Epidemiology, Biological Sciences Lyme Disease and Southern Tick Associated Rash Illness (STARI) in Texas: What we know; what we need to know Stephen Waring, DVM, PhD Associate Professor Epidemiology, Biological Sciences

Lyme Disease Ecology

Lyme Disease: Epidemiology Number of cases – US: 1993 - 2007

Lyme Disease: Epidemiology Number of cases – Texas: 1993 - 2007

Lyme Disease: Epidemiology Incidence in US: 2007 Incidence per 100,000 US 9.1 Combined Incidence (Range)* States above US average States below US average 39.2 (12.4 – 87.3) 0.8 (0.1 – 4.6) Texas 0.4 * Among states reporting at least one case Source: CDC

Lyme Disease: Clinical Early localized (1 - 4 weeks) Flu-like (with or without rash) fatigue chills fever headache muscle/joint aches swollen lymph nodes Erythema migrans (70-80%) site of tick bite 3 – 30 day delay in appearance Source: CDC; WebMD

Lyme Disease: Clinical Early disseminated (1 - 4 months) facial nerve paralysis (Bell’s palsy) meningitis (headaches, neck stiffness, dizziness) cognitive deficits (memory, concentration) migrating pain heart palpatations Source: CDC; WebMD

Lyme Disease: Clinical Late persistent infection (> 4 months) Feder et al NEJM 2007

Lyme Disease: Laboratory diagnosis Test Technique/Use Limitations Role in Chronic LD Antibodies Two-tier testing + ELISA or IFA + IgM immunoblot Acute phase – should be pos if untreated Supportive of clinical diagnosis; no proven utility in absence of symptoms Not essential Antigen PCR Often positive in arthritis samples Not well standardized; not recommended Not validated Culture BSK medium Sensitive in cutaneous samples; not routinely used Slow growth; limited availability Urine antigen Antigen-capture ELISA Not routinely used Lack of accuracy Feder et al NEJM, 2007

Lyme Disease: Clinical 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 Feder et al NEJM, 2007

Chronic debate over chronic Lyme Disease (Post-Lyme disease syndrome) Pros Cons 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 Source: Nature Medicine 2008

Post Lyme Disease Syndrome: Confounding factors with subjective symptoms Patients told they have Lyme but do not >50% in one study at major tertiary care center had symptoms more likely explained by fibromyalgia and chronic fatigue syndrome Lack of laboratory evidence Improper advise based on testing that lacks validation (high rates of false positives) (warning in MMWR, 2005) High prevalence of subjective symptoms in general population creates considerable ‘noise’ - can be even higher than that reported for Lyme disease Hence long standing directives not to perform diagnostic tests for Lyme for subjects with only subjective symptoms Source: Auwaerter CID 2007

Post Lyme Disease Syndrome: Long-term antibiotic therapy Highly vocal debate fueled by frustrations stemming from: unmet needs of patients incomplete understanding of post-Lyme syndrome Bottom line: more research needed Source: Point (A/CounterpointCID 2007

Lyme Disease: Recent findings Genotyping 4 genotypes in outer surface protein C gene (OspC) account for >80% of cases with EM from NY (Wormser et al, JID 2008) Climate 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) Ecology Distribution of Amblyomma americanum, 2006 (courtesy of M. Yabsley, U Georgia) Transmission earlier in year than Lyme disease due to feeding habits of adults/nymphs Vector: Amblyomma americanum (Lone State tick) All stages are aggressive feeders and bite humans

Lyme-like Disease (STARI) Clinical Compared to Lyme disease: Milder flu-like symptoms regional lymphadenopathy less likely patients less symptomatic at time of rash Erythema migrans (100%) site of tick bite patients more likely to report tick bite More rapid recovery from treatment Masters et al Inf Dis Clin NA 2008

Lyme-like Disease (STARI) 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 STARI Etiologic 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 presentation Rash (frequency) Flu-like symptoms Chronic manifestations EM (70%) Common EM (100%) Less likely Less likely, less severe Case definition Yes No

Lyme and Lyme-like Disease What next? Role of co-infection Primary Tick Vector Associated human pathogens Ixodes scapularis/pacificus Borrelia burgdorferi Anaplasma phagocytophila Babesia microti Bartonella spp. Amblyomma americanum Ehrilichia chaffiensis Ehrilichia ewingii Borrelia lonestari Rickettsia amblyomma

Lyme and Lyme-like Disease 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 Disease 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 Disease 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: What we know; what we need to know The art of medicine consists of amusing the patient while nature cures the disease. Voltaire