Steven P. LaRosa,MDStaff Physician-Infectious Disease

Beverly Hospitalslarosamd@gmail.com

Spring Training for Tick Season

• EXTHERA MEDICAL- MEDICAL ADVISORY BOARD• *NEW ENGLAND LIFECARE-ASSOCIATE MEDICAL

DIRECTOR- PROVIDE HOME IV CEFTRIAXONE

Conflicts of Interest

1) EXPLAIN THE SIGNS AND SYMPTOMS OF TICKBORNE ILLNESSES ENCOUNTERED IN MASSACHUSETTS

2) DESCRIBE THE DIAGNOSTIC LABORATORY TESTING OF TICKBORNE ILLNESSES

3) REVIEW THE APPROPRIATE ANTIMICROBIAL TREATMENT OF TICKBORNE ILLNESSES

Learning Objectives

• ANTIMICROBIAL PROPHYLAXIS NOT RECOMMENDED (3.6% RATE OF LYME IN ALL BITES)• TREATMENT OF RECOGNIZED TICK BITE WITH 200MG DOXY IN ADULT UNDER FOLLOWING

CIRCUMSTANCES:• Identify adult or nymphal I. scapularis that is engorged with blood or believed to be attached > or = 36 hrs• Prophylaxis can be started within 72 hrs of removal of tick• Evidence that at least 20% of ticks in that area are infected

• New England• Mid Atlantic states• Parts of Minnesota and Wisconsin

• Doxycyline is not contraindicated

Prophylaxis and treatment of tick bites

Ixodes scapularis ticks demonstrating changes in blood engorgement after various durations of attachment.

Wormser G P et al. Clin Infect Dis. 2006;43:1089-1134

© 2006 Infectious Diseases Society of America

70-80% of patientsUsually within 1-2 weeks of tick bite (range 3-32 days)Usually 5 cm or more in diameter•Grows over time•>1 lesion=hematogenous dissemination•Can have vesicles or pustule in center•Often occur in axilla, popliteal fossa, abdomen

Illustrative examples of culture-confirmed erythema migrans.

Wormser G P et al. Clin Infect Dis. 2006;43:1089-1134

© 2006 Infectious Diseases Society of America

• In absence of AV block or neuro sx:• Doxcycline 100mg po q 12 x 10 days• Amox 500mg TID x 14 days• Cefuroxime axetil 500mg po BID x 14 days• Macrolides are less effective than above agents• 1st Gen CEPHs are not effective

•IF EM CANNOT BE DISTINGUISHED FROM CELLULITIS GIVE AUGMENTIN 500MG PO TID +/- TMP/SMX

• SEROLOGY IS ONLY POSITIVE IN 10-50%, AND IS NOT REQUIRED FOR TREATMENT

Erythema migrans: Treatment

EM vs. Tick Bite

Characteristics EM Tick BiteLocal sx Rare PruritisIncubation period 5-14 days HoursSize >5 cm < 1 cmExpands Over days Over hoursResolves Over weeks Over daysSystemic sx Common Rare

Differential DX of Erythema migrans

Streptococcal cellulitis Patients are illProgresses over hoursVery tender

Trauma/Burn Patients recalls injuryFixed Drug Eruption History of medication useDermatophyte infection Less erythema, slowly

progressingheaped border and central clearing

Necrotic arachnidism In endemic areas

•RADICULOPATHY•CRANIAL NEUROPATHY

•MONONEUROPATHY MULTIPLEX•LYMPHOCYTIC MENINGITIS

•ENCEPHALOMYELITIS

Early CNS Lyme

• USUALLY CN VII, CAN BE BILATERAL• ~1 IN 4 PATIENTS WITH 7TH NERVE PALSY IN NON-

WINTER MONTHS IN ENDEMIC AREAS• LP IS HEADACHES OR NUCHAL RIGIDITY

•IF NO SYMPTOMS OR IF LP IS NEGATIVE CAN TREAT AS EM

Cranial Nerve palsies

•LESS LIKELY TO BE FEBRILE AND MORE LIKELY TO HAVE SX > 7 DAYS THAN VIRAL MENINGITIS

• PMNS < 10% OF CSF CELLS• CAN LOOK FOR INTRATHECAL AB PRODUCTION

OR PCR

Lyme meningitis

• ENCEPHALOMYELITIS• Can look like MS• MRI with increased signal on T2 and FLAIR• Serology should be positive• CSF Abs

