Lyme Disease is a Trainwreck

Lyme Disease is a Trainwreck

Lyme Disease and Post-treatment Lyme Disease Syndrome John N. Aucott, M.D. Assistant Professor, Department of Medicine Johns Hopkins Hospital Lyme Disease Research Foundation Park Medical, L.L.C. 10755 Falls Road, Suite 200 Lutherville, MD www.LymeMD.org John N. Aucott, MD

Disclosures No Relevant Financial Relationships with Commercial Interests We will not reference an unlabeled or unapproved use of a drug or product in my presentation. Learning Objectives Recognize the increasing incidence of Lyme disease Learn about new tick-born pathogens that expand the DDx of Lyme disease

Be aware of the heterogeneity and complexity in patients presenting with a concern of Chronic Lyme disease Understand the clinical features of Post-Treatment Lyme Disease Syndrome (PTLDS) Learn about data from the SLICE Study on immune signatures in Lyme disease and PTLDS Lyme Disease a Leading World Wide Infectious Disease Iceman from Italian Alps 5,300 years ago with Lyme disease

1902-1922 European Tick-borne disease described Erythema chronicum Migrans (ECM) Meningopolyneuritits (Bannwarths Syn.) 1975 Connecticut cluster of arthritis cases in children Link of prior tick bite and rash to arthritis Discovery of bacterial pathogenesis Worldwide expanding infectious disease Climate change and northern expansion of

Lyme disease into Canada Geographic Spread of Lyme Disease Geographic Spread of Lyme Disease Geographic Spread of Lyme Disease 300,000 CASES A YEAR

Ten Most Commonly Reported Notifiable Diseases, Maryland, 2011 Disease 1. Chlamydia 2. Gonorrhea 3. Lyme disease 4. HIV/AIDS 5. Salmonellosis 6. Campylobacteriosis 7. Strep. Group B, invasive 8. Strep. pneumoniae, invasive

9. Meningitis, aseptic Rate Per 100,000 466.9 110.8 23.2 20.1 17.3 10.6 10.4 10.1

9.0 Stages of Lyme Disease are Defined by the Signs of Infection Early Diagnosis and Treatment is Key to Preventing Long-term Complications Erythema Migrans (EM) is the Classic Early Manifestation of Lyme Disease Onset 3-30 days after tick bite

Skin lesion can be unnoticed by patients and physicians Minimal pain and pruritis May mimic spider bites Resolve without therapy over weeks Only 20-30% of EM are Classic Target Lesions Disseminated Rash of Lyme Disease is Atypical in Appearance

Atypical Presentations of Early Lyme Disease Without EM Rash Viral-like presentations of Lyme disease overlap with other acute infectious diseases Enterovirus, west nile, even influenza Tick-borne illnesses: Anaplasma, Ehrlichia, Babesia Tick-borne Illness look similar when there is no rash Fever, headache, malaise, Absence of typical rhinitis of viral URI

Anaplamsa, Ehrlichia, and B. miyamotoi Ehrlichia/Anaplasma Leukopenia Thrombocytopenia Higher fever Elevation AST/ALT Dx: smear, PCR, Acute/conv. serology B. miyamotoi

Symptoms similar to other tick-borne diseases: myalgia, headache, fever Rash uncommon Test (-) on Lyme serology Babesia microti and Co-Infections Babesiosis: First case in Maryland Anemia Splenomegally

Risk splenectomy for severe disease Dx: smear, PCR, serology Coinfection Lyme disease, Anaplasma, Babesia Tick-borne Viruses Flaviviruses Powassan Virus

Transmitted by Ixodes ticks 10% fatality 50% permanent neurologic sequela Tick Borne Encephalitis (Eurasia only) Heartland Virus; Midwest US Transmitted by lone star ticks Fever, fatigue, thrombocytopenia, leukopenia Natural History of Untreated Lyme disease Early Disseminated Infection

Early Disseminated Infection: Cranial nerves, meningitis, radiculitis, carditis Three Sudden Cardiac Deaths Associated with Lyme Carditis United States, November 2012 July 2013. CDC MMWR 2013 Weekly/Vol. 62/No. 49. 993-996 Lyme Carditis Only 40% patients with Lyme carditis report having erythema migrans rash, as compared with 70%-80% of patients overall. Prompt recognition and early, appropriate therapy for Lyme

disease is essential. Healthcare providers should: Ask patients with suspected Lyme disease about cardiac symptoms, including palpitations, chest pain, lightheadedness, fainting, and shortness of breath, and obtain an ECG if indicated; Ask patients with unexplained heart block about possible exposure to infected ticks; and. General Principles in the Diagnosis of Lyme Disease Diagnosis starts with risk factors and clinical signs and

symptoms (pre-test probability) Supportive labs have significant limitations No direct test for presence of pathogen (except PCR in synovial fluid) PCR not sensitive for low # organisms in blood/ CSF Validated Culture not available Serology (ELISA/Western Blot) Sensitivity limited by biologic delay in seroconversion Early disease there is risk of false negative test Specificity limited by persistence of antibody from remote exposure

Late disease cant easily distinguish past exposure from active infection Antibody testing is used for confirming exposure 2 step testing Elisa screening, Western blot for (+) Elisa Criteria for (+) blot Weeks 1-4: IgM 2/3 bands > 4 weeks: IgG 5/10 bands High specificity designed for surveillance

Gaps in sensitivity as currently defined by 2-tier surveillance testing 40% sensitive for early EM Convalescent post-treatment IgG is often negative Treatment Oral doxycycline preferred for adults and children over age of 12 Oral amoxicillin in those allergic to doxycycline Must consider risk of co-infection with anaplasma

