Transcript A Clinicians Guide to Tick Borne Infections

A Clinicians Guide to
Tick Borne Infections
Alan M. Sanders
Upstate Infectious Diseases Associates
Albany, N.Y.
Introduction to the
Tick-borne Diseases
The Vectors
and
Pathogens
Human Tick-borne Diseases

Each of the specific infections are associated with a
host of potentially related symptoms, yet have
unique features that should allow the clinician the
opportunity to make:
 an accurate diagnosis
 prescribe an appropriate course of antibiotics
 achieve a timely cure in all patients
Human Tick-borne Diseases
In the United States
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An array of regional tick species in the United States
are responsible for the transmission of a wide variety
of infections to human hosts:
Rickettsial
 Rocky Mountain Spotted Fever (Rickettsia rickettsii)
 Human Monocytic Ehrlichiosis (Ehrlichia chaffeensis)
 Anaplasmosis (Anaplasma phagocytophilum)
(also known as Human Granulocytic Anaplasmosis HGA)
Spirochetal
 Lyme Disease (Borrelia burgdorferi)
Parasitic
 Babesiosis (Babesia microti)
Human Tick-borne Diseases
in the United States cont.
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Tularemia (Tularemia francesis)
STARI – Southern Tick Associated Rash
Illness
Tick-borne Relapsing Fever – (Borrelia
species)
NOTE: Bartonella infections have not been
proven to be tick - associated
Human Tick-borne Diseases:
A Focus on the Capital Region of
New York State
 Lyme
Disease
 Anaplasmosis
 Babesiosis
 Human Monocytic Ehrlichiosis
Update on
Epidemiology
Tick-borne Diseases
in New York State and
the Capital Region
Lyme and other Tick-borne Diseases
Incidence New York State 2007-11
Excludes NYC. 2011 data provisional. Sources - CDC, NYSDOH.
9000
8000
7000
6000
5000
Lyme Disease
Other TBD
4000
3000
2000
1000
0
2007
2008
2009
2010
2011
Tick-borne Diseases Excluding
Lyme Disease in New York State
2007 (Cases – 452) to 2011 (Cases – 730)
Excludes NYC. 2011 data provisional. Sources - CDC, NYSDOH.
400
350
300
250
Anaplasmosis
Babesiosis
Ehrlichiosis
200
150
100
50
0
2007
2008
2009
2010
2011
Capital Region Lyme Disease
Reported Cases
Albany, Columbia, Greene, Rensselaer, Saratoga and
Schenectady Counties
700
600
500
Albany
Columbia
Greene
Rensselaer
Saratoga
Schenectady
400
300
200
100
0
2007
2008
2009
2010
2011
Lyme Disease
Clinical Features
Diagnosis
Treatment
Lyme Disease:
Objectives
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Provide a more sound approach to the
diagnostic work-up of Lyme Disease
Review the current serologic tests, and
their contribution to accurate diagnoses.
Recognize the limited utility of serologies
in a disease that by in large depends upon
a clinical diagnosis.
Clinical Stages of Lyme Disease
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EARLY LOCALIZED
 Days to Month post tick bite
EARLY DISSEMINATED
 Weeks to Months post tick bite
LATE LYME DISEASE
 Months to Years post tick bite
Early Localized Lyme Disease
Days – One Month
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ERYTHEMA MIGRANS (EM)
May occur in 80%
 “Cellulitis” in an atypical locale
 May see a necrotic center
ASSOCIATED SYMPTOMS
 Fever
 Flu symptoms
 Adenopathy
 Headache
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Early Disseminated Lyme Disease
Weeks - Months
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CARDITIS
 5% untreated patients
 AV blocks/Cardiomyopathy/Myopericarditis
NEUROLOGIC
 15% untreated patients
 Lymphocytic meningitis, encephalitis, cranial
neuropathy (III, VI, VII), radiculopathy
SKIN
 Days to weeks after EM with multiple irregular
sized lesions
Disseminated Lyme Rash
Late Lyme Disease
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MUSCULOSKELETAL
 Seen in about 10% of untreated patients
 Mono-oligoarticular arthritis - mostly knee(s)
 Expect 20-30K PMN-predominant joint fluid
 May include chronic synovitis or a Baker’s cyst
CUTANEOUS
 Acrodermatitis chronica atrophicans
 Morphea-like lesions (Europe)
NEUROLOGIC
 ? incidence because few cases
 Encephalomyelitis (cognitive), peripheral neuropathy
Lyme Disease Diagnostics
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Clinical diagnosis with serologic confirmation
for all stages of Lyme Disease
ELISA screening and Western Blot IgM &
IgG for confirmation utilizing CDC criteria
C6 antibody testing may assist with
equivocal WB results
Fluid analysis for serologic testing and PCR
 Detection in synovial and CSF samples
LYME TESTING
SUPPORTIVE – NOT DIAGNOSTIC
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As with most serologic tests, the pre-test
probability of the disease must be
considered.
