lyme disease update for the general dermatologist

7/25/2019 Lyme Disease Update for the General Dermatologist

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T H E R A P Y I N P R A C T I C E

Lyme Disease Update for the General Dermatologist

Desiree A. Godar

Valerie Laniosz

David A. Wetter

Springer International Publishing Switzerland 2015

Abstract Lyme disease is an Ixodes tickborne illness

that may arise from different species of the Borrelia spi-rochete and may be propagated in various hosts. Humans

are considered dead-end hosts in this propagation cycle but

may have a range of Lyme disease characteristics as a result

of borrelial infection. Lyme disease has varied cutaneous

manifestations, and the approach to diagnosis and treatment

is based on the patient, the region, and suspected coinfec-

tion with another tick-borne illness. An understanding of the

distribution of the Ixodes tick, its vectors, and the most

likely dermatologic presentation based on these factors

allows the dermatologist to make appropriate testing and

treatment recommendations. Our aim is to simplify this

approach for the treating practitioner.

Key Points

The cutaneous manifestations of Lyme disease differ

among the 3 stages of Lyme disease: solitary

erythema migrans (stage 1), multiple erythema

migrans (stage 2), borrelial lymphocytoma (stage 2),

and acrodermatitis chronica atrophicans (stage 3).

Erythema migrans is a clinical diagnosis and should

be treated empirically with doxycycline 100 mg

twice daily for 1421 days in adult, nonpregnantpatients and serologic testing is not indicated in

patients with erythema migrans rash.

Lyme prevention strategies focus around insect

repellence and early tick detection and removal.

1 Historical Perspective and Epidemiology

The eruptions and arthritides associated with what is now

known asLyme diseasehave been reported in the scientific

literature for the past century. Specifically, the bulls eye

rash known as erythema chronicum migrans was first

described by Lipshutz in 1913 [1]. Lyme disease has been

tracked since 1982 by a surveillance program of the Cen-

ters for Disease Control and Prevention (CDC) after

Burgdorfer et al. [2] isolated the spirochete Borrelia

burgdorferi as a causative agent of Lyme disease.

Lyme disease is the most prevalent tick-borne disease in

the United States, and its incidence is increasing [3]. Chil-dren age 714 years and adults age 5570 years represent

the majority of persons affected by Lyme disease [4]. Initial

infection with B. burgdorferi occurs most often during

summer, with the geographical distribution correlating with

the distribution of its vector, the Ixodestick. In the wild, the

white-footed mice and white-tailed deer serve as reservoirs

for B. burgdorferi [1]. Global climate change has, and is

projected to continue to, lead to a northward shift in the

distribution of Lyme disease cases (Fig. 1) [5]. Currently,

most US cases of Lyme disease occur in the northern

Midwest and Northeastern regions. Worldwide, Lyme dis-

ease also affects persons in central Europe and Asia.Table1 describes the worldwide distribution of Borrelia

species, along with tick vectors and host reservoirs.

The risk of a human becoming infected with Borrelia

after a tick bite in an endemic area in Switzerland was

estimated at 4.5 % and was similarly estimated at 3.2 % in

Westchester County, New York [6, 7]. Overall, many

studies cite a risk of acquiring Lyme disease from a tick

bite to be 16 % [6]. This risk calculation is contingent, of

course, on patients recognizing that they had a tick bite, as

D. A. Godar V. Laniosz D. A. Wetter (&)

Department of Dermatology, Mayo Clinic, 200 First St SW,

Rochester, MN 55905, USA

e-mail: [email protected]

Am J Clin Dermatol

DOI 10.1007/s40257-014-0108-2


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well as their geographic location. This detail is important

because many tick bites go unrecognized. Statistically, the

risk of infection can be estimated from knowing theprobability of being bitten by 1 tick, the number of tick

bites per person, and the spirochete prevalence in the

region [8]. Risk factors for infection include time spent

outdoors, geographic location, duration of tick feeding, and

time of year [1].

Unfortunately, Ixodes ticks can be coinfected with other

infectious agents, includingAnaplasma phagocytophilum and

Babesia microti, the causative agents of human granulocytic

ehrlichiosis and babesiosis, respectively [1, 9]. Detailed

information regarding coinfection rates has been obtained for

many states in North America, as reported by Swanson et al.

[10]. As few as 1 % of ticks are coinfected with multiplepathogens in California, whereas as many as 28 % of ticks in

New York may harbor more than 1 pathogen [10].

2 Pathogenesis of Lyme Disease

Ticks acquire Borrelia when they take a blood meal from

an infected reservoir host. The spirochetes express the

adhesion lipoproteins OspA and OspB that allow them to

Fig. 1 Maps depicting current distribution of Lyme disease in the

United States and the world. a Predominance of US cases in the

Midwest and Northeast. b US distribution of babesiosis. c US

distribution of anaplasmosis. d Worldwide distribution of the Ixodes

tick vectors. e The projected shift by 2050 in Lyme disease

distribution in the United States as a result of climate change.

(Adapted from Centers for Disease Control and Prevention [25])

D. A. Godar et al.


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adhere to the tick midgut epithelium [11]. The Borrelia

organism then migrates to the salivary glands with a pro-

tein called OspC[12], which is upregulated when the tick

feeds and is essential for the infectivity of the organism

[13]. B. burgdorferi is protected from antibody-mediated

killing because of Salp15, a protein found in tick saliva that

binds to the outer surface protein ofB. burgdorferi [14].

