ARTICLE
Auteur(s) :, Robert R. MÜLLEGGER*
Department of Dermatology, Medical University of Graz,
Auenbruggerplatz 8, A-8036 Graz, Austria.
*R. Müllegger. Fax: (+43) 316 385 2466.
E-mail: robert.muellegger@meduni-graz.at
accepté le 14 Mai 2004
Lyme borreliosis (LB) is a complex multisystem infectious disease
caused by spirochetes of the Borrelia burgdorferi
(Bb) sensu lato complex, which are transmitted primarily by
ixodid ticks. LB is the most common vector-borne disease [39]. It
occurs focally clustered in temperate climates of the northern
hemisphere with a peak incidence between May and September [39,
133, 141]. The most endemic regions are the northeastern and
north-central states of the U.S.A. and Central European, and
Scandinavian countries [39, 115, 133]>400 cases per
100,000 persons per year [39, 111, 115]. The disease affects
both sexes and all age groups, but is most often seen in children
and adults aged 30-50 years [39, 65, 115].
Clinical aspects of Lyme borreliosis
The natural course of LB can be divided into three clinical stages
(Table I( Table I )). The
infection usually begins with a rash (erythema migrans; EM) at the
site of an infectious tick bite. With spread of Bb to
various other organs, the infection may proceed to an early
disseminated stage in days to weeks, and to a late persistent or
progressive stage in months to years. As a result, LB has a wide
spectrum of clinical manifestations. Besides skin manifestations,
which are described in detail in this article, LB includes
neurological, musculoskeletal, cardiac, and ocular disorders. The
most important neurological manifestations (neuroborreliosis) are
meningitis, cranial neuritis, radiculoneuropathy, and
encephalopathy [49]. Lyme arthritis is typically an intermittent
oligoarticular arthritis that lasts weeks to months, but may
sometimes become chronic [138]. Cardiac manifestations develop in a
small percentage of patients and include atrioventricular block,
ventricular tachycardia, bundle branch block, myopericarditis, and
dilated cardiomyopathy [50, 104]. For eye diseases, it is often
difficult to definitely prove the causal relationship with
Bb infection. It becomes clear that LB may cause relatively
severe systemic disorders. They can be avoided by prompt
recognition and appropriate antibiotic therapy in most cases. On
the other hand, LB must not be overdiagnosed, for example in the
case of the presence of serum antibodies to Bb in a patient
with unspecific complaints. Thus, a thorough knowledge of the
clinical features, laboratory tests, and therapy of LB is
important.
Dermatoborrelioses
About 80% of all LB cases represent skin manifestations,
collectively dermatoborrelioses (DB). The three characteristic
manifestations of DB, in which the etiopathogenetic role of
Bb has been undoubtedly proven, are EM, borrelial
lymphocytoma (BL), and acrodermatitis chronica atrophicans (ACA).
Theses three entities affect the skin during different stages of LB
(Table I).
Table I Stages and organ manifestations of Lyme
borreliosis
|
Organ
|
Early localized disease
|
Early disseminated disease
|
Chronic disease
|
|
Skin
|
Erythema migrans
|
|
Acrodermatitis chronica atrophicans
|
|
Disseminated erythema migrans
|
|
|
Borrelial lymphocytoma
|
|
|
Nervous system
|
|
Meningo-polyradiculoneuritis
|
Encephalopathy Encephalomyelitis
|
|
Cranial neuritis
|
Neuropathy
|
|
Musculoskeletal system
|
|
Arthritis
|
Chronic arthritis
|
|
Myositis
|
|
|
Heart
|
|
Carditis
|
Cardiomyopathy
|
|
Tachycardia
|
|
|
Atrioventricular block
|
|
Erythema migrans
EM is the hallmark of acute LB and its most frequent manifestation,
occurring in 60-90% of patients with symptomatic infection. It is a
round to oval, sharply demarcated, red to bluish-red expanding skin
lesion. The rash usually appears at the site of the tick bite after
an average incubation period of 10-30 days with a range of a few
days to six months [99, 102, 141, 142, 146]. The tick bite,
however, is recalled by only 21-73% of patients [8, 102, 113, 141,
142, 146]. Corresponding to the most frequent sites of tick bites,
the location of EM is usually the calf/popliteal fossa region, or
the thigh/groin/buttock region, or the armpit/shoulder region. In
children, EM is located in the head-neck region in many cases. The
median duration of EM prior to first examination is about
10 days with a range from one day to 10 months [141, 145,
146]. The size of EM is primarily a function of disease duration,
but also depends on the site of EM. The mean of the largest
diameter of EM is 10-16 cm with a range of 4-87 cm [102, 141, 146].
