Lyme Disease and Southern Tick Associated Lyme Disease and Southern Tick Associated Rash Illness (STARI) in Texas:Rash Illness (STARI) in Texas:

What we know; what we need to knowWhat we know; what we need to know

Stephen Waring, DVM, PhDStephen Waring, DVM, PhDAssociate ProfessorAssociate Professor

Epidemiology, Biological SciencesEpidemiology, Biological Sciences

Lyme DiseaseLyme DiseaseEcologyEcology

Lyme Disease:Lyme Disease:EpidemiologyEpidemiology

• Number of cases – US: 1993 - 2007Number of cases – US: 1993 - 2007

Lyme Disease:Lyme Disease:EpidemiologyEpidemiology

• Number of cases – Texas: 1993 - 2007Number of cases – Texas: 1993 - 2007

Lyme Disease:Lyme Disease:EpidemiologyEpidemiology

• Incidence in US: 2007Incidence in US: 2007

Source: CDC

* Among states reporting at least one case

Incidence per Incidence per 100,000100,000

USUS 9.19.1

Combined Incidence (Range)*Combined Incidence (Range)*States above US States above US

averageaverageStates below US States below US

averageaverage

39.2 (12.4 – 87.3)39.2 (12.4 – 87.3)0.8 (0.1 – 4.6)0.8 (0.1 – 4.6)

TexasTexas 0.40.4

Lyme Disease:Lyme Disease:Clinical Clinical

Early localized (1 - 4 weeks)Early localized (1 - 4 weeks)

• Flu-like (with or without rash)Flu-like (with or without rash)– fatiguefatigue– chillschills– feverfever– headacheheadache– muscle/joint achesmuscle/joint aches– swollen lymph nodesswollen lymph nodes

• Erythema migrans (70-80%)Erythema migrans (70-80%)– site of tick bite 3 – 30 day delay in appearancesite of tick bite 3 – 30 day delay in appearance

Source: CDC; WebMD

Lyme Disease:Lyme Disease:ClinicalClinical

Early disseminated (1 - 4 months)Early disseminated (1 - 4 months)

• facial nerve paralysis (Bell’s palsy)facial nerve paralysis (Bell’s palsy)• meningitis (headaches, neck stiffness, dizziness)meningitis (headaches, neck stiffness, dizziness)• cognitive deficits (memory, concentration)cognitive deficits (memory, concentration)• migrating painmigrating pain• heart palpatationsheart palpatations

Source: CDC; WebMD

Lyme Disease:Lyme Disease:ClinicalClinical

Late persistent infection (> 4 months)Late persistent infection (> 4 months)

Feder et al NEJM 2007

Feder et al NEJM, 2007

Lyme Disease: Lyme Disease: Laboratory diagnosisLaboratory diagnosis

Test Technique/Use Limitations Role in Chronic LD

Antibodies Two-tier testing• + ELISA or IFA• + IgM immunoblotAcute phase – should be pos if untreated

Supportive of clinical diagnosis; no proven utility in absence of symptoms

Not essential

Antigen PCROften positive in arthritis samples

Not well standardized; not recommended

Not validated

Culture BSK mediumSensitive in cutaneous samples; not routinely used

Slow growth; limited availability

Not validated

Urine antigen Antigen-capture ELISANot routinely used

Lack of accuracy Not validated

Feder et al NEJM, 2007

Lyme Disease:Lyme Disease:ClinicalClinical

Results of clinical trials on Category 4 patients:

Substantial risk with little or no benefit of continued antibiotics after appropriate initial treatment of Lyme disease

Source: Nature Medicine 2008

ProsPros ConsCons

Argument Persistent infection resistant to antibiotics

B. burgdorferi sensitive to antibiotics

Solution Long-term antibiotics Consider other diagnosis

Endorsements LDA, ILADS IDSA, NIAID, CDC

Scientific basis •Peer-review validation ?•More obscure literature

•Rigorous scientific review in high-profile journals•Reproducible findings

Legal issues • IDSA guidelines restrict treatment•antitrust suit by AG in CT

• IDSA – nothing wrong with guidelines but agreed to re-assess with new panel•Solid evidence that long-term

treatment not the answer

Chronic debate over chronic Lyme DiseaseChronic debate over chronic Lyme Disease(Post-Lyme disease syndrome)(Post-Lyme disease syndrome)

Post Lyme Disease Syndrome:Post Lyme Disease Syndrome:Confounding factors with subjective symptomsConfounding factors with subjective symptoms

• Patients told they have Lyme but do notPatients told they have Lyme but do not– >50% in one study at major tertiary care center had symptoms more >50% in one study at major tertiary care center had symptoms more

likely explained by fibromyalgia and chronic fatigue syndromelikely explained by fibromyalgia and chronic fatigue syndrome– Lack of laboratory evidenceLack of laboratory evidence– Improper advise based on testing that lacks validation (high rates of Improper advise based on testing that lacks validation (high rates of

false positives) (warning in MMWR, 2005)false positives) (warning in MMWR, 2005)

• High prevalence of subjective symptoms in general population High prevalence of subjective symptoms in general population creates considerable ‘noise’ - can be even higher than that creates considerable ‘noise’ - can be even higher than that reported for Lyme diseasereported for Lyme disease– Hence long standing directives not to perform diagnostic tests for Hence long standing directives not to perform diagnostic tests for

Lyme for subjects with only subjective symptomsLyme for subjects with only subjective symptoms

Source: Auwaerter CID 2007

Source: Point (A/CounterpointCID 2007

Post Lyme Disease Syndrome:Post Lyme Disease Syndrome:Long-term antibiotic therapyLong-term antibiotic therapy