Importantly, a study by Sood et al. [15] showed that the

risk of Borrelia transmission increases with a duration of

tick attachment greater than 72 h. Sood et al. showed poor

correlation between patient-predicted duration of tick

attachment and duration of attachment determined by

scutula measurement, which was used for the study.

After entering the human host, the Borrelia organism

disseminates widely, activating toll-like receptor 2, mye-

loid differentiation antigen 88, and CD14, and this acti-

vation leads to subsequent cytokine production.

Complement system activation also occurs; however, some

Borrelia species have mechanisms to evade complement-

mediated immunity [16]. OspC is downregulated after

long-term infection has been established in the host, and

the organism undergoes genetic recombination to evade

host humoral responses [17]. Specifically, vlsE proteins

have been implicated in this process that allows for per-

sistent infection [17].

3 Clinical Features

Lyme disease has three stages: early localized, early dis-

seminated, and chronic. Further details about the derma-

tologic manifestations are included herein, and their

associated Borrelia species are summarized in Table2.

Early localized disease (stage 1) can present as erythema

chronicum migrans, also known as erythema migrans(EM). Patients at this stage often have regional lymphad-

enopathy, with up to two-thirds of patients having consti-

tutional symptoms, such as fever, myalgias, arthralgias,

malaise, headache, and fatigue [1]. EM is a common

clinical presentation across Europe, Asia, and the United

States.

Early disseminated disease (stage 2) is characterized by

involvement of internal organ systems, including the cen-

tral nervous system (CNS), musculoskeletal system, and

heart. Dissemination may occur within days to months after

the initial infection [1]. Borrelial lymphocytoma is a

cutaneous manifestation that may be seen at this stage, andpatients also may have multiple EM patches. Borrelial

lymphocytoma is caused by Borrelia afzelii, which is

endemic to Europe and Asia.

Chronic Lyme disease (stage 3) is characterized by

encephalopathy and chronic arthritis, with only rare cuta-

neous manifestations. Acrodermatitis chronica atrophicans

(ACA) is a cutaneous feature of stage 3 disease. This form

of Lyme disease is not seen in the United States because it

is caused by B. afzelii, endemic to Europe and Asia. Bor-

relial infections also have been linked to morphea and

lichen sclerosus, with rare and controversial associations

with various granulomatous skin diseases such as sarcoid

and granuloma annulare [1, 18].

3.1 Erythema Chronicum Migrans

Among persons with Lyme disease, 50 % of adults and

90 % of children have EM [1]. EM typically appears

714 days following infection but may occur as early as

3 days or as late as 1 month after tick exposure [4]. EM is

often associated with constitutional symptoms, including

fever, malaise, fatigue, and headache [4]. It is characterized

by an erythematous macule that begins at the site of a tick

bite and spreads centrifugally to a diameter of at least 5 cm

(Fig.2ad). A range of 550 cm (median 13 cm) has been

reported in the literature [19]. The lesion can expand rap-

idly, sometimes growing 3 cm in 1 day. As it expands, the

center may clear, resulting in an annular or targetoid

morphology.

In the United States, less than 10 % of patients present

with the classic targetoid morphology and instead have a

homogeneous patch of erythema [4]. The annular mor-

phologic pattern is more common in Europe [4]. Rare

Table 1 Geographic Distribution of Borrelia, Tick Species, and

Reservoirs

Agent United States Europe Asia

Borrelia

species

implicated

in Lyme

disease

Borrelia

burgdorferi

Common

Borrelia garinii

Borrelia afzelii

OccasionalB. burgdorferi

Rare

Borrelia

lusitaniae

Borrelia

valaisiana

Borrelia bissettii

Borrelia

spielmanii

Common

B. garninii

B. afzelii

RareB. valaisiana

Tick vector Ixodes scapularis

Ixodes pacificus

Ixodes

persulcatus

Ixodes ricinus

I. persulcatus

Ixodes ovatus

Host

reservoir

Northeast: white-

footed mouse,

white-tailed

deer, and

raccoons

West: wood

mouse

Dusky-footed

wood rat,

cotton rat,

cotton mouse,

and many other

rodents and

birds

Long-tailed

shrew and

wood

mouse

Data from Bhate and Schwartz [1]

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vesicular, purpuric, and necrotic variants of EM have been

reported [4, 20]. Lesions of the lower leg may have pete-

chial qualities [21]. The most common EM locations cor-

relate to the most frequent areas of tick bites: intertriginous

areas in adults and head and neck in children [21]. EM

lesions usually are asymptomatic, but up to one-half of

patients report mild itching or burning [21]. EM lasts

approximately 6 weeks if untreated, with treatment leading

to EM resolution in a median of 18 days [ 22]. EM tends to

be less inflammatory and more insidious in Europe [23].

Although EM is traditionally thought to be an isolated

lesion, up to 20 % of patients have multiple lesions as a

result of spirochetemia, multiple tick bites, or lymphatic

spread [24] (Fig. 2eg). The existence of multiple EM

lesions is considered stage 2 disease, with lesions appear-

ing either simultaneously or sequentially [1]. Conversely,

disseminated disease may be present in the absence of

multiple EM lesions [1]. Patients with multiple EM lesions

typically have smaller lesions than patients with an isolated

EM lesion, and the lesions are less likely to be annular [ 1].