EM lesions with less than 5 cm in diameter are only rarely
observed [134]. There are different clinical forms of typical EM,
the solitary annular type and the more frequent solitary macular
type [99, 113, 131, 146]. The difference between these two types is
that annular lesions are ring-like (( Fig. 1 )), whereas
macular lesions do not show central clearing, but remain homogenous
(( Fig. 2
)). The latter is characterized by a conspicuous inflammatory edge
in most cases. EM lesions on the calf tend to develop a hemorrhagic
component due to stasis. EM usually lacks epidermal changes,
although vesicular centers or minimal scaling may sometimes be
observed [131]. Localized alopecia has been reported at the site of
EM [132]. Atypical variants of EM also include lesions with shapes
that are not round to oval, or form only incomplete rings. Local
symptoms are reported in up to 53% of patients [142, 146]. Itching
or burning are generally mild, but pain, due to local neuritis, may
become quite severe and can last for weeks. Up to 15% of EM
patients develop a second EM episode (reinfection) within several
years after antibiotic therapy [e.g. 110].
Extracutaneous nonspecific signs and symptoms are associated
with EM in 30-68% of patients and are more common in America than
in Europe [102, 142, 146]. They are generally moderate and
transient and include fatigue, malaise, arthralgias, myalgias,
headache, lymphadenopathy, (low-grade) fever, chills, vertigo,
nausea, and anorexia [156]. In an important Finnish study [113], it
was demonstrated that the frequency of general symptoms was nearly
the same in EM patients with as in those without dissemination of
Bb as analyzed by blood polymerase chain reaction (PCR) or
culture. Thus, these symptoms do not necessarily point to
dissemination of the spirochete to other organs. Apart from these
unspecific symptoms, true manifestations of LB in other organs
(neuro- or cardioborreliosis) may occur in close temporal relation
to EM [e.g. 104].
The simultaneous development of multiple EM lesions (( Fig. 3 )) in one
patient is more frequent in the USA than in Europe, where it is
observed in 4-20% of EM cases [99, 102, 146, 156]. The suspected
underlying pathogenic mechanism is hematogenous dissemination of
the spirochete [13], although the occurrence of multiple lesions
may also be due to more than one infectious arthropod bite or local
spread of Bb in several patients. Usually, a primary EM with
typical clinical aspect is followed by disseminated or clustered
secondary lesions after a latency period of a few days. The mean
total number of lesions per patient is 3-5 (range, 2-70) with a
higher average number in American patients [8, 10, 89, 99, 102]. Up
to two thirds of all patients with multiple EM lesions, adults more
often than children, are affected by extracutaneous signs and
symptoms or additional organ manifestations [8, 89]. Cerebrospinal
fluid examinations revealed findings typical for meningitis in 31%
and intrathecally produced Bb antibodies or positive
Bb cultures in up to 4% of patients with multiple lesions
[8, 89]. Interestingly, up to 40% of those patients with laboratory
confirmation of central nervous system infection had no
extracutaneous signs and symptoms [89]. In synopsis with the
Finnish study on Bb detection in blood samples [113], it
becomes evident that dissemination of the spirochete and clinical
complaints often do not correlate in EM patients.
Differential diagnoses of solitary EM include unspecific
arthropod bite reaction, erysipelas, circumscribed scleroderma
(morphea) (CS), granuloma annulare, tinea, fixed drug eruption, and
erysipeloid [15]. The most important differential diagnoses for
multilocular EM are urticaria, multilocular fixed drug eruption,
erythema annulare centrifugum, and erythema infectiosum. An
important criterion for the differentiation between EM and
unspecific arthropod bite reaction is the course of the lesion. An
unspecific reaction develops immediately after the bite and will
clear within several days without antibiotic therapy, whereas EM
occurs after a latency period following the bite and does not clear
spontaneously in such a short time. Arthropod reactions are
associated with more intense local subjective symptoms.
