Peter J. Weina, PhD, MD, FACP, FIDSA. Colonel, Medical Corps, US Army Deputy Commander Walter Reed Army Institute of Research

Transcription

1 Peter J. Weina, PhD, MD, FACP, FIDSA Colonel, Medical Corps, US Army Deputy Commander Walter Reed Army Institute of Research

2 Background Most common vector-borne disease in U.S. First described in Lyme, Connecticut in children in the mid-1970s. Deer and other mammals form a reservoir of infection. Spirochetes first identified in the mid-gut of the black-legged tick, Ixodes scapularis. Later isolated from blood, skin, and CSF of patients with early Lyme disease.

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4 Background >8,000 cases per year Also most common vector-borne disease in Europe (19 different countries) Causative agent is Borrelia burgdorferi B. burgdorferi sensu lato isolated from animals & ticks B. burgdorferi sensu stricto expressing OspA in humans only B. garinii, B. afzelli (in Europe) Several other species in UK, Japan, etc. Spirochete transmitted by ticks

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7 Most commonly found in boys, ages 5 9 years old

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11 Tick First Aid Remove Tick immediately Grasp the tick with clean tweezers as close to the skin as possible to remove the head and mouthparts Pull straight out gently and steadily. Do not twist. Do not use a hot match or petroleum jelly. Save the tick. Cleanse and Protect the Area Wash hands and clean the bite area with warm water and gentle soap. Apply alcohol to the bite wound to prevent infection. See a Health Care Provider if: the tick has burrowed into skin or if the head, mouthparts, or other tick remains cannot be removed you develop a flu-like symptoms, fever, headache, nausea, vomiting, muscle aches, or a rash within one month the bite area develops a lesion within 30 days there are signs of infection such as redness, warmth, or inflammation

12 Lyme - The Organism Taxonomically described in 1984 flagellated, helical, spirochaetal bacterium protoplasmic cylinder surrounded by cell membrane and from 7 to 11 periplasmic flagella in loose outer membrane DNA sequenced in 1997 used B. burgdorferi type strain B kilobase linear chromosome, 9 linear plasmids, and 12 circular plasmids

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15 Clinical Presentation Typical picture in U.S. 70% of patients will develop and erythematous, expanding skin rash (erythema migrans) Onset is usually 7 10 days after exposure < 50% report a tick bite (or even remember a tick) Picture in Europe < incidence of arthritis; incidence of neurologic symptoms (meningoencephalitis) and chronic cutaneous lesions (acrodermatitis chronica atrophicans)

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17 Case Definition Clinical case definition Erythema migrans, or At least one late manifestation and laboratory confirmation of infection Laboratory criteria for diagnosis Isolation of Borrelia burgdorferi from clinical specimen, or Demonstration of diagnostic levels of IgM and IgG antibodies to the spirochete in serum or CSF, or A two-test approach using a sensitive enzyme immunoassay or immunofluorescence antibody followed by Western blot is recommended.

18 Definitions Erythema migrans (EM) The diagnosis of EM must be made by a physician. Late manifestations Late manifestations include any of the following when an alternate explanation is not found: Musculoskeletal system Recurrent, brief attacks (weeks or months) of objective joint swelling in one or a few joints, Nervous system Any of the following, alone or in combination: Lymphocytic meningitis; cranial neuritis, particularly facial palsy (may be bilateral); radiculoneuropathy; or, rarely, encephalomyelitis. Cardiovascular system Acute onset, high-grade (2nd or 3rd degree) atrioventricular conduction defects that resolve in days to weeks and are sometimes associated with myocarditis.

19 Definitions Exposure Exposure is defined as having been in wooded, brushy, or grassy areas (potential tick habitats) in a county in which Lyme disease is endemic no more than 30 days before onset of EM. A history of tick bite is NOT required. Disease endemic to county A county in which Lyme disease is endemic is one in which at least two definite cases have been previously acquired or in which a known tick vector has been shown to be infected with B. burgdorferi Laboratory confirmation Laboratory confirmation of infection with B. burgdorferi is established when a laboratory isolates the spirochete from tissue or body fluid, detects diagnostic levels of IgM or IgG antibodies to the spirochete in serum or CSF, or detects a significant change in antibody levels in paired acute- and convalescent-phase serum samples. Syphilis and other known causes of biologic false-positive serologic test results should be excluded when laboratory confirmation has been based on serologic testing alone.

20 Stages of Lyme Disease Disease develops in three stages Stage 1 (early-localized) Onset days to weeks from infection Stage 2 (early disseminated) Onset days to months from infection Stage 3 (late) Onset months to years from infection

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22 Major Lyme Manifestations Early Early Late System Stage 1 localized Stage 2 disseminated Stage 3 chronic Skin Erythema migrans Secondary annular lesions Acrodermatits chronica atrophicans Musculoskeletal Myalgias Migratory pain in joints, bone, muscle, brief arthritis attacks Prolonged arthritis attacks, chronic arthritis Neurologic Headache Meningitis, Bell s palsy, cranial neuritis, radiculoneuritis Encephalopathy, polyneuropathy, leukoencephalitis Carditis Atrioventricular block, myopericarditis, pancarditis Constitutional Flulike symptoms Malaise, fatigue Lymphatic Regional lymphadenopathy Regional or generalized lymphadenopathy Fatigue

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25 Diagnosis History Tick bite in endemic area, hobbies with exposure Immunoglobulin antibodies IgM = Can start at 2 weeks; peak 3rd 6th week IgG = raised by about 6 weeks ELISA Can detect both IgM & IgG Positive indicates exposure, not active disease Usually positive after 2 to 4 weeks (70%)

