2015 Agricultural Medicine Course October 14, 2015

Vector Borne Illnesses in the Northeast

• and others • West Nile infection • Eastern Equine • Encephalitis

Christopher Grace, MD, FIDSA Jeffrey Heath, RN Director, Infectious Diseases Unit Vermont Department of Health University of Vermont Medical Center In the US Lyme Disease is Caused by Borrelia burgdoferi

• Cork screw shaped motile bacterium (Spirochete)

• Able to change the outer surface proteins (OSP)

• Fastidious and difficult to culture

• Inflammatory symptoms due to host immune response

Lyme Diseases is a Worldwide Infection

Borrelia burgdoferi B. afzelii; and B. garinii

www.thelancet.com Vol 379 February 4, 2012 Two Year Cycle of Black- Legged ()

MEAL 1 EGGS LARVAE • Mouse • Bird NYMPHS

MEAL 2 (peak feeding Nymphs Eggs laid, time May-mid July) molt into adults die • Person adults • Mouse • Dog MEAL 3 * For adults SPRING SUMMER Larvae molt that did not into nymph feed in fall WINTER FALL stage • Person • Deer • Dog ADULTS

MEAL 3 • Person • Deer • Dog

Nymphs dormant Relative abundance of the three major tick stages

Connecticut Tick Management Handbook Lyme Transmission

• Nymphs account for most human cases: – Only 1 prior blood meal (only 1 chance to acquire B. burgdorferi, while adults have had 2) – Often unrecognized so allowed to feed >24 hours (adults usually removed sooner)

Vermont Cases of Lyme Disease by Month of Onset and Status: 2008 - 2011 600

500

400

300 Probable Confirmed Number Cases of Reported Number 200

100

0 Jan Feb Mar Apr May June July Aug Sept Oct Nov Dec Month of Onset

Vermont and

• Deer tick – Lyme disease, anaplasmosis, babesiosis, deer tick virus (Powassan-type virus) • Dog tick – Rocky Mountain spotted , tularemia • Woodchuck tick – Powassan virus • Lone star tick – Ehrlichiosis, STARI (southern tick-associated rash illness)) Tick Surveillance Project

• Began in 2013 • Surveillance at 12 sites around state – 6 on either side of state • Collect ticks in spring and fall – at least once per site • Test deer ticks for pathogens: – B.burgdorferi, A. phagocytophilum, B. microti • Study leader: Lyndon State College Tick Surveillance – 2013/2014

Vermont Lyme Cases, 2002 – 2014

900 800 700 600 500 400 300 200 100 Number Cases of Number 0

Indigenous - Confirmed Imported/Unknown - Confirmed Indigenous - Probable Imported/Unknown - Probable

U.S. Distribution of Lyme Disease 2001 - 2013 Age Distribution Untreated Lyme Disease Often Evolves Through Stages Days Weeks Months Years

Early localized • skin • constitutional Early disseminated • skin Symptoms resolve • cardiac Late disease • neurologic • arthritis • neurologic

Symptoms resolve Symptoms resolve Early Localized Disease is Characterized by

• At tick bite site – after 7-14 days – range 3 to 32 days • Occurs in 80% of patients with Lyme • Slowly expanding over days to weeks . homogenous in 59% . central clearing in 9% Tick bite . > 5 cm, up to 20 cm lesion < 5 cm

Jones KL. CID.2008;46:85 Mayo Clin Proc 2008;83:566 Erythema Migrans Can Take Many Forms

Jones KL. CID.2008;46:85 Mayo Clin Proc 2008;83:566 Early Localized Disease Nonspecific Symptoms

• Incubation: 3 to 30 days after tick bite • Constitutional symptoms: – Fatigue 54% – Anorexia 26% – Headache 42% – Neck stiffness 35% – 44% – Arthralgia 44% – Regional lymphadenopathy 23% – Fever 16% • Laboratory: – Elevated LFTs 37% – Leukocytosis 5% – Leukopenia 4% Nadelman RB et al. Am J Med 1996:100;502 Early Disseminated Lyme Multiple Erythema Migrans Lesions

Early Disseminated Lyme Facial Palsy

• lower motor neuron lesion • weakness of both the lower face and forehead • 25% bilateral • HSV, VZV, CMV, EBV • Mycoplasma • HIV • syphilis • stroke • injury Can last for many months • ear disease

Early Disseminated Lyme Meningitis

• “Aseptic” or viral meningitis-like presentation

• Headache, stiff neck, photophobia

• Head CT or MRI most often “normal” • Enterovirus • Lumbar puncture: • HSV-2 • lymphocytic pleocytosis • VZV • Mean ~ 160 cells • HIV • elevated protein • Syphilis • Usually < 200- 300 mg% • normal glucose • RMSF • (+) Lyme antibody • Ehrlichia • may be local or from blood • may be long lasting – PCR • low sensitivity