Erythema migrans in special patient groups
In a study on 105 pregnant women with EM [87], maternal and
fetal outcome after a 14-day treatment with beta-lactam antibiotics
(mostly intravenous ceftriaxone) was analyzed. The outcome of the
disease was good in all mothers. Pregnancies were normal in
93 cases (89%). In 12 cases (11%), an adverse outcome was
observed. Importantly though, a causal association with Bb
infection could not be proven in any infant. This study is in line
with American investigations [147], which found that maternal
exposure to LB before conception or during pregnancy was not
associated with fetal complications. In a study on 67 adult
immunocompromised EM patients [86], disseminated infection,
treatment failure, and necessity of retreatment were found
significantly more often than in control patients. However, all
other clinical characteristics, including disease outcome after one
year, were comparable to controls.
Borrelial lymphocytoma
BL is a benign B-cell lymphoproliferative process that represents
an immunologic reaction to the presence of Bb as antigenic
stimulus in the skin [13]. To date, it has been reported
exclusively from Europe [120]. In LB endemic regions, BL is the
most common type of cutaneous B-cell pseudolymphoma [62], but it is
the least common manifestation of DB (5%). It is observed more
often in children than in adults [14, 156]. BL has been defined as
subacute manifestation of early disseminated LB, but may sometimes
occur at the site of a tick bite (early localized infection) [13,
14]. The incubation period after the tick bite is usually longer
than in EM.
BL is a solitary lesion in the great majority of cases [90, 120,
144, 156] and typically appears as bluish-red nodule or plaque with
a size between 1-5cm, sharply demarcated, and often with a slightly
atrophic surface. On palpation, BL is a soft and non-tender lesion.
BL is located typically on the ear(lobe) (( Fig. 4 )), breast
(nipple, areola), and less frequently on the scrotum or the
(anterior) axillary fold [14, 62, 90]. Clinical differential
diagnoses include insect bite reactions, cutaneous lymphoma [53],
foreign body granuloma, sarcoidosis, cutaneous metastasis, keloid,
perichondritis, and granulomatous contact dermatitis.
Extracutaneous signs and symptoms are very infrequent [14, 90].
Acrodermatitis chronica atrophicans
ACA is the characteristic cutaneous manifestation of late LB in
Europe, where it is the second most common form of DB. In the USA,
only very few cases have been described. ACA has been observed
mainly in elderly patients, particularly women [13], and occurs
only exceptionally in children [96]. Almost no patient specifically
recalls a tick bite at the affected body site, but most of them are
bitten repeatedly each year or are outdoor workers in endemic
areas. According to Åsbrink [10] and our own experience, ACA was
preceded by an EM lesion in the same location several months to
many years earlier in <10-20% of patients. ACA is usually
located on the extensor surfaces of the distal extremities,
including the back of the hands and feet. The most common sites are
the lower leg and foot. ACA has been described to occur on the face
in exceptional cases. ACA typically begins with an early
inflammatory phase with a bluish-red discoloration and doughy
swelling of the skin that is not sharply demarcated (( Fig. 5 )) [10, 13, 16,
155]. ACA does not resolve spontaneously [13, 16], but gradually
progresses to an atrophic phase over many weeks to months due to
persistence of Bb in the skin. The skin becomes thin and
wrinkled due to loss of epidermal and dermal structures (( Fig. 6 )) [13,
16, 155]. In advanced atrophic cases, the skin also becomes dry and
hairless owing to a decline of skin appendages. Underlying
structures, such as vessels, become easily recognizable, and
multiple telangiectases occur [10]. With the progression of ACA,
skin changes may also expand to more proximal areas of the
extremity and/or affect additional extremities, but only very
rarely the trunk. In 10-20% of ACA patients, localized increase of
dermal collagen produces indurated bands, most often along the ulna
or tibia, and/or fibrotic nodules [91, 155]. Fibrotic nodules occur
as solitary or multiple, firm, skin-colored to bluish-red,
dome-shaped nodules in juxtaarticular locations, such as over the
dorsal aspects of the elbows (( Fig. 7 )) or knees
[91, 155]. In 5-10% of patients, sclerosing, morphea-like areas
(‘pseudoscleroderma’) may be present within or adjacent to the ACA
lesion [10, 155]. They appear as indurated, whitish, shiny, sharply
demarcated patches or bands of variable size and can lead to
limitations of joint movement [10].
The most frequent extracutaneous manifestation of ACA is
peripheral neuropathy. It develops in about 60% of patients [70].
Clinical and neurophysiological examinations reveal a sensory or
sometimes motor mono- or polyneuropathy, mainly affecting large
nerve fibers, and usually corresponding in distribution to the
cutaneous ACA lesions, although limbs without visible signs of ACA
may also be affected [70]. Patients complain of mostly mild to
moderate muscular weakness, dysaesthesias, muscle cramps, and pain.