In addition, patients with multiple lesions are more likely

to report extracutaneous symptoms than those with isolated

lesions [21]. In patients who have EM resolution with

persistent flulike symptoms, coinfection with another

microorganism, such as B. microti or A. phagocytophilum,

should be considered [25].

3.2 Borrelial Lymphocytoma

Lymphocytoma presents as a soft, nontender erythematous

to violaceous nodule that may occur within an EM lesion

[1] (Fig.2h). The earlobe frequently is an area of

involvement in children; the nipple area is most frequently

seen in adults [21,26]. Lymphocytoma is more common in

Europe and in children and is essentially nonexistent in the

United States [1,21]. Its lesions are not usually associated

with systemic symptoms [21].

3.3 Acrodermatitis Chronica Atrophicans

ACA is a skin manifestation of chronic late-stage Borreliainfection, occurring months to even years after the initial

infection and more commonly in elderly persons [1]. ACA

is rare as sequelae of Lyme disease in the United States, but

it has been reported in approximately 10 % of patients with

Lyme borreliosis in Europe.

ACA lesions favor the distal extensor surfaces of the

extremities, presenting initially as edematous plaques and

progressing to hyperpigmented atrophic plaques, resulting in

a cigarette paper appearance of the skin if untreated

(Fig. 2i, j). These plaques are progressive,coalescing to cover

large areas over time. Some patients with ACA recall having

EM in the same body region in the past [21]. ACA may beassociated with development of subcutaneous firm nodules

that develop primarily on the elbows and knees [1,21].

Dermatitis atrophicans maculosa is a variant of ACA

that resembles anetoderma and frequently affects the but-

tocks and thighs. Another variant of ACA is a pseudo-

sclerodermatous presentation in which persons have

indurated, white plaques within or near existing ACA

lesions and favoring the distal extremities [21]. ACA is

associated with peripheral neuropathy in up to 60 % of

patients, often with allodynia [21].

4 Diagnosis

The diagnosis of Lyme disease requires presence of a

lesion consistent with EM and history of tick exposure or

laboratory evidence of Borrelia infection [27]. Thus, the

diagnosis does not require that the patient recall a tick bite.

The CDC and the Infectious Diseases Society of America

state that any annular, erythematous lesion occurring

within several hours of a tick bite likely represents a

hypersensitivity reaction and not EM [3,27]. Few patients

sustaining a tick bite have Lyme disease, although this

occurrence depends on the local prevalence of infection in

ticks; the tick must have been attached for at least 24 h for

Borrelia transmission to occur [24]. If a patient does not

have the characteristic EM lesions or cannot recall a tick

bite, diagnosis of Lyme disease is more difficult.

4.1 Pathologic Characteristics

Although skin biopsy is not routinely obtained for the

evaluation of Lyme disease, when it is performed, the

Table 2 Borrelia species associated with major cutaneous manifes-

tations of Lyme disease

Cutaneous manifestation Borrelia

species

Geographic locationa

Erythema migransb Borrelia

afzelii

Europe, Asia

Borrelia

garinii

Europe, Asia

Borrelia

burgdorferi

North America, Europe

(uncommon)

Borrelia

spielmanii

Europe

Lymphocytoma B. afzelii Europe, Asia

Acrodermatitis chronica

atrophicans

B. afzelii Europe, Asia

a Geographic information from Bhate and Schwartz [1]b Homogeneous erythema is observed more commonly in North

America; erythema migrans is observed more commonly with annular

morphologic characteristics in Europe [4]

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Fig. 2 Cutaneous

manifestations of Lyme disease.

ac The classic single annular

patch of erythema with central

clearing. Annular erythema

migrans surrounds tick in image

(c). d Atypical presentation of

erythema migrans with a

homogeneous, expanding

erythematous patch; in this case

with central necrotic eschar,

hemorrhage, and vesiculation.

(Adapted from Wetter and Ruff

[20]. Used with permission.) e

g Multiple dusky patches of

erythema migrans that may be

associated with spirochetemia

(eg) and which may become

nearly confluent (g). h An

infiltrated red plaque due to a

lymphocytoma. i, j Cigarette-

paper changes in acrodermatitis

chronica atrophicans, rarely

seen in the United States

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histopathologic evaluation often shows nonspecific features

(Table3; Fig. 3). If high clinical suspicion exists, Warthin-

Starry and Steiner stains may be used to demonstrate

Borreliaspirochetes in the skin or internal organs (Fig. 3d)

and tissue culture may be performed on skin specimens

obtained from EM lesions. Although borrelial organisms

can be visualized on tissue samples with special stains, this

is not a standard means for the diagnosis of Lyme disease.Because this is not a routinely used method of diagnosing

EM, sensitivity and specificity information regarding

visualization of Borrelia spirochetes in the skin is not

readily available. Mitchell et al [28] described a case series

in which spirochetes were able to be visualized in 24 of 34

specimens of patients with confirmed Lyme disease.

4.2 Tissue Testing

4.2.1 Culture

Culture to grow and detect the Borreliaspirochetes can beperformed on skin, blood, or cerebrospinal fluid (CSF).