IV antibiotics indicated for neurologic involvement or refractory arthritis Borrelia NOT sensitive to 1st generation cephalosporins, quinolones Prognosis Prognosis depends on stage of infection at which treatment is given Treatment of early disease speeds resolution of EM rash and prevents development of later objective finding of disease (meningitis, arthritis)

No biomarker for establishing eradication of infection. Serology does not act as test of cure no PSA test for Lyme disease Treatment of late Lyme arthritis is 90% effective 10% develop post treatment antibiotic refractory arthritis Do symptoms persist or recur after treatment?? Post-treatment Symptoms are Real, But What Should we Name Them? Minor late symptoms Steere 1983

Lyme disease associated with Fibromyalgia Dinerman & Steere 1992 Post-infectious Syndrome Asch &Weinstein 1994 Chronic Lyme disease Donta 1997 Post-Lyme Syndrome IDSA Guidelines - 2006 Post-Treatment Lyme disease Syndrome CDC website - 2012 PTLDS/CLD Name reflects the audience Controversy over pathophysiology and treatment

Does Chronic Lyme Disease Exist? Chronic Lyme disease is a legitimate patient concern and the chief complaint they may present with. Does everyone with a chief complain of Chronic Lyme have an illness related to Lyme disease or PTLDS ?? No (think chest pain and Coronary disease) Incidence and severity depend on risk factors: Low risk patients with early, adequate treatment 10-20% incidence Often mild/intermittent symptoms High Risk with late diagnosis or initial misdiagnosis Severe/persistent

Z- pack, quinolone phenomenon Categorization of patients presenting for evaluation of Lyme disease with symptoms 12 weeks duration (n = 235) Aucott JN, Seifter A, Rebman AW. (2012). Probable late lyme disease: a variant manifestation of untreated Borrelia burgdorferi Infection. BMC Inf Dis, 12:173. 10.00% Confirmed Late Lyme 6.00% Probable Late Lyme 15.00%

PTLDS 54.00% Other, non-Lyme dx 67% female Medically Unexplained Symptoms 15.00% Model for Post Treatment Lyme Disease Syndrome

Model for Post Treatment Lyme Disease Syndrome Model for Post Treatment Lyme Disease Syndrome PTLDS/CLD Excluding re-infection in Patients with Persistent or Recurrent Symptoms Prior Lyme disease does not prevent future new infection New episode best diagnosed by new EM rash

If no rash, symptoms alone do not mean new infection, could be symptoms of PTLDS or other illness Serology more difficult to interpret in context of previous infection (+) IgM more likely to represent old infection than new episode. IgM persists for long periods after treatment (+) IgG, especially if with more bands or higher ELISA titer support diagnosis of new episode of infection Patients with prolonged symptoms and no physical findings and only IgM (+) are more likely to have PTLDS than a new episode of Lyme disease

Hypothesis for Pathophysiology of PTLDS Hum of general population Triggered anxiety or depression Susceptibility from traumatic life events Autoimmune Anti-neural antibodies Dependent or independent on bacterial products

Post-infectious syndromes of arthritis, fatigue Persistent damage Campylobacter-triggered reactive arthritis, postinfectious fatigue Persistent post-treatment infection Q fever, brucellosis SLICE Study First prospective cohort study with non-Lyme affected controls for comparison 5 year prospective cohort with 2 year follow up At enrollment all patients have documented EM

Pretreatment and 6 post treatment visits Validated symptom/severity of illness measures Unique opportunity to study disease process At onset and over time Biorepository for future studies Frozen Blood, DNA, RNA, serum, urine Beyond the Mouse and Test Tube Human Disease Based Research 24%

n=18 65% n=48 11% n=8 Clinical outcomes of Lyme patientsa (n=74) Returned to pre-Lyme health status Post-Treatment Lyme Disease Syndrome Persistent symptoms with normal functioning

a Determined at visit 5 (six months following the end of treatment) Blood Cytokine and Chemokine levels in Acute Lyme Disease vs. Uninfected Controls Lyme Patients Visit 1 Controls CXCL10 CXCL9

PTLDS Status Take-Home Points Post-treatment Lyme Disease Syndrome is a potential long term complication of Lyme disease. Patients who are self-identified as having Chronic Lyme Disease need a thorough diagnostic evaluation including a detailed history to identify those with PTLDS There is evidence that depression is not the cause of symptom persistence in PTLDS After an extensive evaluation many patients will have Medically

Unexplained Symptoms or may fit a syndrome such as fibromyalgia or Chronic Fatigue PTLDS presents opportunity to model symptom based syndromes models incorporate both biologic and behavioral variables that interact to determine patients phenotype Biomarkers for diagnosis and monitoring of Post Treatment Lyme Syndrome are urgently needed SLICE Study: Understanding the Impact of Lyme disease on human health and immune

function Lyme Disease Research Group Hopkins Green Spring Station Alison Rebman, MPH Johns Hopkins Schools of Medicine Mark J. Soloski, Ph.D., Immunology Kate Kortee, Ph.D., Neuropsychology Stanford U. School of Medicine William Robinson, MD Abbott; Ibis Biosciences division Mark W. Eshoo, Ph.D. Chris C. Crowder, Ph.D.

McHughs four perspectives The perspective of disease: what is wrong with the structure of the brain itself? Multiple Sclerosis or Depression from the disease perspective. Genetics, environmental exposure, organ pathophysiology The perspective of dimension: in what way does an individual's character cause him trouble Extraversion/introversion, stoic vs. catastrophizer The perspective of behavior: what actions persist because they have

been reinforced, or are driven by biological means Conversion disorder, Addiction The perspective of life-story: what has happened to a person which leads him to experience life (Health) as he does? Grief, loss, betrayal, lack of validation How is PTLDS distinguished from other Symptom based syndromes

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