• PERIPHERAL NEUROPATHY• Stocking glove• Intermittent limb paresthesias• Reduced vibratory sense in LEs

• ENCEPHALOPATHY• Cognitive and memory• Supported by serology• Difficult dx

Late CNS Lyme

•LYME MENINGITIS OR RADICULOPATHY: CEFTRIAXONE 2GMS Q 24 X 14 DAYS

• LATE CENTRAL OR PERIPHERAL OBJECTIVE FINDINGS: CEFTRIAXONE 2GMS IV Q 24 X 14-28 DAYS

• RETREATMENT IS NOT NECESSARY• LYME ENCEPHALOPATHY CAN TAKE 6-24 MONTHS BEFORE

THE PATIENTS SHOW IMPROVEMENT

CNS Lyme Treatment

Occurs within 2 months of infectionHospitalize if symptomatic or:2nd or 3rd degree AV block1st degree AV block with PR > or= 300msA temporary pacemaker may be neededCeftriaxone while hospitalizedCan complete 14 days with orals when discharged

Lyme Arthritis Monoarticular or oligoarticularFavors the knee

Large effusions out of proportion to painOften intermittent in nature

Median synovial WBC = ~ 25k with PMN predominance

DX= PCR

Requires serological confirmation

• 28 DAY COURSE OF ORAL DOXY, AMOX OR CEFUROXIME AXETIL• SECOND 28 DAY COURSE IF SYMPTOMS PERSIST OR RECUR

•14 DAYS OF PARENTERAL CEFTRIAXONE 2GMS Q24 IF SECOND ORAL COURSE FAILS•PERSISTENT SX AFTER PARENTERAL ABXS WARRANTS JOINT ASPIRATION FOR PCR

• IF SYNOVIAL PCR IS NEGATIVE THEN REFER TO A RHEUMATOLOGIST• These patients often respond to a synovectomy or Plaquenil

Lyme arthritis: Treatment

• NOT STAND ALONE TESTS FOR LYME DISEASE• SHOULD ONLY BE DONE IF:

• Patient had resided in an endemic area• Has a risk factor for exposure to ticks• Has a compatible presentation:

• Meningitis• Radiculopathy• Mononeuritis• Cranial nerve palsy• Arthritis • Carditis

• Don’t do serology for:• EM rash• Screening asymptomatic patients• For non-specific complaints of fatigue, myalgias and arthralgias

Serologic testing

•

1) ELISA FOR IGM AND IGG OR COMBINED

• 5 % of patients will be false positive due to cross reacting Abs

•NEED CONFIRMATORY WESTERN BLOT

Serologic Testing

-Early antibiotics can prevent seroconversion-IgG should be positive for sx> 4weeks-Antibody levels can remain persistently high with treatment and should not be followed for decline

•CHRONIC SUJECTIVE SX AFTER RECOMMENDED TREATMENT FOR OBJECTIVE EVIDENCE OF LYME DISEASE

•REQUIRES ONSET OF SX WITHIN 6 MONTHS OF DX OF LYME DISEASE AND PERSISTENCE OF FOR > 6 MONTHS

• SUBJECTIVE SYMPTOMS OFTEN PERSIST FOR A YEAR AFTER TREATMENT• NO EVIDENCE OF ONGOING INFECTION

• RULE OUT CO-INFECTION WITH BABESIA. HGA• RULE OUT MIMICKERS- DEPRESSION, RA, BURSITIS, MYASTHENIA GRAVIS

•NO CLINICAL TRIAL SUPPORTS PROLONGED ANTIBIOTIC THERAPY IN THIS POPULATION

Post Lyme/Post-Treatment Chronic Lyme Disease/Chronic

Lyme Disease

Longer- Term Antibiotic Therapy in Lyme Disease

RCT Inclusion criteria:

Persistent sx attributed to Lyme (Musculoskeletal pain, arthritis, arthralgia, neuralgia, sensory disturbances, dysesthesia, neuropsychologic disorders) History of erythema migrans or proven symptomatic Lyme OR Positive Lyme IgM or IgG by immunoblot