Bottom line: more research needed

• Highly vocal debate fueled by frustrations stemming from:Highly vocal debate fueled by frustrations stemming from:• unmet needs of patientsunmet needs of patients• incomplete understanding of post-Lyme syndromeincomplete understanding of post-Lyme syndrome

Lyme Disease: Lyme Disease: Recent findingsRecent findings

• GenotypingGenotyping– 4 genotypes in outer surface protein C gene (OspC) account for 4 genotypes in outer surface protein C gene (OspC) account for

>80% of cases with EM from NY >80% of cases with EM from NY (Wormser et al, JID 2008)(Wormser et al, JID 2008)

• ClimateClimate– climate-associated variability in the timing of I. scapularis host

seeking contributes to geographic heterogeneities in frequencies of B. burgdorferi genotypes (Gatewood et al, App Environ Microbiol 2009)

• Virulence factor– bacterial protein (BmtA) associated with transporting manganese

across membrane important in growth of organism (Ouyang et al PNAS 2009)

Lyme-like Disease (STARI)Lyme-like Disease (STARI)EcologyEcology

Distribution of Amblyomma americanum, 2006 (courtesy of M. Yabsley, U Georgia)

Vector: Amblyomma americanum (Lone State tick)All stages are aggressive feeders and bite humans

Transmission earlier in year than Lyme disease due to feeding

habits of adults/nymphs

Lyme-like Disease (STARI)Lyme-like Disease (STARI)Clinical Clinical

Compared to Lyme disease:Compared to Lyme disease:• Milder flu-like symptomsMilder flu-like symptoms

– regional lymphadenopathy less likelyregional lymphadenopathy less likely– patients less symptomatic at time of rashpatients less symptomatic at time of rash

• Erythema migrans (100%)Erythema migrans (100%)– site of tick bitesite of tick bite– patients more likely to report tick bitepatients more likely to report tick bite

• More rapid recovery from treatmentMore rapid recovery from treatment

Masters et al Inf Dis Clin NA 2008

Lyme-like Disease (STARI)Lyme-like Disease (STARI)Diagnosis Diagnosis

• Causative organism undetermined– Borrelia lonestari isolated from dermatological biopsy of one

case but later series have failed to isolate organism– Therefore, no serological test available at present

• Clinical diagnosis based on presence of rash

Masters et al Inf Dis Clin NA 2008

Comparison of Lyme Disease and STARIComparison of Lyme Disease and STARI

Lyme DiseaseLyme Disease STARISTARIEtiologic agent B. burdorferi ??

Region NE US, upper Midwest SE US

Vector

Stage

Black-legged tick(I. scapularis, pacificus)

Nymph (primarily)

Lone Star tick(A. americanum)

All stages

Clinical presentationRash (frequency)Flu-like symptomsChronic manifestations

EM (70%)CommonCommon

EM (100%)Less likely

Less likely, less severe

Case definition Yes No

Lyme and Lyme-like DiseaseLyme and Lyme-like DiseaseWhat next? What next?

• Role of co-infection

Primary Tick Vector Associated human pathogens

Ixodes scapularis/pacificusIxodes scapularis/pacificus Borrelia burgdorferiBorrelia burgdorferiAnaplasma phagocytophilaAnaplasma phagocytophila

Babesia microtiBabesia microtiBartonella spp.Bartonella spp.

Amblyomma americanumAmblyomma americanum Ehrilichia chaffiensisEhrilichia chaffiensisEhrilichia ewingiiEhrilichia ewingiiBorrelia lonestariBorrelia lonestari

Rickettsia amblyommaRickettsia amblyomma

Lyme and Lyme-like DiseaseLyme and Lyme-like DiseaseWhat next? What next?

• Transmission studies– role of outer surface proteins (OspA & Osp B) -essential for

colonization and survival of Bb in ticks– role of gene BptA (Borrelia persistence in ticks-Gene A) - major role

in virulence and survival of organism in vector– Role of global warming favoring emergence of more

persistent/virulent strains in endemic regions with lower incidence (Upper Midwest) and in non-endemic regions

Lyme and Lyme-like DiseaseLyme and Lyme-like DiseaseWhat next for Texas? What next for Texas?

• Burning question: why such a low prevalence of tick-borne zoonoses (human cases) with so many ticks, so many people, and such a high risk for exposure?– Systematic surveillance (ticks and reservoir hosts)– Comparative studies of phenology (ecologic and climatic influences

on ticks and persistence/virulence of pathogens– What is the etiologic agent for STARI and is it just one mutation

away from producing a much more serious Lyme-like illness?– Does tick behavior in defined ecologic niches favor a vector that is

just less efficient in transmitting virulent human disease?– The role of co-infection with animal and human pathogens in

modifying infectivity/virulence (ex: could B. lonestari be a primary animal pathogen that just ‘outcompetes’ B. burgdorferi?

Stay tuned…

Lyme and Lyme-like DiseaseLyme and Lyme-like DiseaseWhat next? What next?

• Genomics/phylogenetics– Ex: study ‘in press’ indicates B. burgdorferi isolates from northern

US not genetically distinct from isolates in the southern US (M. Yabsley, personal communication)

• Role of pathogen-host relationships in tick-borne zoonoses– Ex: borreliacidal saliva in Ambloymma in modifying virulence

• Ecological characteristics– Ex: geospatial analytic methods to study factors in emergence and

to inform transmission cycles (sylvatic, peridomestic, domestic)

Lyme Disease and Lyme-like Disease in Texas:Lyme Disease and Lyme-like Disease in Texas:What we know; what we need to knowWhat we know; what we need to know

The art of medicine consists of amusing the patient while nature cures the disease.

Voltaire