NO DISCLOSURES Fact and Fiction Richard A. Jacobs, M.D., PhD. - PDF document

3/15/18 Lyme Disease NO DISCLOSURES Fact and Fiction Richard A. Jacobs, M.D., PhD. Willie Burgdorfer, Ph.D. (1925-2014) RM Lab in Hamilton, MT Polly Murray who first reported an outbreak of arthritis in 12 children from Old Lyme, CT in 1975—the first description of what would become to be known as Lyme disease. Author of “The Widening Circle: A Lyme disease Pioneer Tells Her Story” 1

3/15/18 Dr. Allen Steere, who at the time Outline was a Rheumatology Fellow at Yale University, was sent to investigate the • Clinical manifestations outbreak of arthritis. • Diagnosis In 1977 published a paper on Lyme Arthritis. (Arthritis and • Therapy Rheumatism 1977;20:7) • Prevention • Controversies Case Case • Serologies • A 35 yo woman is being evaluated for a 6 month h/o – CDC recommends 2-stage testing fatigue, arthalgias without arthritis and memory loss manifest as word-finding difficulties and • Screening ELISA or IFA—very sensitive but not forgetfulness. The work-up has been thorough but specific frustrating for both the provider and the patient – If negative—>no further testing because answers have not been forthcoming. Finally, after an exhaustive internet search, she requests that – If positive/equivocal—>confirmatory test Lyme disease serologies be performed. The provider • Confirmatory Western blot reluctantly agrees. – IgM – IgG 2

3/15/18 Case Questions • Serologies return: – Screening test is equivocal • How do you interpret the serologies? – Confirmatory Western blot is IgM (+) • Does she have Lyme disease? and IgG (-) Definition “Tick Biology 101” Lyme disease is a bacterial infection caused primarily by the spirochete Borrelia burgdorferi in the US ( less commonly by B. mayonii in the upper mid-West) and B. afzelii, and garinii in Europe and Asia (less commonly by B. burgdorferi and rarely by B. speilmanii and B. bavariensis) and is transmitted to humans by the bite of infected Ixodes ricinus complex deer tick. The clinical manifestations can be complex but affect primarily the skin, joints, nervous system and heart 3

3/15/18 “Tick Biology 101” “Tick Biology 101” (continued) • Hard ticks (over 700 species) • Three stages: – Ixodes ricinus complex – Larval—feeds from August to September on – Different geographic distributions white-footed mouse • Northeastern and upper midwestern states – Nymphal ★★ --feeds from May through July on – Ixodes scapularis (also called Ixodes dammini ) white-footed mouse • Western states— Ixodes pacificus – Adult—feeds on larger mammals, especially deer • Europe— Ixodes ricinus in the spring and fall • Asia— Ixodes persulcatus ★★ Nymph primarily responsible for disease transmission • Soft ticks (over 150 species) Most clinical cases occur in the summer months Tick Biology (continued) Tick Biology (continued) 4

3/15/18 Tick Biology (continued) Engorged Tick Clinical Manifestations Early Localized Disease • Early Localized Disease • Erythema Migrans – Usually occurs 7-10 days after the bite – Seen in 70%-80% of cases – Range 3-30 days – Begins 7-10 days after the bite (3-30 day range) – Starts at the site of the the tick bite • Early Disseminated Disease – Slowly expanding (over several days to weeks), flat – Weeks to months after the bite or slightly raised, erythematous rash that is often • Late Disease described by patients as burning or itching or less – Months to years after exposure commonly, painful – Clears spontaneously over weeks 5

3/15/18 Central Clearing Bulls Eye Rash 6

3/15/18 Early Localized Disease Early Localized Disease • Erythema Migrans • Erythema Migrans – Usually with – Usually accompanied with • Nonspecific systemic symptoms • Nonspecific systemic symptoms – Fatigue – Fatigue – Anorexia “SUMMER FLU” – Anorexia – HA – HA – Myalgias – Myalgias – Fever – Fever • About 40% of patients have spirochetemia Early Disseminated Disease Early Disseminated Cutaneous Disease (weeks to months) • Cutaneous Manifestations – EM at sites other than the original bite • Neurologic (15% of UNTREATED patients) – Lymphocytic meningitis – Cranial nerve palsies (especially the facial nerve) – Radiculoneuritis • Heart (5% of UNTREATED patients) – Atrioventricular block – Myocarditis (rarely) 7