Tissue culture from skin requires an EM eruption and skin

biopsy. The skin biopsy specimen should be obtained from

the edge of the EM lesion [4].Borreliatypically is cultured

on modified Kelly-Pettenkofer and Barbour-Stoenner-

Kelly II media [29]. Culture is specific but the sensitivity is

poorly defined [19,30]. Recovery of the organism is more

likely when the EM lesion has been present for a short

duration and generally cannot be recovered in patients

taking oral antibiotics [30]. Yield rates on culture from skin

samples reportedly range from 40 to 86 % [30]. Culture has

limitations. It can only be performed on untreated patients

[30]. Also, it is labor intensive and can take up to 3 months

to yield negative results, which substantially limits its

clinical utility [1, 30].

4.2.2 Polymerase Chain Reaction

Polymerase chain reaction (PCR) is an excellent test early

in Lyme disease and can be performed using sera, CSF,

synovial fluid, or even skin obtained through biopsy [31].

Specificity approaches 100 % and the test may yield

positive results in early Lyme disease, before the serologic

testings are positive [3032]. Sensitivity ranges from 36 to88 % in samples taken from EM lesions [30]. PCR has

reduced sensitivity due to destruction of the DNA during

sample processing or transport [30]. To minimize this

effect, DNA should be extracted shortly after collecting the

sample [30]. PCR also has decreased sensitivity because of

lack of conservation of target genes between different

Borrelia species [3032]. PCR sensitivity is better when

performed on skin and synovial fluid samples than blood or

CSF samples [32]. Unfortunately, PCR may not be widely

available and has a risk of unreliable results due to lack of

standardization [32].

4.3 Lyme Disease-Specific Serologic Testing

Serologic testing is indicated when all of the following

conditions are true [25]:

1. Recent history of living in or traveling to an area

endemic for Lyme disease

2. Risk factor for tick exposure

3. Symptoms concerning for disseminated Lyme disease

(eg, neurologic symptoms, carditis, arthritis)

Serologic testing is not indicated for patients with an

EM rash or when the pretest probability exceeds 80 % [ 4].

These patients should be treated empirically. Serologic

testing should not be obtained for patients with nonspecific

symptoms.

Initial screening may be performed with an enzyme-

linked immunosorbent assay (ELISA) or an indirect fluo-

rescent antibody (IFA) test. If the results from initial

screening tests are equivocal or positive, the diagnosis

should be confirmed with a Western blot. Patients with a

positive ELISA and negative Western blot should be con-

sidered negative for Lyme disease [4]. ELISA and IFA

tests are both limited by false-positive and false-negative

results. Early in the disease course, these tests may be

falsely negative. False-positive results occur in approxi-

mately 5 % of cases and have been reported in patients

with Epstein-Barr virus infection and syphilis infection, as

well as autoimmune conditions [4,33]. Thus, testing is not

recommended when the pretest probability of Lyme dis-

ease is low [4]. The sensitivity of these tests is good; the

specificity is excellent and is discussed in further detail

herein. Serologic testing for Lyme disease has limitations.

It often shows negative results early in the disease, cannot

Table 3 Histopathologic features of Lyme disease

Clinical finding Pathologic correlation

Erythema migrans Thickened stratum corneum

Epidermal atrophy

Focal eosinophilic spongiosis

Deep dermal perivascularlymphocytes

Plasma cells

Loss of pilosebaceous units

Lymphocytoma Dense dermal lymphocytic

infiltrate

Infiltrate containing B and T cells

Acrodermatitis chronica

atrophicans

Sclerosis

Plasma cells

Data from Bhate and Schwartz [1]

D. A. Godar et al.


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reliably distinguish between active and past infection, and

cannot be used to monitor treatment response [32]. Of note,

more than 70 types of immunoassay have been approved

by the US Food and Drug Administration for use in

detecting B. burgdorferi [30]. The pros and cons of the

different serologic tests are detailed in Table 4.

4.3.1 Enzyme-Linked Immunosorbent Assay

ELISA is the most commonly used initial test for Lymedisease. ELISA detects immunoglobulin M (IgM) and

immunoglobulin G (IgG) antibodies toB. burgdorferi, with

IgM antibodies usually detected 2 weeks after exposure

and IgG positivity at 4 weeks after exposure [1, 34]. IgM

testing should be used only during the first 4 weeks of

infection [1, 35]. Prolonged IgM positivity may correlate

with more severe disease [34]. IgG levels typically stay

elevated for 216 weeks after remission of Lyme disease

[34]. ELISA traditionally has targeted the entire organism;

however, this targeting increases the rate of false positives

because of antigens cross-reacting with other bacteria [30].

Recently, more targeted assays with v1sE and C6 have

been developed and have considerably enhanced the sen-

sitivity and specificity of ELISA [36]. Several enzyme

immunoassays are commercially available, and each differs

slightly in its sensitivity and specificity. The specificity of

the traditional 2-tier testing with sonicate ELISA and

confirmatory Western blot has been estimated at 99 % [35].