Allodynia, a characteristic exaggerated pain reaction in ACA, is
believed to be nociceptive rather than neurogenic and to be caused
by the release of cytokines [25, 70]. Bone and joint involvement in
ACA is particularly found in patients with long-standing disease.
Abnormalities most frequently described include subluxations and/or
luxations of small joints of the hands or feet, arthritis in large
joints, bursitis, Achilles tendinitis, and periosteal bone
thickening [10, 13]. The affected joints or bones are usually
located underneath the skin lesion [10], which may be explained by
local progression of Bb infection from the skin. Some ACA
patients also suffer from nonspecific symptoms, such as headache,
myalgia, (profound) fatigue, emotional disturbances, personality
changes, or loss of weight [10, 11].
ACA has many differential diagnoses, which partly depend on the
stage of the disease. ACA is most often mistaken for a vascular
disorder, including chronic venous insufficiency, deep vein
thrombosis, superficial thrombophlebitis, arterial occlusive
vascular disease, acrocyanosis, livedo reticularis, or lymphedema
[10, 45]. ACA may also be misdiagnosed as perniones, aged skin,
erysipelas, erysipeloid, bursitis/arthritis, or CS [10, 16]. Very
often, ACA has already been present for months to years at the time
of diagnosis, which is due to its insidious course and the frequent
misinterpretation, especially as chronic venous insufficiency or
skin aging. It is thus emphasized that ACA should be considered as
a possible diagnosis in a patient with bluish-red discoloration of
a limb with or without swelling and/or atrophy.
Borrelia burgdorferi as possible cause of other skin
diseases
Circumscribed scleroderma and lichen sclerosus et
atrophicus
Since initial positive serologic, immunohistochemical, and cultural
studies in the 1980s [e.g. 1], Bb has been discussed as
causative agent of CS and lichen sclerosus et atrophicus (LSA),
sclerotic skin lesions of unknown etiology. Since that time,
conflicting results have been reported based on different
investigational methods and from various geographic regions.
Humoral immune responses to Bb have been examined in more
than 600 patients with CS or LSA. The highest prevalence of
antibodies to Bb was found among CS patients from Austria
(33-54%) [e.g. 26], and Switzerland (up to 38%) [e.g. 30], whereas
no differences were found in the frequency or level of Bb
antibodies compared to controls in most other European countries
[e.g. 6, 123, 126, 164], the USA [60], and Japan [5]. The attempt
to isolate Bb from lesional skin was successful in five CS
patients from Austria and Southern Germany [e.g. 1, 158], but
failed in most other studies, including a larger patients series in
Austria [e.g. 6, 123]. For LSA, the demonstration of Bb by
cultivation succeeded in only one patient so far [28]. PCR studies
of lesional skin have yielded positive results in a total of
21/140 CS patients and 15/40 LSA patients in Europe
(particularly Germany and Italy) and Japan [e.g. 48, 126], whereas
Bb-specific DNA could not be amplified in any of 98 CS
and 48 LSA patients from the USA, respectively [e.g. 40, 48].
In the PCR studies, different primers were used (e.g. specific for
the flagellin, ospA, or rRNA genes of Bb). The negative
studies appear to be more comprehensive in that usually more than
one primer set [e.g. 6] was applied to larger patients’
collectives. Spirochetes were also found by immunohistology or
silver staining in lesional tissue of about 20 CS and LSA
patients each [e.g. 1, 125]. Those methods, however, are
susceptible to artifacts and interpretation faults [34], and the
first results could not be reproduced by other investigators [e.g.
123]. Finally, lymphoproliferative responses to Bb,
reflecting the cellular immune response of patients, were found to
be elevated in about one third of 39 Austrian CS patients
[26], whereas analyses of 52 Swiss patients gave inconclusive
results [e.g. 30]. The lymphocyte proliferation assay has
limitations in specificity and sensitivity. Several case reports
have also implicated Bb infection as a possible cause of two
subtypes of CS, progressive facial hemiatrophia (silver staining)
and eosinophilic fasciitis (Shulman syndrome) (silver staining,
immunohistology, PCR) [e.g. 54, 59]. In summary, no decision can be
made to date as to whether or not Bb plays a role as
causative agent of different types of CS and LSA. With regard to
the disparate findings in different geographic areas, it can be
speculated that CS may be caused in some cases by Bb
genotypes which are present in that area only.