Early Disseminated Lyme Radiculopathy

• Inflammation at or near the • Can mimic mechanical spinal nerve root radiculopathy • No injury • Imaging studies are usually not revealing

• Motor and sensory abnormalities • Pain, numbness, weakness along the dermatones or myotomes • Pain may be on the side of the tick bite

Early Disseminated Lyme Cardiac Manifestations

• Atrioventricular block • Lyme disease in 875 patients: • 1-2 months (<1 to 28 weeks) • Cardiac manifestations (10%) after the onset of infection • 20% hospitalized • Can occur alone or with • Palpitations, 6.6% erythema migrans, neurologic • Conduction block, 1.8% symptoms • Myocarditis, 0.9 % • Lightheadedness, syncope, shortness of breath, • LV failure, 0.5 % palpitations, and/or chest • Pericarditis, 0.2% pain Late Disease Lyme Disease Rheumatologic and/or Neurologic

• Arthritis – knee > shoulder, ankle, elbow, TMJ, wrist – begins abruptly and lasts from several weeks to months – not particularly painful, except from a tensely swollen joint – affected joints are usually very swollen and warm – synovial fluid ~ 24,000 WBC • Neurologic – encephalomyelitis (rare in US, but more common in Europe) – peripheral neuropathy – radiculopathy

Lyme Disease is Treatable

• Early localized and early disseminated – oral therapy for 14-21 days – doxycycline, amoxicillin, cefuroxime axetil – heart block • ceftriaxone 2g q24h  oral x 14-21 days • temporary pacer, if necessary

• Arthritis – doxycycline or amoxicillin for 28 days

• Meningitis or radiculopathy – ceftriaxone or penicillin x 14-28 days – doxycycline may be adequate

• Encephalomyelitis – ceftriaxone for 4 weeks

Recovery Is Not always Straight Forward • Complete recovery in majority within ~ 3 wks

• Jarisch-Herxheimer reaction in ~ 15%

• Improvement may be slow 1,2,3: – more common in disseminated or severe illness – ongoing symptoms in 10 - 15% for > 6 months • fatigue • difficulties with concentration • musculoskeletal pain • no objective findings • no evidence of spirochete replication

1Ann Int Med 2003;138:697, 2Am J Med. 2003;115:91, 3The Lancet 2012;379:46 • Can get re-infected4 4N Engl J Med 2012;367:1883-90

Antibodies to Borrelia Infection Develop and Can be Tested For

Acute Infection Chronic Infection IgG False (-) Antibody Titer IgM False (+)

• weak bands • increased binding

0 1 2 3 4 5 6 7 8 Weeks Years Antibodies are Detected by Two Tier Testing ELISA • FDA • NIH Whole cell • Council of State and Sonicate Sensitive Territorial Epidemiologists • Association of Public Health Laboratories Western Blot • Clinical Laboratory Standards Institute • Canadian Public Health Specific Laboratory Network IgG (+): 5 of 10 bands • IDSA IgM (+): 2 bands

BJB Johnson. Lyme Diseases: Evidence Based Approach. Ed Halperin. 2011 How Good is the Two Tier Test?

(+)

indeterminate

(-)

The sensitivity of 2-tier testing in patients with later manifestations of Lyme disease was 100% and the specificity was 99%

Steere et al CID 2008:47 (15 July). Chronic Symptoms are often Incorrectly Attributed to Ongoing Active Infection

Persistent Lyme disease Treatment symptoms • Fatigue • Pain • Cognitive Post Lyme Treatment Syndrome impairment

• How common are these symptoms post treatment?

• Are the spirochetes still alive ? This is not “chronic” active • Do prolonged courses of antibiotics help? Borrelia

• If not due to infection, then what? infection Are Spirochetes Still Alive After Treatment?

• Animal studies have shown that antibiotics cure B. burgdorferi infection even those that are highly immunocompromised1,2,3 • In humans, B. burgdorferi can be cultured from skin lesions prior to treatment but not afterwards4 • In none of the 843 specimens of blood or CSF, tested by culture or PCR, from the 129 patients enrolled in two of the controlled treatment trials could B. burgdorferi be detected5,6

National Institute of Allergy and Infectious Diseases7 Despite extensive study, no clear evidence has emerged to support the contention that post treatment Lyme syndrome results from persistent spirochete infection.