2 weeks open label IV Ceftriaxone 2gms/day then: Randomized 1:1:1 12 weeks placebo, Doxycycline or Clarithromycin and Hydroxychloroquine Primary Outcome: health-related quality of life by physical component summary score of RAND SF-36 at end of treatment period (14 weeks) Results: 281 patients randomized No difference between groups in primary outcome (p=0.69)

N Engl Jnl Med 2016;374:1209-1220

N Engl Jnl Med 2016;374:1209-1120

• BORRELIA BURGDORFERI• ANAPLASMA PHAGACYTOPHILUM

• BABESIA MICROTII

• CONSIDER COINFECTION FOR:• Fever > 48 hours on Doxy• Unexplained leukopenia, thrombocytopenia , LFT abnormalities, anemia or

hemolysis

Co-infection

Babesiosis

Babesiosis (American malaria)

Intracellular protozoal parasite- Babesia microti

Same vector as B. burgdorferi= I. scapularisNE USA with Cape Cod, MA as epicenter

Babesiosis: Lifecycle and Transmission

INCUBATION PERIOD AFTER TICK BITE= 1-6 WEEKS

INCUBATION PERIOD AFTER TRANSFUSION 1-9 WEEKS BUT UP TO 6

MONTHS

Babesiosis

Babesiosis

Clinical Symptoms:Can be asymptomatic in immunocompetent host (25%)Nonspecific febrile illness with chills, sweats, myalgia,

arthralgia, nausea and vomitingPhysical exam (may have):

Fever Splenomegaly Hepatomegaly jaundice

• LABORATORIES:• ANEMIA

• THROMBOCYTOPENIA• ELEVATED LDH *

• DECREASED HAPTOGLOBIN• ELEVATED INDIRECT BILIRUBIN, INCREASED AST

Babesiosis

Babesiosis

Risk Factors for Persisting or Relapsing Disease:Splenectomy or functionally asplenicB cell LymphomaRituxamab

Babesiosis: Diagnosis

* Peripheral Blood smear-organisms in RBCs on thin smear

Babesia IgM and IgGBabesia PCR- even after treatment it can be

positive for 12 months

Date of download: 4/26/2016 Copyright © 2016 American Medical Association. All rights reserved.

From: Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis:  A Review

JAMA. 2016;315(16):1767-1777. doi:10.1001/jama.2016.2884

Babesia microti Parasites in Human Red Blood CellsA, Babesia microti trophozoites often appear as rings with 1 chromatin dot. Arrowhead indicates a classic ring form of babesia. B, Asexual division of the parasite yields up to 4 merozoites that can arrange in a tetrad, also known as a Maltese cross (arrowhead). Maltese crosses can be formed by B microti, B duncani, and B divergens in human red blood cells. C, After rupture of an infected red blood cell, free merozoites (arrowhead) quickly seek to adhere and invade an intact red blood cell. Original magnification ×1000; Giemsa stain. Micrographs courtesy of Rouette Hunter, BS, MT(ASCP), and Stephen Johnson, BS, from the Hematology Laboratory, Tufts Medical Center, Boston, Massachusetts.

Figure Legend:

Babesia vs Falciparum malaria

No travel history to malaria endemic area

No pigment= BabesiaExoerythrocytic rings=BabesiaTetrads= Babesia

Babesia treatment:

Don’t treat: Asymptomatic and parasites or DNA present < 3

months Symptomatic, positive serology and negative PCR and

blood smear

Treat: Symptomatic with +ve blood smear or PCR Asymptomatic but +ve blood smear or PCR > 3months Positive blood smear or PCR > or = 3 months after

therapy

Babesia treatment:

Atovaquone and azithromycin (best tolerated) Clindamycin and Quinine (not well tolerated) Triple therapy with IV Clinda, atovaquone and Azithro in

severe disease RX= 7-10 days Persisting and relapsing disease-treat for 6 weeks and with at

least 2 weeks beyond 1st negative blood smear Should start to get better in 48 hours Consider Exchange transfusion:

>10% parasitemia Renal , hepatic, pulmonary compromise Renal failure

• LONG SLEEVES AND PANTS• DEET, PERMETHRIN

• PLACE WOOD CHIPS OR STONE PATHWAYS AROUND PERIMETER OF YARD

• HOST TARGET ACARACIDE- DEER POSTS, MOUSE HOUSE

Babesia Prevention

Ehrlichiosis and Anaplasmosis

Human monocytic ehrlichiosis (HME)Ehrlichia chaffeensisinfects monocytes, south central USReservoir-deers, dogs, goatsVector= Lone star tickHuman granulocytic anaplasmosis (HGA)Anaplasma phagocytophiluminfects PMNs- Northeast USReservoir- deer and rodentsVector- Ixodes scapularis