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28 Western Blots Western Blot sandwich-type immunoassay Lyme IgG/IgM antibody serology is equivocal or positive IgM 24 kda (OspC); 39 kda (BmpA); 41 kda (Fla) IgG 18 kda, 21 kda (OspC); 28 kda, 30 kda, 39kDa (BmpA); 41 kda (Fla); 45 kda, 58 kda (not GroEL); 66 kda, and 93 kda. "kda" = "kilodalton" "Osp" refers to outer surface protein of the bacteria. The CDC/ASTPHLD criteria are conservative require 2 of 3 IgM bands for a positive result require 5 of 10 IgG bands for a positive result

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30 Appropriateness of Lyme disease serologic testing Ramsey AH, Belongia EA, Chyou PH, Davis JP. 303 clinicians surveyed regarding 356 Lyme Disease Serologic Tests (LDSTs) 72 tests (20%) were appropriate, 95 (27%) were inappropriate, and 189 (53%) were discretionary. More likely to be inappropriate if ordered by ER or urgent care physician compared with other specialists (AOR=5.2), or if preceded by a known tick bite (AOR=6.8) The patient rather than the clinician requested 26% of tests, which were more likely to be inappropriate than clinician-requested tests (COR=5.8) Tests were more likely to be patient-requested if they were ordered by an internist (AOR=2.6) or if the patient was > or =40 years old (AOR=2.2) Many LDSTs are ordered inappropriately, often influenced by patient demand Ann Fam Med Jul-Aug;2(4):341-4

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32 Recommended therapy for patients with Lyme disease. Wormser G P et al. Clin Infect Dis. 2006;43: Infectious Diseases Society of America

33 Recommended antimicrobial regimens for treatment of patients with Lyme disease. Wormser G P et al. Clin Infect Dis. 2006;43: Infectious Diseases Society of America

34 Selected antimicrobials, drug regimens, or other modalities not recommended for the treatment of Lyme disease. Wormser G P et al. Clin Infect Dis. 2006;43: Infectious Diseases Society of America

35 LongLong-term followfollow-up of patients with culturecultureconfirmed Lyme disease Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, Gaidici A, Wormser GP. Prospective data from adults from a highly endemic area in NY State who were diagnosed with early Lyme disease between 1991 and Culture-confirmed EM evaluated at baseline, 7-10d, 21-28d, 3m, 6m, 1y, and annually All patients were treated with antibiotics at the time of diagnosis. Evaluated 96 cases on 709 occasions (8 evals/case) EM rash resolved within 3 weeks in all of the 94 evaluable cases Am J Med Aug 1;115(2):91-6

36 LongLong-term followfollow-up of patients with culturecultureconfirmed Lyme disease Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, Gaidici A, Wormser GP. 81 cases followed for >/=1 year all but 8 (10%) were asymptomatic at their last visit, a mean of 5.6y into follow-up, and only 3 (4%) were symptomatic at every follow-up visit Intercurrent tick bites were reported by 45 cases (47%), and 14 (15%) developed a second episode of erythema migrans Four cases who were asymptomatic seroconverted between years 2 and 5 The long-term outcome of patients w/ EM after antibiotic therapy was excellent Patients from a highly endemic area in NY State remained at high risk of re-exposure to ticks and reinfection Subjective symptoms during follow-up evaluations tended to be mild to moderate, intermittent, and associated with more symptomatic illness at the time of initial diagnosis Am J Med Aug 1;115(2):91-6

37 Disappearance of specific immune response after successful therapy of chronic Lyme borreliosis Hassler D, Schnauffer M, Ehrfeld H, Muller E. Consecutive patients suffering from chronic Lyme borreliosis have been treated according to a standardized therapy regimen which was developed using the results of a controlled trial (developed by the Author). Follow up was performed for at least 6 (maximum 16) years. In the first two years after initial therapy clinical and serological data were collected every six months including Western blot testing, later once a year. Int J Med Microbiol Apr;293 Suppl 512

38 Two Controlled Trials of Antibiotic Treatment in Patients with Persistent Symptoms and a History of Lyme Disease Two different double-blind, placebo-controlled trials, each at 3 different sites Symptomatic individuals began 6m after initial infection, persisted at least 6m but not longer than 12y Seropositive cohort and seronegative cohort Seropos = western blot positive Seroneg = h/o erythema migrans skin lesion Klempner MS, Hu LT, et al., N Engl J Med, 2001, Jul 12:345(2):85-92

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40 Controlled Trials in Persistent Lyme Study stopped at interim analysis since further gain not felt to be made from full enrollment (107/260) Intention-to-treat analyses: no differences in the outcomes with prolonged antibiotic treatment versus placebo MOS SF-36 = measures physical, social, emotional, and mental health Seropositive group w/ abx: 37% improvement, 29% no change, 34% worsening Seropositive group w/o abx: 40% improvement, 26% no change, 34% worsening (p=0.96) Seronegative group w/ same outcome

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42 Lyme Vaccine Less than 20 years elapsed between the 1982 report of the identification and isolation of Borrelia burgdorferi and the licensure and marketing in the USA of a prophylactic vaccine against this pathogen. The manufacturer removed the vaccine from the market under 4 years after its release. The low demand undoubtedly was the result of limited efficacy, need for frequent boosters, the high price of the vaccine, exclusion of children, fear of vaccine-induced musculoskeletal symptoms and litigation surrounding the vaccine. Second-generation polyvalent outer surface protein (Osp)C vaccines may overcome some of these concerns but the precise antigenic components required for efficacy are uncertain.

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44 Lyme Disease today appears as clear as