Cutaneous lymphomas
A possible association between primary cutaneous B-cell lymphomas
(PBCL) and Bb infection was first suspected because of
raised serum anti-Bb antibody titers in several small series
of PBCL patients. For example, Jelic and Filipovic-Ljeskovic [68]
found a positive borrelial serology in 55% of PBCL patients
compared to 4.6% in control patients. Recently, other authors have
provided more definite evidence for the pathogenic role of
Bb in PBCL. Kutting et al. [75] were able to isolate
Bb from skin lesions in two patients with PBCL. Applying
Bb-specific PCR to specimens of lesional skin, several
European authors have found positive results in 18-35% of patients
with various types of PBCL [e.g. 33]. In contrast, neither
molecular [169] nor epidemiologic [100] studies could demonstrate
an etiopathogenetic role for Bb in PBCL in the USA. and
Asia. This discrepancy may be due to differences between Bb
strains on the different continents. Bb can persist in the
skin for many years despite the presence of an active host immune
system, possibly by modulation of surface antigens by the
spirochete [13, 128]. In analogy to Helicobacter
pylori-associated MALT-lymphomas, it is conceivable that the
resulting chronic stimulation of skin-associated lymphoid tissues
may be operative in the pathogenesis of a subset of PBCL. As a
proportion of PBCL patients may be cured with adequate
antimicrobial therapy [61, 75], antibiotics effective against
Bb should always be considered in LB-endemic areas before
patients are started on more aggressive therapies.
In addition, several investigators have postulated a causative
or triggering role of Bb in other skin diseases, such as
granuloma annulare, sarcoidosis, panniculitis, and roseolar
erythemas. These concepts were based on few case reports or (not
consistent) serologic data only. Thus, a link between these skin
disorders and Bb infection has not widely been accepted. The
spectrum of cutaneous LB is more restricted than sometimes
suggested.
Etiology and pathogenesis
LB is an intriguing example for a disease in which the clinical
outcome is determined by interactions between a microorganism, its
vector, and the host. Several spirochetal and host factors will be
discussed, which have been demonstrated to be important in the
pathogenesis of LB.
Spirochetal factors
To date, 11 different genospecies have been characterized
within the Bb complex (Bb sensu lato). Only three
genospecies, Bb sensu stricto, B. garinii, and B.
afzelii have been recognized as human pathogens [19]. Strains
found in the U.S.A. are relatively homogeneous and conform to the
definition of Bb sensu stricto [151]. In Europe, all three
genospecies have been found, but most isolates have been B.
afzelii or B. garinii strains [151]. These differences
may account for certain regional variations in the clinical
presentation of the infection, because different clinical
manifestations of LB are correlated with distinct genospecies [121,
148, 152]. Based on various molecular investigations, it has been
demonstrated that B. afzelii is the predominant borrelial
species in EM lesions in Europe, followed by B. garinii, and
Bb sensu stricto, whereas the latter is the agent of EM in
the USA [31, 116, 174]. A comparison of European EM patients with
B. afzelii infection and American patients with EM caused by
Bb sensu stricto [145] has shown that american patients had
significantly more often extracutaneous signs and symptoms, whereas
European patients were more likely to have central clearing of
their EM lesions. Almost all ACA cases are caused by B.
afzelii[78, 121]. In the few BL patients tested so far, B.
afzelii or B. garinii were identified [90, 120].
Conversely, B. garinii appears to be particularly associated
with neuroborreliosis in Europe [78, 116]. Finally, Bb sensu
stricto is the major pathogen in American as well as European
patients with Lyme arthritis [67, 138]. Besides the different
tissue tropisms of the three genospecies, additional differences
concerning e.g. cytokine induction [66] and susceptibility to
complement-mediated lysis [73] may influence their pathogenic
potential.
Host factors
The host’s immune response mounted during LB includes cellular and
humoral components which are involved in both the defense against
Bb and the subsequent pathology, i.e. strong inflammatory
reactions with a prominent perivascular accumulation of mononuclear
leukocytes, and sometimes damage of infected tissues. Although the
severity of symptoms has been correlated with spirochetal load, the
generally low number of spirochetes in infected tissues clearly
contrasts with the strong local inflammatory reaction [e.g. 107].
This may indicate that Bb induces mechanisms that amplify
the inflammatory response. In fact, in vitro and animal
studies have demonstrated that Bb has potent stimulatory
effects on a variety of host cell types, including endothelial
cells, monocytes/macrophages, lymphocytes, and neutrophils,
eliciting proliferation, cytokine-, and chemokine secretion, and
up-regulation of adhesion molecules [e.g. 42, 85, 94, 122, 127].