Ehrlichiosis and Anaplasmosis: Clinical features

Tick bite to sx= 5-10 daysFever, headache, myalgiasCough is commonUsually without rash (6%)Can go on to MOSF and deathCan be a cause of FUOLab pearls:

Leukopenia, thrombocytopenia and transaminitis

Ehrlichiosis and Anaplasmosis: Diagnosis

Blood Smear- groups on organisms (morula) within PMN (RARELY POSITIVE)

EPIC ordering (ANAPLASMA AND EHRLICHIA PCR)

Anaplasma Serology – can be negative initially

E. chafeensis IgM and IgG is the wrong test !

Date of download: 4/26/2016 Copyright © 2016 American Medical Association. All rights reserved.

From: Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis:  A Review

JAMA. 2016;315(16):1767-1777. doi:10.1001/jama.2016.2884

Anaplasma phagocytophilum Bacteria in Human NeutrophilsAnaplasma phagocytophilum microcolonies (often called morulae) are observed within a neutrophil on a Giemsa-stained buffy coat smear (original magnification ×1000). Arrowheads indicate the morulae. Micrograph courtesy of Maria Aguero-Rosenfeld, MD, New York University, New York, New York.

Figure Legend:

Ehrlichiosis and Anaplasmosis: Treatment

Empiric therapy is appropriate in the right clinical context

IV or po Doxy until patient is afebrile at least 3 days- total course usually=10 days

Should improve in 48-72 hours (ALMOST A DIAGNOSTIC TEST)

Consider co-infection if doesn’t improveRifampin in pregnant patients

TULAREMIA

Francisella tularensis Can be acquired from tick bite, inhalation, direct inoculation

and ingestion Tick bite is associated with Ulceroglandular fever MA cases ~ 7% of US cases- epicenter in Nantucket Incubation period is 1-9 days Usually febrile, leukocytosis, can have thrombocytopenia DX: DFA stain, PCR, Serology ( CALL MICRO LAB IF YOU

SEND A CX= lab hazard)Treatment-

Severe or kids= Gentamicin 5mg/kg IV daily X 10 days Non-severe= Doxycycline 100mg po q 12

Symptoms

Localized lymphadenopathy (cervical>axillary>inguinal)

Cutaneous ulcerMistaken for:

Bacterial lymphadenitis Cat Scratch Disease EBV

Tularemia

Rocky Mountain Spotted Fever (RMSF)

Rickettsia rickettsiiVector- dogs and wood ticksSouth Central and southeast USA(Oklahoma

to Carolinas including Arkansas and Tennessee)

Incubation 3-14 days after tick bite (avg=4 days)

50-66% remember tick bite

Rocky Mountain Spotted Fever (RMSF): Clinical

Flu-like illness in summer3-4 day prodrome of fever, headache and myalgiasUsually a rash by day 4(10% =no rash)Rash erythematous macules or petechiae, wrist and

ankles centripetallyLaboratory pearls:

Leukopenia, thrombocytopenia, hyponatremiaDon’t forget Meningococcemia and disseminated GC in

diff dxMortality increases with treatment delayTreatment is DoxycyclineDiagnosis by serology

RMSF

Powassan Virus Encephalitis

Transmitted by Ixodes Scapularis (Lyme Vector)8 cases in MA and NH between 2013-2015Infections between May-SeptOutdoor hobbies+/-tick exposureAges 21-82 (mostly healthy)Incubation period 1-5 weeksUsually febrile, confusion and focal neuro signsLabs largely unremarkable (thrombocytopenia)Clin Infect Dis 2016;62;707-713

Powassan Virus Encephalitis

CSF: Up to 700 WBCS- most cases lymphocytic but can be

polymorphonuclear Nl glucose, elevated protein

MRI: T2/FLAIR hyperintensities described in:

Putamen Caudate Thalamic (can look like EEE) Basal ganglia

Restricted diffusion described Diagnosis: serum or CSF Powassan IgM Treatment- ?corticosteroids, ? IVIGClin Infect Dis 2016;62;707-713