The sensitivity of the 2-tier testing with IgM or IgG is29 % during acute phase EM, 64 % during convalescent

phase EM, and 100 % in patients with neurologic, cardiac,

or joint manifestations of Lyme disease [35]. The sensi-

tivity and specificity of the IgG v1sE C6 peptide was

comparable in the discussion of Steere et al [35], but

according to Liang et al [37], it was improved at 74, 8590,

and 100 % for acute, convalescent, and late phase speci-

mens, respectively. The advantage of ELISA testing is that

it is automated and thereby less expensive [32]. ELISA

Fig. 3 Histopathologic features of Lyme disease. a Superficial

lymphoplasmacytic inflammation in erythema migrans (H&E 94).

b Deep perivascular lymphoplasmacytic inflammation in erythema

migrans (H&E 940). c Dense collections of lymphocytes in the

dermis in a lymphocytoma (H&E 94).d Spirochetes (arrow) shown

on WarthinStarry stain of cardiac tissue of a patient with Lyme

carditis (WarthinStarry 9158). (Adapted from Centers for Disease

Control and Prevention [CDC]. Three sudden cardiac deaths associ-

ated with Lyme carditis: United States, November 2012July 2013.

MMWR Morb Mortal Wkly Rep. 2013 Dec 13;62(49):9936. http://

www.cdc.gov/mmwr/preview/mmwrhtml/mm6249a1.htm )

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results also are quantitative because they correlate with the

amount of antibody response [30]. The interpretation of

ELISA results is detailed in Table 5.

4.3.2 Indirect Fluorescent Antibody Testing

IFA testing uses immunofluorescence to test for the pre-

sence of antibodies in the serum of affected patients. This

test is not automated and thus its reliability is operator-

dependent [32]. Therefore, ELISA is more sensitive than

IFA and thus is generally the preferred initial screening test[34].

4.3.3 Western Blot

Western blot is more sensitive and more specific than both

ELISA and IFA; however, given the greater costs and labor

associated with performing this test, it currently is used as

confirmatory and not as an initial test [32]. According to

the CDC, at least 2 of 3 bands must be present for a

positive IgM blot and at least 5 of 10 bands must be present

for a positive IgG blot [32,38].

4.4 Other Laboratory Findings

According to the CDC, general laboratory findings may

include elevated erythrocyte sedimentation rate, mildly

elevated levels of hepatic transaminases, and microscopic

hematuria or proteinuria. Complete blood cell count (CBC)

and renal function tests usually show normal findings [4].

In patients with neurologic symptoms (eg, headache, nervepalsies, neck pain or stiffness), CNS involvement should be

suspected and a spinal tap performed. CSF typically

demonstrates lymphocytic pleocytosis, an elevated protein

level, and a low glucose level in patients with CNS

involvement; however, glucose levels can also be normal

[4].

Approximately 15 % of patients with Lyme disease may

be coinfected with a second tick-borne illness. Swanson

et al. [10] showed that in patients with multiple tick-borne

Table 4 Pros and cons of diagnostic tests for Lyme disease

Diagnostic

test

Advantages Disadvantages Comments

ELISA Strong sensitivity

Cost-effective

Fast

Variation between strains of different

geographic origin

False positive with EBV, malaria, syphilis,

other spirochetal illnesses, and

autoimmune diseases

False negative early in disease

Does not reliably distinguish past and

active infection

False-positive IgM testing is more common

than false-positive IgG testing

5 % of normal US population test positive on

ELISAa

IFA Good sensitivity Variation between strains of different

geographic origin

False positive with EBV, syphilis, and

autoimmune disease

False negative early in disease

Does not reliably distinguish past and

active infection

Operator-dependent

Westernblot More specific than ELISA and IFAtest Expensive

Tissue

PCR

Can be performed on various sample

sources (eg, blood, CSF, synovial

fluid, skin)

Poor sensitivity

Generally not recommended because of

limited duration of circulating organisms

in the blood

Tissue

culture

High specificity Poor sensitivity

Time- and labor-intensive; expensive

May be helpful in cases of suspected

reinfection because serologic testing may

be difficult to interpret

Histologic

analysis

Can rule out other dermatologic

diseases on differential diagnosis

Nonspecific findings WarthinStarry and Steiner stains can be used

to confirm presence ofBorrelia

CSFcerebrospinal fluid, EBVEpsteinBarr virus, ELISA enzyme-linked immunosorbent assay, IFA indirect fluorescent antibody, IgG immu-

noglobulin G, IgMimmunoglobulin M, PCR polymerase chain reactiona

Table4 describes standard ELISA testing. Comparison of v1sE testing and traditional 2-tier ELISA is discussed in the text

D. A. Godar et al.


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illnesses, 81 % had both borreliosis and babesiosis, 9 %

had borreliosis and anaplasmosis, and 5 % had 3 tick-borneillnesses. The decision regarding further laboratory testing

for these other organisms should be based on which tick-

transmitted organisms are endemic to the area. If a patient

presents with EM and treatment is initiated empirically,

then serologic testing to document coinfection with A.

phagocytophilum is not necessary because the therapy is

effective for both organisms. A CBC, peripheral blood

smear, and liver function testing (LFT) help to determine

whether a coinfection is highly likely [10]. Patients with

anaplasmosis often have laboratory abnormalities, such as

leukopenia, lymphopenia, granulocytopenia, and elevated

LFTs [10].

Patients with babesiosis often have evidence of anemia.

BothB. microti and A. phagocytophilum can be visualized

with Giemsa stain [10]. If coinfection is strongly suspected

on the basis of CBC and LFT findings, then PCR for other

tick-transmitted organisms can be obtained to confirm the

diagnosis in patients whose specimen smears are negative

[10].

5 Differential Diagnosis

Lyme disease must be distinguished from other tick-borne

illnesses, such as ehrlichiosis, southern tick-associated rash

illness, and babesiosis [1]. Fever, headache, and arthralgias

are common symptoms seen in these conditions.