IDSA and ACP guidelines have both
concluded that a clinician should NOT test a
patient in whom the assessment does not
suggest a high likelihood of Lyme (<20%)
A positive serologic test does not constitute
proof of active Lyme Disease without clinical
support.
SEROLOGIC TEST FOR LYME
A TWO-TIER APPROACH
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FIRST TIER TESTING- ELISA or IFA which
are very sensitive (re: false +).
IF A FIRST TIER TEST IS NEGATIVENO ADDITIONAL TESTING IS NEEDED.
SECOND TIER TESTING – WESTERN BLOT
for both IgM and IgG. Indicated for both
equivocal and positive ELISA/IFA.
Inter-laboratory variability exists for both
tests, notably with WB interpretation.
TIMING OF SEROCONVERSION
IgM – Will be positive in 1-2 weeks after
a bite/ECM. Therefore, expect a positive
test for early localized (ECM) in only 2040% of patients.
Most sensitive in early disseminated
disease stage (neuritis/carditis) -90%+
IgG – tend to convert from 4-6 weeks after
bite/ECM.
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When Is An IgM WB Helpful ?
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Narrow window with early disseminated
disease (carditis/neuritis) with no rash hx.
High positivity (90%) vs IgG WB (30-40%).
Must reconcile a positive IgM and negative
IgG WB in all other clinical presentations
where timing does not support serology and
assume a FALSE POSITIVE test
IgM WB and “Chronic Lyme”
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Recognize that CDC guidelines limit the application of
IgM testing to the first month of illness.
Misuse/misinterpretation of IgM WB has led to
overdiagnosis of Lyme in pts with other illnesses.
When is an exclusive positive IgM WB helpful in cases of
chronic complaints – fatigue, myalgias, arthralgias,
cognitive ?
EVER ?
NEVER ?
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CORRECT ANSWER:
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NEVER EVER
LYME C6 TESTING
Another Second Tier Test
Steere et al. CID 2008;47:188-95
Branda et al. CID 2010;50:20-26
 Another tool in Lyme sero-diagnosis is an IgG
ELISA from the C6 region of the variable major
protein-like sequence-expressed (VlsE)
lipoprotein of B.burgdorferi - Lyme C6.
 In prospective studies against two-tier testing,
the C6 ELISA proved to have a high sensitivity
(100%) of and specificity(96%) in pts with
stage 2 or 3 disease.
 EM cases only about 30% sensitive with both
methods.
LYME C 6 Testing
in a 2 Tier IgG-only Approach
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Using only C6 test as a second tier
test after a positive ELISA screen
C 6 peptide ELISA IgG proved
positive earlier in the progression
of stages of LD (Stage 2) in 2
independent labs.
This approach eliminates the need
for, and confusion with, IgM
testing.
As a “stand alone” test, C6 had a
lower sensitivity (96%) and
specificity (96%) in late LD than
2-tier testing
100%
90%
80%
70%
60%
Std. 2 tier
C6 2-tier
IgM WB
50%
40%
30%
20%
10%
0%
Stage Stage Stage
1
2
3
CAVEATS WITH LYME SEROLOGIES
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Early/appropriate antibiotic therapy may often abort a
seroconversion.
Background rates of seropositivity in highly endemic
areas maybe higher than 5%.
High rates of p23 band positivity (false+) in the
general population.
WB are semi-quantitative/subjective –faint bands “+”
Both ELISA and WB (IgM/IgG) positivity may persist
for 10-20 years. Subsequent infection can only be
made clinically. 79% had + 2-tier testing when
asymptomatic as controls in prospective study.
MISUSE OF LYME SEROLOGIES
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There is no serologic “test of cure”, so repeated
testing after treatment has no prognostic utilitysimply adds to patient anxiety, and repeated
courses of antibiotics.
There is no marginal change in WB band
conversions – ie: declining number of bands to
monitor response to treatment.
UTILITY and FUTILITY OF
SEROLOGIC TESTING FOR LYME
DISEASE
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Use serologic studies to support clinical findings of disease
stages.
Have a clear understanding of seroconversion timing and rates
based on large data bases (IDSA GUIDELINES: CID 2006;43:1089)
Sequential testing may prove useful in evolving cases ie: flu
sxs/headache (neg. test) followed by neuritis/carditis/arthritis.
Once serologically positive, future testing for subsequent
infections become futile. Must base dx on clinical findings
alone.