3/15/18 Early Disseminated Cutaneous Disease Early Disseminated Cutaneous Disease Early Disseminated Disease Late Disease (weeks to months) (months to years) • Cutaneous Manifestations – Arthritis (60% of UNTREATED patients) – EM at sites other than the original bite • Large weight bearing joints • Neurologic (15% of UNTREATED patients) • Often recurrent (70%) – Neurologic – Lymphocytic meningitis – Cranial nerve palsies (especially the facial nerve) • Polyneuropathy • Encephalomyelits – Radiculoneuritis – True infection of the neuroaxis • Heart (5% of UNTREATED patients) – Very rare < 1/10 6 – Atrioventricular block – More common with B. garinii – Myocarditis (rarely) 8

3/15/18 Late Disease (months to years) – Arthritis (60% of UNTREATED patients) • Large weight bearing joints • Often recurrent (70%) – Neurologic • Polyneuropathy • Encephalomyelits – True infection of the neuroaxis – Very rare < 1/10 6 – More common with B. garinii Encephalopathy Diagnosis • Encephalopathy (memory difficulties/cognitive • Early Disease slowing) – Clinical Diagnosis – Common problem in patients with inflammatory diseases – 2-tier testing only 25% sensitive because of slow – Common background complaint in the general rise in IgM antibodies (1-2 weeks) and IgG population antibodies (2-6 weeks) • THESE SYMPTOMS ARE NOT MANIFESTATIONS OF CNS LYME DISEASE IN THE ABSENCE OF SEROLOGIC EVIDENCE OF EXPOSURE 9

3/15/18 Diagnosis of Late Manifestations Diagnosis (Steere AC et al. Clin Infect Dis 2008:47:188) • Late Stages – CDC recommends 2-stage serologic testing • Sensitivity of 2-tier testing in late Lyme disease • Screening ELISA or IFA—very sensitive but not is 100% and specificity is 99% specific (syphilis, gingivitis, LYMErix, SLE, RA etc) • “Therefore, current thinking is that all patients – If negative—>no further testing with objective neurologic, cardiac, or joint – If positive/equivocal—>confirmatory test abnormalities associated with Lyme disease • Confirmatory Western blot have serologic response (a + IgG western blot titer) to B. burgdorferi” New Approaches to Serodiagnosis Commonly Asked Questions • V1sE C6 peptide ELISA (C6 test) —measures • What is the explanation of an isolated positive antibodies to a protein-like sequence expressed Western blot IgM? in the sixth invariant region – FALSE POSITIVE – More sensitive in early disease than 2-stage testing • Can you get Lyme disease more than once? – More sensitive for European strains – Almost always re-infection • CDC, IDSA and AAN have yet to endorse the test – NOT relapse – Stand alone • Does Lyme disease in pregnancy affect the fetus? – Replace Western blot – Does not predispose to congenital anomalies or fetal demise 10

3/15/18 Clues to Diagnosis • EM occurs 3-30 days after bite--most commonly in 7- 10 days – Early reactions that fade are due to the tick bite and are not EM • Ticks must feed 24-36 hours to transmit organism • Know prevalence in your area – East Coast 60-70% infected – West Coast < 5% infected Clues to Diagnosis • EM occurs 3-30 days after bite--most commonly in 7- 10 days – Early reactions that fade are due to the tick bite and are not EM • Ticks must feed 24-36 hours to transmit organism • Know prevalence in your area – East Coast 60-70% infected – West Coast < 5% infected 11

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3/15/18 Prevention Proper Tick Removal • Light colored protective clothing with shirt tucked into pants and pants tucked into socks • DEET • Permethrin spray for clothes • Tick checks with prompt removal • Antibiotic prophylaxis—200 mg doxycycline – Ixodes tick; fed for 36 hours; tick infection rate >20%; antibiotics given within 72 hours of tick removal Prevention Back to the Case • A 35 yo woman is being evaluated for a 6 month • Light colored protective clothing with shirt h/o fatigue, arthalgias without arthritis and tucked into pants and pants tucked into socks memory loss manifest as word-finding difficulties • DEET and forgetfulness. • Permethrin spray for clothes • Lab tests – ELISA –equivocal • Tick checks with prompt removal – WB—positive IgM and negative IgG • Antibiotic prophylaxis—200 mg doxycycline • NOTE—EXPLANATION OF AN ISOLATED (+) – Ixodes tick; fed for 36 hours; tick infection rate Western blot IgM IS THAT IT IS A FALSE (+) >20%; antibiotics given within 72 hours of tick • IN LATE STAGES OF DISEASE ALMOST ALL HAVE A removal (+) IgG ANTIBODY TITER 13