The differential diagnosis of EM is broad (Table6). Enti-

ties in the differential of EM include exaggerated arthropod

reaction, cellulitis, granuloma annulare, subacute cutaneous

lupus erythematosus, and many other considerations.

The most important considerations are to distinguish

EM from a tick-bite hypersensitivity reaction or cellulitis.

Hypersensitivity reactions to tick bites generally occur

within 48 h of tick detachment, are usually less than 5 cm

in diameter, and begin to resolve within 2448 h of onset

[3]. This response is in contrast to the EM lesion, which

generally appears later, is larger than 5 cm by definition,

and continues to expand rather than resolve [3]. Unlike

cellulitis, EM lesions are not usually indurated or warm or

painful to the touch. They also are not typically vesicular orpruritic, features that are more typical of acute allergic

contact dermatitis. In addition, EM lesions are not usually

scaly, a characteristic observed in cases of dermatitis or

fungal infection.

6 Management

The first-line treatment of early localized disease is doxy-

cycline at 100 mg orally every 12 h for 1421 days

(Table7). Doxycycline should be avoided in children

younger than 8 years and in pregnant women [3]. Of note,unfavorable fetal outcomes have been reported in pregnant

women who acquire Lyme disease [32]. Children younger

than 8 years should be treated with 50 mg/kg of amoxi-

cillin per day and adults should be treated with 500 mg

orally 3 times a day as an alternative [4]. In patients with

allergies to penicillin or unable to take tetracyclines, ce-

furoxime 500 mg orally twice a day for adults or erythro-

mycin 250 mg orally 4 times a day may be used for the

same duration [4]. Early disseminated disease should be

treated for 21 days, and ACA is generally treated for

1 month [4]. Approximately 15 % of patients may have a

Jarisch-Herxheimer reaction within the first 24 h of treat-

ment [4]. These patients had worsening malaise with

sweating and rigors that resolved spontaneously [4].

Patients who have persistent or recurrent EM, persistent

borreliosis, or major sequelae after appropriate treatment

should be re-treated [19]. Patients with a longer duration of

EM lesions or lesions of larger size are more likely to have

persistent positive antiborrelial IgG after antibiotic treat-

ment [19]. Patients with previous Lyme infection have no

protection against repeat infection. Conversely, patients

who continue to experience subjective symptoms, such as

pain, fatigue, or altered cognition, will not improve with

recurrent antibiotic treatment because these symptoms are

not caused by persistence of the spirochete [19, 39].

Instead, they are considered to be part of postLyme dis-

ease syndrome and may persist for a year or longer after

treatment of the initial infection [19].

For patients who have coinfection with A. phagocyto-

philum, doxycycline 100 mg orally twice daily is the

treatment of choice, even in young children [10]. Doxy-

cycline should still be avoided in pregnancy. Rifampin and

levofloxacin can be considered alternative treatments in

Table 5 General interpretation of ELISA testing in Lyme disease

ELISA finding Interpretationa

IgM?, IgG- Early infection; isolated IgM? with no IgG

seroconversion after repeat testing is a nonspecific

finding and suggestive of a false-positive IgM

IgM?, IgG? Suggestive of active infection; obtain confirmatory

testing

IgM-, IgG- Negative testing rules out Lyme disease; if testing

obtained within 2 wk of tick bite, testing may be

repeated 4 wk later, and if it is still negative,

results are consistent with no disease

IgM-, IgG? IgG levels may persist, indicating exposure, but do

not necessarily indicate active disease

ELISA enzyme-linked immunosorbent assay, IgG immunoglobulin G,

IgMimmunoglobulin Ma The interpretation does not account for pretest probability and the

sensitivity and specificity of the test performed for stage of disease

Lyme Disease Review


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necessary situations; however, little to no data exist

regarding their efficacy in a clinical setting [10]. Of note,

A. phagocytophilum is resistant to b-lactams, macrolides,

sulfa antibiotics, clindamycin, and aminoglycosides [10].

Treatment for at least 14 days is recommended in cases of

coinfection with B. burgdorferi and A. phagocytophilum

[10].

Patients with babesiosis often have a mild, self-limitedinfection without need for treatment [10]. If they are

symptomatic, oral clindamycin 600 mg 3 times per day can

be administered for adults and 2040 mg/kg per day

divided in 3 daily doses given to children. In addition, oral

quinine 650 mg 3 times per day for adults and 25 mg/kg

per day divided in 3 daily doses for children can be con-

sidered. For severely ill patients, intravenous clindamycin

300600 mg every 6 h is recommended for adults; for

severely ill children, 2040 mg/kg per day and oral quinine

are recommended [10]. Nevertheless, a notable amount of

morbidity is associated with this treatment, with approxi-mately 72 % of patients having adverse reactions, includ-