N Engl J Med 2007;357:1422-30 4Am J Med 1993;94:583 1 Antimicrob Agents Chemother 1996; 40:2632–6. 5 N Engl J Med 2001;345:85-92 2 Antimicrob Agents Chemother 2002; 46:132–4 6 Vector Borne Zoonotic Dis 2002;2(4):255-63 3 Antimicrob Agents Chemother 1994; 38:1567–72 7 www3.niaid.nih.gov/topics/lymeDisease/understanding/chronic.htm Are Post Treatment Symptoms due to Immune Dysregulation?

During the first visit, prior to antibiotic therapy

A subset of patients with EM may have immune dysregulation reflected by the persistently elevated levels of IL-23, resulting in post-Lyme disease symptoms.

Levels during the first year post therapy Strle et al. CID 2014:58 Do Prolonged Antibiotics Improve Symptoms? All participants had clinically documented Lyme: • Treated • 3 courses, 2 months • Randomized • Persistent symptoms > 6 m • Double blind • 4.6 years • Placebo controlled No iv ceftriaxone x 1 month  doxycycline x 2 months 107 difference iv placebo x 1 month  placebo pill x 2 months between groups Interfered with functioning • musculoskeletal pain Medical Outcome 36 item General Health Survey • cognitive impairment • fatigue Adverse effects in 25% of antibiotic group: • pulmonary embolism • fever, anemia, GI bleed Klemper et al. • rash, diarrhea, vaginitis NEJM 2001;345:85 Chronic Symptoms May be Attributed to Lyme Disease

Subjective (+) Lyme test Symptoms symptoms (-) Lyme test attributed to Lyme • Fatigue • Pain • Cognitive impairment

How common are these symptoms in the general population? Chronic Symptoms in the General Population are Common

• Chronic fatigue: 20%–30% of adults1 • Self-reported chronic widespread pain: 11.2% (frequently associated with feelings of depression and anxiety, fatigue, and somatic symptoms)2 • Severe emotional or cognitive dysfunction: 2.17%–3.42%3 • Self-reported unhealthy days during the preceding month: mean of 6.14 • Self reported health status of the 4,048 US adults5 . severe pain: 3.75 – 12.1% . moderate pain: 36.4 – 45.1% 1Ann Intern Med 2001; 134:838–43 2J Rheumatol 1993; 20:710–3 . 25-33% had chronic cognitive dysfunction 3 Med Care 2005; 43:1078–86 4MMWR Surveill Summ 2005; 54:1–35 5 Luo et al. Med Care. 2005;43(11):1078 Over Diagnosis of Lyme Disease is Dangerous

209 • Yale Lyme Disease Clinic • Lyme disease by self report or by physician 44 active 40 treated • Complete H&P, 50 item questionnaire, serologic testing 125 without Lyme • CDC criteria for diagnosis used • F, M, A: 34% • Joint problems: 25% • antibiotic courses: 232 • physician visits: 4 (1-17) • serologic tests: 4 (1-13) Minor adverse reactions: 55%  rash Major adverse reactions: 6%  diarrhea  C. difficile colitis  nausea, vomiting  septic phlebitis  yeast infection  neutropenia Ann Int Med 1998;128:354 The Ixodes Tick Can Transmit Other Pathogens

• Anaplasma phagocytophilum

• Babesia microti

• More severe initial symptoms

• High grade fever for >48 hours despite Lyme targeted antibiotics • EM resolved but systemic symptoms persisting

• Borrelia miyamotoi

• Powassan virus

Anaplasma phagocytophilum

• Obligate intracellular bacteria that grow within membrane bound vacuoles in human and animal white blood cells

• Flu-like illness • Rash • Headache • Anemia, thrombocytopenia • Blood PCR, Serology • Treatment: doxycycline

Anaplasmosis Vermont Surveillance Data

*2015 numbers are YTD (through July 11, 2015) Vermont Surveillance Data Anaplasma Investigations from MMWR week 1 through week 27 • 2014: – 42 Investigations • Confirmed cases: 16 (38%) • Probable cases: 10 (23.8) • Not cases: 16 (38%)

• 2015: – 106 Investigations • Confirmed cases: 48 (45. 2%) • Probable cases: 15 (14.2%) • Not cases: 43 (40.6%) Babesia microti

• Malaria appearing protozoan • Only 1 case from VT (blood transfusion related) • Consider in: – flu-like illness – hepatosplenomegaly – hemolytic anemia, thrombocytopenia – patients with Lyme or Anaplasma • Most mild infections are self-limited • Can also be very severe • Diagnosis: Treatment if (+) smear or PCR – blood smear • Atovaquone + azithromycin – PCR • Quinine + Clindamycin for severe • 7- 10 days – serology

Lyme Disease Prevention

• Personal prevention measures – The best way to prevent Lyme disease is to prevent tick bites

• Environmental/landscaping strategies

• Community intervention Avoid Tick Habitats

• Ticks don’t jump, fly or run.