THERE IS NO TEST OF CURE !
Early Lyme Disease
Treatment Recommendations
Doxycycline or Amoxicillin for 10 to
14 days
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Erythema Migrans
Disseminated skin lesions
Early neurologic - cranial neuropathy
Parenteral Ceftriaxone for 28 days
 Early neurologic – meningitis/radiculitis
Late Lyme Disease
Treatment Recommendations
Doxycycline or Amoxicillin po for 28
days
 Arthritis
 Recurrent arthritis (see below)
Ceftriaxone 2 gm IV qd
 Central or peripheral nervous system disease
 Recurrent arthritis
 Cardiac disease
Treatment Recommendations
Secondary and Late Stage Lyme
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IV therapy should be reserved for neurologic disease, cardiac
involvement or chronic arthritis
Do not expect serologies to become negative with treatment.
There is no role for sequential testing for cure.
There is no data supporting treatment for longer than six
weeks.
Consequences of prolonged antibiotic therapy include:
 Development of resistant bacteria
 C. difficile diarrhea
 Cholecystitis (Ceftriaxone therapy)
 Line–associated bacteremia and venous thrombosis.
Single Dose Therapy
for Tick Exposure
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Considered effective therapy to prevent
Lyme disease in the following settings:
If tick is attached for at least 36 hours engorged
 If endemic area
 If tick bite occurred within 72 hours
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Doxycycline 200 mg PO x 1 dose
BECOME LYME LITERATE
Our Patients Deserve It
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Clinical Practice Guidelines by IDSA: Lyme, HGA
and Babesiosis CID 2006:43;1089-1134.
Clinical Appraisal of “Chronic Lyme Disease”
Feder, et al. NEJM 2007;357: 1422-30.
2-Tiered Antibody Testing for Early and Late
Lyme Disease using IgG Blot with C-6 test>
Branda, et al. CID 2010;50:20-26.
Final Report of the Lyme Disease Review Panel
of IDSA. Lantos,et al. CID 2010;51:1-5
Anaplasmosis
Clinical Features of
Infection and Disease
Human Granulocytic Anaplasmosis
Cellular Pathogenesis
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Obligate intracellular organisms that replicate within
phagosomes of host cells (PMN) and form
microcolonies within vacuoles – MORULAE
Anaplasma phagocytophilum binds preferentially
to neutrophil surfaces, and monocytes are resistant
due to inability to bind/uptake.
Once in neutrophils, Anaplasma evades oxidative
killing, and inhibits PMN phagocytosis.
Anaplasmosis Trends:
New York State and the Capital Region
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Over the period 2007 through 2011, the number of
Anaplasmosis cases reported in NYS rose 1.6 fold,
from 205 to 318.
Over the same period, the number of cases in the
six-county Capital Region rose over 3.6 fold, from
31 to 113.
The Capital Region represented only 15% of NYS
cases in 2007, but nearly 37% in 2011.
The Capital Region accounted for 73% of the total
rise in NYS Anaplasmosis cases over this five (5)
year period.
Anaplasmosis and Ehrlichiosis
Age Distribution of Cases
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Historically, both Anaplasmosis (HGA) and Ehrlichiosis
(HME) have had the highest age-specific incidence in the
60 – 69 and > 70 age groups.
Sub-clinical cases most likely exist in the younger age
groups, as tick exposures would be more predictable.
Infection clears without treatment.
Theoretically, the waning immune status of healthy,
elderly individuals ( “immunosenescence” ) plays a role
in the development of symptomatic disease with both
HGA and HME.
Transmission of Anaplasmosis
 Anaplasmosis may be transmitted via blood transfusion,
vertically maternal-child, and by direct contact with a
slaughtered deer.
 A review of nine (9) woman who were diagnosed and
successfully treated during pregnancy (rifampin or
doxycycline). CID 2007;45:589
 A single perinatal transmission to a newborn was
confirmed and successfully treated.
Anaplasmosis: Clinical Presentation
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Fever – otherwise undetermined - 93%
Malaise – 94 %
Headache - 76 %
Myalgias - 77 %
Arthralgias – 46 %
Nausea (38%), Vomiting (26%), Diarrhea
(16%)
Rash is Rare – 6 % Yet , in HME – 31 %
Anaplasmosis: Complications
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Rarely, fulminant cases of untreated
Anaplasmosis and HME can occur.
Complications may include acute renal failure,
respiratory failure and shock.
Immunocompromised patients, including HIV,
may have a complicated course, especially with
HME.
Case fatality rates are low.
Anaplasmosis - < 1% and HME about 3%.