ing tinnitus, diarrhea, and hearing loss [10]. An alternative

regimen includes atovaquone 750 mg twice daily with

Table 6 Differential diagnosis for the cutaneous manifestations of Lyme disease

Differential diagnosis Characteristics that distinguish from Lyme disease

Clinical Pathologic Laboratory

Erythema migrans

Tinea corporis Scaly annular plaque

KOH test positive for fungal elements

Fungal stains positive for fungal

elements

No significant laboratory

findingsGranuloma annulare Smooth, indurated, nonscaly annular plaques

Asymptomatic to mildly pruritic

Palisading granulomas with altered

collagen and mucin

No abnormalities

Cellulitis Tender, indurated plaques

Associated fever or malaise

Leukocyte infiltration, capillary

dilatation, and bacterial invasion

Leukocytosis

Elevated levels of

inflammatory markers

Fixed drug eruption Dusky plaques

Typically with medication history

Vacuolar interface dermatitis with

pigment incontinence

None

Hypersensitivity or

exaggerated arthropod

bite reaction

Develops within 48 h of tick bitea

Usually more pruritic or more painful than

erythema migrans

Resolves spontaneously in a few days

Clears from periphery rather than centrally

Increased risk in persons with hematologic

cancers

Eosinophilic spongiosis None

Allergic contact dermatitis Lichenification or vesiculation, depending on

acuity

Geometric borders

Pruritus

Eosinophilic spongiosis None

Erysipelas Usually associated with fever and chi lls

Well-defined raised border

Firm and painful to the touch

Dermal edema, vascular dilatation,

and neutrophilic inflammation

Elevated ESR and CRP

levels

Leukocytosis

Disseminated erythema migrans

Tuberculoid and borderline

forms of leprosy

Well-circumscribed erythematous to

violaceous or hypopigmented macules or

plaques; lesions in borderline forms have a

more punched-out shape

History of exposure

Lesions with associated anesthesia

Lesions possibly associated with alopecia and

scaling

Affecting cooler body parts

Perineural granulomas

Foamy macrophages

Positive results on Fite and AFBstains

Serologic assays to detect

phenolic glycolipid-1

(specific for

Mycobacterium leprae) andlipoarabinomannan

(common in mycobacteria)

SCLE Annular plaques with or without scale

Photodistributed

May be associated with arthralgias and malaise

Interface dermatitis with

perivascular and periadnexal

lymphocytes

Positive SSA antibodies

D. A. Godar et al.


11/14

Table 6 continued

Differential diagnosis Characteristics that distinguish from Lyme disease

Clinical Pathologic Laboratory

Erythema infectiosum Slapped cheeks rash followed by

development of a reticular maculopapular

rash

Rash often pruriticAssociated with joint pains, especially in

adults

Nonspecific Positive PCR or

immunoassay testing for

parvovirus

Erythema multiforme Associated with herpes simplex virus,

medications, and mycoplasma

Targetoid lesions with mucosal involvement

common

Painful lesions

Partial to full-thickness epidermal

necrosis with vacuolar interface

dermatitis and intraepidermal

vesiculation

None

Erythema annulare

centrifugum

Annular lesions with trailing scale Tight perivascular lymphocytic

inflammation

None

Urticarial vasculitis Urticarial plaques with burning sensations

Purpura common

Leukocytoclastic vasculitis May have

hypocomplementemia

Urticaria Transient and recurrent wheals

Pruritus

Superficial perivascular infiltrate

with eosinophils and lymphocytes

None

Erythema marginatum Polycyclic, asymptomatic eruption

Preceding streptococcal infection

Additional manifestations of rheumatic fever

(eg, carditis, arthritis, fever)

Scant neutrophilic perivascular

infiltrate without vasculitis

Elevated ESR and CRP

levels

Prolonged PR interval on

ECG

Positive streptococcal

culture or rising

antistreptolysin O or anti-

DNase B titer

Lymphocytoma

Lymphoma Firm plum-colored nodules Atypical lymphocytic infiltration Variable CBC and bone

marrow biopsy findings

Sarcoidosis Reddish-brown papules and plaques with

minimal epidermal change

Lesions in old scars

Erythema nodosum

Noncaseating granulomas Elevated ESR

Hypercalciuria

Leukopenia uncommon but

possible

Increased ACE level

Acrodermatitis chronica atrophicans

Morphea Insidious devel opment of indurat ed violaceous

plaques

Thickening and homogenization of

collagen bundles, with loss of

subcutaneous fat and trapping of

eccrine glands

Peripheral eosinophilia

possible

Antinuclear, anticentromere,

anti-Scl70,

antiphospholipid,

antitopoisomerase,

antihistone, antiMMP-1,

anti-dsDNA and anti-

ssDNA antibodies possible

Lichen sclerosus et

atrophicus

Atrophic white plaques common in genital

areas; possible in extragenital sites

Often pruritic in genital locations

Atrophic epidermis

Papillary dermal pallor

Lymphoid band beneath zone of

pallor

None

Superficial

thrombophlebitis

Painful subcutaneous nodules Thrombi within veins, surrounded

by inflammation

Possible hypercoagulability

ACEangiotensin-converting enzyme, AFB acid-fast bacteria,CBCcomplete blood cell count, CRP C-reactive protein, DEJdermal-epidermal junction,

ECGelectrocardiography,ESR erythrocyte sedimentation rate, KOHpotassium hydroxide, MMP-1matrix metalloproteinase-1, PCR polymerase chain

reaction,SCLEsubacute cutaneous lupus erythematosusa Information from Wormser et al. [3]

Lyme Disease Review


12/14

meals for adults and 20 mg/kg twice daily with meals for

children [10]. Azithromycin 500 to 1,000 mg daily has also

had success and is better tolerated [10]. Patients with

severe hemolysis may require exchange transfusions [10].Of note, babesiosis treatment is not effective for Lyme

disease or anaplasmosis.