• They quest – hang out and wait for you to come to them.

• Avoid tall grass, brushy areas, leaf litter as much as possible.

• Keep to center of trails when hiking. Hiking off trail increases risk. Protective Clothing

• Wear light colored clothing. • Tuck pants into socks. • Long sleeve shirts, long pants. • Tuck shirt into pants. • Avoid sandals even with socks. • Tight weave socks. • Tie back long hair. Insect Repellents

• Use insect repellents that are EPA registered.

• DEET 30% is safe and effective for children and adults.

• Picaridin, oil of lemon eucalyptus, IR3535.

• Permethrin-based repellent on clothes.

• Tick repellent clothing is also available. Inspect and Remove

• Check yourself daily for ticks and remove promptly.

• A tick has to be attached for about 36 hours to transmit Lyme disease.

• Shower within 2 hours of coming inside.

• Launder clothing and gear. Use dryer high heat for 60 minutes. Tick Removal

• Use fine-tipped tweezers. • Grasp tick very close to the skin.

•Using a steady motion, pull tick’s body away from the skin.

• Clean skin with soap and water.

•Avoid crushing the tick’s body.

• Don’t use petroleum jelly, a hot match, nail polish, or other products to remove a tick.

Tick Removal Tools Entomologist Recommended !!

Tick Spoon Tick Lifter

Tick Twister Tick Noose Landscape Management

•Assess your property

•Identify high risk areas

•Discourage tick habitat

•Manage host populations

•Acaracides

Tick Management Handbook, CT Agricultural Experiment Station at http://www.ct.gov/caes/lib/caes/documents/publications/bulletins/b1010.pdf Discourage Tick Habitat •Keep grass mowed

•Remove brush and leaf litter

•Increase sunlight

•Limit ground cover

•Swing sets, children’s toys

•Firewood, stone walls, bird feeders

•Pathways, perimeter, trails Tick Management Handbook, CT Agricultural Experiment Station at http://www.ct.gov/caes/lib/caes/documents/publica •Area application acaracides tions/bulletins/b1010.pdf Vector Bourne

West Nile Virus (WNV)

Eastern Equine Encephalitis virus

• uncommon brain infections Powassan virus

• spread by mosquitoes or St. Louis Encephalitis virus  ticks summer / fall • not human to human California Encephalitis virus • due to RNA virus La Crosse virus

• significant morbidity and Western Equine Encephalitis virus mortality virus • supportive treatment Tyler et al. Neurology Clinics. 2008:727

West Nile Virus Transmission Cycle

Mosquito vector Incidental infections

West Nile virus

Incidental infections

Bird reservoir hosts West Nile Virus Surveillance

• 2000-present

• Mosquito Pool Testing

• Dead Bird Testing-discontinued in 2012

• Equine Surveillance

• Human Surveillance West Nile Virus Surveillance Data

• 2013: 28 positive mosquito pools in Addison, Rutland, and Franklin counties. One horse tested positive in Lamoille county.

• 2012: 3 human cases, 2 horses, one mosquito pool.

• 2011: 2 human cases, 3 mosquito pools, 16 birds (last year of bird surveillance).

• Prior years: 2 horses in 2005, 3 human cases in 2003. Birds and mosquitoes have tested positive every year 2000-2010.

West Nile Virus Surveillance Data

• 2014: 8 positive mosquito pools in Franklin, Orange, Windham, and Windsor counties

• No human or equine cases reported

• 2015: 35 positive mosquito pools as of September 5, 2015

• No human or animal cases reported

• No part of the state appears to be at higher risk for WNV infection West Nile Virus Cases Reported to CDC finches West Nile Virus

• First US cases in 1999, now spread throughout US

September, 2015

• Majority of infections are asymptomatic • ~ 20% develop febrile flu-like illness – Fever, headache – Eye pain – Facial congestion – Rash (50%), hepatomegaly (20%), – Myocarditis, pancreatitis, hepatitis in severe infection J Infect Dis. 2010;202(9):1354.

