a couple of those dog tick collars formyself and use them to close up my trouser legsnext time i'm hiking. is that a wearablecollar or bracelet or anklet strategysomething worth exploring. >> so i think the closestyou would come is repellant or permethrin-treated clothing.
but you hit on one ofthe toughest challenges. >> oh i think i can get a dogtick collar pretty easily. i'm sure amazon willship them overnight. >> it would be fashionable. the one thing to note, chrishad a notable success story with prevention oftick-borne diseases. rhipicephalus sanguineusis a very different tick from the others thatwe described. it's a single host.
so it can be very effectiveto target domestic dogs. whereas with your ixodesscapularis-borne diseases, you tend to have theimmature life stages feeding on small mammals,medium sized mammals, the adults feeding on deer. so you have multiplehosts to keep track of, as well as those ticksare often found very close to people's homes andin areas where they like to recreateduring the tick season.
so repellant use,permethrin-treated clothing and daily tick checks. until the dog collar for people. yep. >> so, on a number of theslides, especially having to do with the ixodes range, the tick-borne disease rangewas actually a much smaller than the ixodes range. so what is the ecologicdifference outside
of the disease range wherethe ticks still exist? >> yeah, that's agreat question. and there are severaldifferences. i think one of the key piecesthat separates your risk in the north and the southis the behavior of the ticks. the southern ixodes ticksare different enough from the norther ixodes ticks that at one point theywere two different species. and their host-seekingbehavior is really different.
in the north the ticks moreactively ascend to vegetation and more aggressivelyseek human hosts. of course, humans arestill incidental hosts. but you're more likely toencounter a tick in the north than in the south strictly because of theirhost-seeking behavior. infection rates aregenerally a little bit, are higher in the norththan the south, particularly for borrelia burgdorferi.
the other pathogensare quite low in prevalence across the board. but largely differences inthat host-seeking behavior. >> hi, thanks for agreat presentation. you mentioned inone of the slides that doxycycline is theantibiotic of choice. but there are somechallenges associated with it. it's not the first antibiotica doctor will usually prescribe for somebody with afever, for example.
and it's also a challengewhen it comes to pediatric population. so, i was just curiousif you had any insights into doxycycline usein the united states and if there was anythingpeople should be doing if they know they've beenexposed to ticks when they go to their doctor to maybe pushthem in that right direction. >> yeah, that's agreat question, jenny. so, doctors are taught inmedical school very strongly
that you don't givetetracyclines to kids under the age of eightbecause it stains the enamel and causes hypoplasiaof the permanent teeth. those studies were based on, or that dogma isbased on old studies. you know, essentially women whowere receiving tetracyclines in pregnancy for acne,for multiple weeks and, what we know now is thata single short course of doxycycline in kidsdoesn't cause cosmetic staining
of teeth. so the real push now, and whatwe've been trying to emphasize for the last two decades is that doxycycline isthe drug of choice. it's really the only drug thatdiminishes the fatality rates when administered in thefirst five to six days. so we've been pushingreally hard to get physiciansto be aware of that. that you give thatdrug regardless.
it's not going to causestaining of the teeth if you give a fiveto ten day course. i think that comes back to the,you know, the very beginning in terms of how we preventand control these diseases. and you know, education and awareness are our mostpowerful tools right now. you know, we are the cdc,but i think the control part of this is going to be verytough for years to come. really the key to all thesetick-borne diseases is awareness
and education of the clinicianswho are seeing patients, as well as the publicwho are getting infected and presenting totheir clinicians. >> thank you very much. and i'd like to take amoment to thank the speakers for excellent presentations. thank you very much for joiningus, and we'll see you next month for cdc public healthgrand rounds.
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