7 Prevention

7.1 Tick Bite Avoidance

Avoidance of tick bites with use of insect repellant and

protective clothing is recommended for all patients who

choose to engage in outdoor activities in endemic areas.

Insect repellents most effective against ticks include trans-

p-menthane-3,8-diol and N,N-diethyl-3-methylbenzamide

(DEET) [40]. Synthetic repellants including picaridin and

IR3535 are less effective [40]. Trans-p-menthane-3,8-diol

is the most highly repellent substance for ticks, and

repellency is long-lived, lasting for several days [40]. Its

use is not associated with toxicity [40]. In contrast, labo-

ratory testing of DEET has shown repellency of up to

80100 % with concentrations of 30 %, but the effect is

relatively short-lived, lasting 25 h [40]. DEET has been

unpopular in the general public also because of reports of

seizures in children; however, research suggests that this

adverse effect is more of a concern with ingested DEET

than topically applied DEET [40]. DEET has also been

used safely in pregnancy [40].

Protective clothing treated with permethrin has been

effective in repelling ticks [40]. In a field study of outdoor

workers, researchers found a 93 % reduction in the number

of tick bites in persons wearing permethrin-treated clothing

compared with controls [40]. It is best to buy clothing in

which the permethrin is polymerized to the clothing fibers

as this is more long lasting and resists washing compared

with clothing dipped in permethrin, which must be

retreated every 20 washes [40]. Clothing treated with

DEET is generally less effective [40].

7.2 Tick Removal

Following exposure to a tick-infested area, complete

inspection of skin and scalp should be performed and ticksremoved promptly. Patients should be advised to remove

ticks immediately using a fine-tipped tweezers or forceps to

grasp the tick as close to the skin as possible and with

steady upward pulling, avoiding twisting movements [40].

The forceps method is the recommended tick removal

strategy from several organizations. Methods using petro-

leum jelly, nail polish, or other substances to suffocate the

tick are generally ineffective because the tick has a very

low respiratory rate [40]. Of note, some laboratory studies

have not found a significant difference in risk of trans-

mission with methods that squeeze the tick vs pull the tick;

however, it is still recommended to remove ticks with theforceps method [40,41].

The guidelines of the Infectious Diseases Society of

America cite that after a tick bite, a sole 200-mg dose of

doxycycline should be administered to adults and to chil-

dren age 8 years or older when all of the following situa-

tions exist [3]:

1. An attached tick is reliably identified as an adult or

nymphal Ixodes scapularis and has been attached for

an estimated 36 hours or more, based on the extent of

its blood engorgement or certainty about the time of

tick exposure2. Prophylaxis is started within 72 h of tick removal

3. Ecologic information indicates a local infection rate of

20 % or more for B. burgdorferi in ticks

4. Doxycycline use is not contraindicated

No recommended prophylaxis is available for children

younger than 8 years or for pregnant women because no

trials have been performed in these patient groups [4].

Instead, they should be observed for EM development and

should be treated if necessary [4].

7.3 Vaccines

Only 1 human-targeted Lyme disease vaccineLYMEr-

ixhas ever been approved by the US Food and Drug

Administration. LYMErix was a recombinant protein

vaccine against OspA that became available commercially

in 1998 [42]. The vaccine was efficacious and well toler-

ated but required multiple boosters, and there were con-

cerns regarding potential risk of autoimmunity; thus it was

removed from the US market in 2002 because of poor sales

[42].

Table 7 Treatment regimens for Lyme disease

Cutaneous

manifestation

First choice

treatment

Alternative

treatment

Early localized disease

(solitary erythema

migrans)

Doxycycline

100 mg PO Q12h

for 1421 daysa

Amoxicillin

500 mg PO Q8h

for 1421 days

Early disseminated

disease (multiple

erythema migrans;

lymphocytoma)

Doxycycline

100 mg PO Q12h

for 1428 daysa

Amoxicillin

500 mg PO Q8h

for 1428 days

Chronic disease

(acrodermatitis

chronica atrophicans)

Ceftriaxone 2 g IV

once daily for

1428 days

Cefotaxime 2 g IV

Q8h for

1428 days

IV intravenously, PO orally, Q8h every 8 h, Q12h every 12 ha Doxycycline should be avoided for children\8 years old and for

pregnant women

D. A. Godar et al.


13/14

Vaccines targeting the tick and its reservoir have been

postulated and investigated; however, numerous obstacles

have led to little progress on this front [42].

8 Conclusions

Lyme disease has varied cutaneous manifestations thatdiffer among the 3 stages of Lyme disease, and the

approach to diagnosis and treatment is based on the patient,

the region, and suspected coinfection with another tick-

borne illness. Erythema migrans is the most common

clinical presentation of Lyme disease and is a clinical

diagnosis, although atypical cases require careful clinico-

pathologic correlation to differentiate the cutaneous man-

ifestations of Lyme disease from other dermatologic

conditions. An understanding of the distribution of the

Ixodes tick, its vectors, and the most likely dermatologic

presentation based on these factors allows the dermatolo-

gist to make appropriate testing and treatment recommen-dations for patients with suspected Lyme disease who are

encountered in the general dermatologic setting.

Acknowledgments No sources of funding were used to prepare this

review. D. A. Godar, V. Laniosz, and D. A. Wetter have no conflicts

of interest that are directly relevant to the content of this review.

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