West Nile Virus Neuroinvasive Disease

• 1/150 of febrile persons – 2/3 encephalitis September – 1/3 meningitis 2015

– Lymphocytic pleocytosis

– Flaccid paralysis Diagnosis • Myelitis of anterior horn cells Serum four fold rise • Similar appearing to polio and/or

– Coma CSF IgM antibody – Seizures in 30%

Supportive care Cranial neuropathies JAMA. 2013 Jul;310(3):308-15. – Rev Med Virol. 2006;16(4):209. – 4-14% case fatality Lancet Neurol. 2007 Feb;6(2):171-81. JAMA. 2003;290(4):511. Vector Bourne Viral Encephalitis

West Nile Virus (WNV)

Eastern Equine Encephalitis virus

• uncommon brain infections Powassan virus

• spread by mosquitoes or St. Louis Encephalitis virus  ticks summer / fall • not human to human California Encephalitis virus • due to RNA virus La Crosse virus

• significant morbidity and Western Equine Encephalitis virus mortality Japanese Encephalitis virus • supportive treatment Tyler et al. Neurology Clinics. 2008:727

Culiseta melanura ?

Aedes, Coquillettidia, Culex species EEE Surveillance

• Expanded testing of mosquito pools for presence of virus. • Blood testing of deer for presence of EEE antibodies. • Veterinary sample testing of horses and other domestic animals. • Human case surveillance.

• Prior to 2010: no reported human or animal cases, limited mosquito surveillance. • 2010-present: deer serology testing has shown wide distribution of virus across Vermont. • 2011: first evidence of EEE in domestic animals. • 2012: first detection in mosquito pools and first report of EEE in humans.

EEE Surveillance

2013 • Mosquito Pools: Of 1328 mosquito pools tested, 22 pools were positive from sites in Addison, Rutland, and Franklin Co. • Domestic Animals: EEE was diagnosed in 2 horses in Franklin Co. • Human Cases: none

2014 • Mosquito Pools: Of 3242 mosquito pools tested, 8 pools were positive from sites from Chittenden, Addison, and Franklin Co. • Domestic Animals: None • Human Cases: None

Eastern Equine Encephalitis

• Incubation period; 8-10 days (up to 20+ days)

• Prodrome; 5- 10 days – Headache, fever, nausea, vomiting diarrhea

• CNS involvement; 1-3 weeks – confusion, somnolence, seizures, coma – Limb dysesthesia and flaccid paralysis

• Physical exam: – Nuchal rigidity, depressed or hyperactive reflexes, CN palsies, facial or periorbital edema Mandel. Infectious Diseases 7th edition. 2010 Duprey et al. Curr Opin in Virology. 2012;2:336 Eastern Equine Encephalitis

• Laboratory:

– Blood leukocytosis – Lymphocytic “aseptic” appearing pleocytosis CSF – 4-fold rise in antibody titer – Virus isolation in csf, blood

• Treatment: supportive

• Prognosis: poor

Mandel. Infectious Diseases 7th edition. 2010 Duprey et al. Curr Opin in Virology. 2012;2:336 Powassan Virus Encephalitis

• Spread between ticks and rodents

• Spread to humans by Ixodes sacpularis • Uncommon, but incidence appears to be increasing – From 2004 through 2013, 57 cases reported

Annu Rev Entomol. 2010;55:95-110, CMAJ. 1999;161,): MMWR Recomm Rep. 1997;46(RR-10):1, Neurology. 2003;60(10):1726 Powassan Virus Encephalitis

• Fever, headache, weakness, paralysis, somnolence, confusion, seizures

• Diagnosis: – CSF with “aseptic” lymphocytic pleocytosis – IgM antibody of CSF, a fourfold rise in serum antibody titers

• Treatment: Supportive

• Case-fatality rate is 5 to 10 percent,

• High incidence of residual neurological dysfunction among survivors Annu Rev Entomol. 2010;55:95-110, CMAJ. 1999;161(11):1419, MMWR Morb Mortal Wkly Rep. 2001;50(35):761 MMWR Recomm Rep. 1997;46(RR-10):1, Neurology. 2003;60(10):1726 Summary Lyme Disease • Bacterial spirocheate • Multisystem inflammatory disease caused by Borrelia burgdorferi • Lyme disease is increasing in the Northeast • Diagnosis is based on characteristic signs and symptoms and confirmed with a CDC approved two tiered test

Be careful out there!

• Short course antibiotic treatment is effective • Keep an eye out for co-infection with Babesia and Anaplasma • There is no evidence that prolonged antibiotics improve health • Chronic fatigue, pain and cognitive dysfunction are common • Excessive antibiotics are dangerous

Summary Vector Borne Encephalitis

• RNA • Spread by mosquitoes and rarely ticks • Rare • Brain infection (encephalitis) – fever, headache …then progressive neurologic decline – Confusion, seizures, coma

Be Really careful out there!

• Warm weather • Treatment is supportive • Outcome poor