Anaplasmosis
Laboratory Findings and
Diagnostic Testing
Anaplasmosis in the Capital Region
2007 ( Cases - 31) – 2011 (Cases – 113)
Source - NYSDOH
60
50
Albany
Columbia
Greene
Rensselaer
Saratoga
Schenectady
40
30
20
10
0
2007
2008
2009
2010
2011
Anaplasmosis Laboratory Features
Several very suggestive laboratory findings often
bundled
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Leukopenia
Immature neutrophils – Marked left shift
Atypical lymphocytes
Thrombocytopenia
Inverse relationship between mean WBC and platelet
count and probability of Anaplasmosis
Rise in LFT’s, notably transaminases and LDH
Anaplasmosis Diagnostics
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Peripheral Blood Smear to search for
morulae in neutrophils with sensitivity of
20 – 80% .
PCR for both Anaplasmosis and HME with
sensitivity of 55 - 87%. Expect a drop in
sensitivity > 1 week after illness, and also after
treatment onset.
Serology – selective IFA of ELISA for
Anaplasmosis and HME. Look for a rise in
convalescent titer 4 weeks after illness onset.
Morula
Anaplasmosis Treatment
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Doxycycline 100 bid for at least 3 days
after defervescence, or 7 – 10 days total.
Chloramphenicol is an option.
Rifampin for pregnant women.
Quinolones have variable in vitro efficacy.
American Academy of Pediatrics revised
guidelines in 1997 and recommends
doxycycline as safe for short-course
treatment of tick-borne diseases in
children of all ages.
Anaplasmosis Treatment
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Beta-lactam and macrolide agents have no efficacy
against Anaplasmosis or HME.
Will see prompt response to treatment in 24 - 48 hrs.
Persistent fever would suggest another diagnosis.
There is no reported relapse after effective therapy
and no syndrome of chronic disease.
With objective evidence of concurrent Lyme disease,
doxycycline can be trusted to treat both infections
(10 - 14 days).
Babesiosis
Clinical Features
Diagnostic Testing
Treatment
Babesiosis
Clinical Features
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Similar clinical presentation to malaria, but may range
from asymptomatic to fulminant.
Most severe in asplenics and immunocompromised.
Fevers, chills, sweats
Myalgias and arthralgias
One-fourth of adults, and one-half of children, may
have asymptomatic infection as evidenced by IgG
serologies.
Babesiosis
Laboratory Features
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Anemia
 Often hemolytic anemia
Thrombocytopenia
Elevated LFT’s
NOT the leukopenia and atypical
lymphocytosis as evidenced in
Anaplasmosis.
Babesiosis
Diagnostic Testing
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Because of non-specific clinical features, a specific
diagnosis is made via :
 Giemsa staining of thin blood smears to detect
intraerythrocytic ring-like structures
 PCR testing of blood is more sensitive than
microscopy
 Antibody testing, with paired convalescent
samples 4 - 6 weeks after illness are most often
positive
It is NOT reasonable to make a diagnosis of Babesiosis
based solely on serology, without other features of
disease, especially in an endemic setting with background
of asymptomatic disease.
Babesiosis
Treatment Recommendations
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Atovaquone 750 b.i.d. and Azithromycin 500 mg x 1
followed by 250 mg qd for seven (7) days.
Alternative is Clindamycin 600 mg t.i.d. and Quinine
650 mg t.i.d.. This may be used in more severe cases,
and immunocompromised.
Exchange RBC transfusions may have to be considered
in cases of high parasitemia ( >10%).
Repeated smears to insure clearance of parasitemia.
Bartonella
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Only 3 of 22 distinct species cause human disease- B. henselae
,B. quintana, B.bacilliformis
Disease states include cat scratch fever, bacillary angiomatosis,
endocarditis, peliosis/splenitis (HIV), and Oroya fever.
Vectors are unique: B.henselae (fleas/cat bite-scratch)
B.quintana (louse), B.baciliiformis (sandflies).
With such a wide array of syndromes and exposures, the
inclusion of Bartonella disease in a chronic fatigue work-up is
not warranted.
There is no evidence of transmission of any Bartonella species
by tick bite to human (EID Journal v.16 n.3 Mar 2010)
Therefore, Bartonella infection should not be included in a
differential diagnosis of tick borne illnesses at this time.
Summary of Tick-borne Disease
Antibody Testing
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Recognize that serologic testing for all of the tickborne diseases is only a useful tool when wellrecognized, clinical and associated laboratory
findings are present.
Positive IgG serologies for any of these diseases are
not the basis for diagnosing disease, or initiating
antibiotic therapy, especially when no chronic
syndrome exists (Anaplasmosis, Babesiosis, HME).
Consider a positive IgG a possible marker of prior
exposure, a potential false positive, but NOT an
exclusive tool to diagnose an active infection.