First examinations have also shown a role of these molecules in the
pathogenesis of human LB. Cytokine analyses in patients with Lyme
arthritis and neuroborreliosis revealed a mainly proinflammatory
response to Bb infection with some antiinflammatory cytokine
expression. High amounts of IFN-γ, TNF-α, IL-1ß, IL-17, TGF-β1, and
IL-6 but little or no IL-4 and IL-10 were produced [e.g. 43, 55,
58, 112, 151, 173]. This phenomenon was more pronounced in earlier
than in late stages of the disease [43]. The only study on
cytokines in DB performed so far [98] examined mRNA expression of
proinflammatory and antiinflammatory cytokines by in situ
hybridization in lesional skin of patients with EM and ACA.
Activation of many cytokines has been found in EM patients with a
predominant expression of IFN-γ and IL-10, whereas ACA patients
expressed mostly TNF-α and IL-4. Collectively, the activation of
proinflammatory cytokines in early LB, particularly IFN-γ, seems to
be important in the control of the spirochetal infection.
Coinfection with other tick-transmitted pathogens
LB patients may be coinfected with a second pathogen, as
Ixodes ticks potentially carry different microorganisms at
the same time. For example, dual infection of ticks with Bb
and Anaplasma phagocytophila (AP), a Gram-negative,
leukocyte-infecting bacterium, has been reported in up to 4% [24].
Infection with AP may be clinically silent or lead to human
granulocytic ehrlichiosis (HGE) [e.g. 24, 118, 149]. Most HGE
patients present with flu-like signs and symptoms, including fever,
rigors, myalgias, arthralgias, headache, malaise, and
lymphadenopathy with acute onset between 1-4 weeks after tick
exposure [e.g. 118]. Those nonspecific clinical features do not
readily allow the differentiation between HGE, extracutaneous
symptoms in early LB, or another tick-bite-associated febrile
illness. HGE appears to be a less severe disease in Europe than in
the U.S.A. [4, 18], where deaths may occur particularly in
immunosuppressed patients, due to severe opportunistic infections
[18]. Other complications of AP infections include
disseminated intravascular coagulation, adult respiratory distress
syndrome, peripheral neuropathies, pancarditis, and rhabdomyolysis
[e.g. 149, 168]. Laboratory tests typically show leukopenia,
thrombocytopenia, and elevations of liver enzymes. Diagnosis of HGE
can be confirmed by culture [52], detection of morulae
(intracellular clumps of AP) within neutrophils on Wright-
or Giemsa-stained peripheral blood smears [4, 18], or PCR on an
acute-phase blood sample. Currently, immunofluorescence antibody
tests are most commonly used as a diagnostic tool [106]. Serologic
studies in patients with various manifestations of LB or
tick-exposed but healthy individuals in endemic areas have found
elevated antibody titers to AP in 4-21% compared to a
maximum of only 4% in blood donors [e.g. 41, 47, 76]. The drug of
choice for HGE patients is doxycycline (200mg once daily) for at
least seven days, which is a great advantage regarding possible
coinfections with AP and Bb, as doxycycline is also
the preferable drug for LB.
Babesiosis is another emerging febrile illness that is caused by
four different species of babesia (Babesia divergens or
Babesia microti, WA1, MO1). Babesia spp. are
intraerythrocytic protozoan parasites that are transmitted by the
same ticks as Bb and AP and cause a malaria-like
illness. In a 4-year prospective study [139], Steere et al.
have found that 2% of 93 EM patients had coinfection with
B. microti in the Northeastern U.S.A. In a German study
[64], IgG reactivity against at least one of the babesial antigens
was detected significantly more often in tick-exposed individuals
(11.5%), including patients with positive LB serology and/or EM,
than in healthy blood donors (1.7%).
Diagnosis
Diagnosis of LB should be based on a thorough history and objective
clinical findings, supported by appropriately chosen laboratory
tests. Early localized LB is best diagnosed by clinical recognition
of the EM skin lesion. Diagnostic tests are not mandatory in case
of classic EM, but should be applied in patients with atypical skin
lesions. However, for all other manifestations of LB, including BL
and ACA, laboratory confirmation of the diagnosis is obligatory. In
clinical practice, analyses of serum IgG and IgM antibodies to
Bb are most often applied, although they are not helpful in
early stages of the disease. Microbiological confirmation of
Bb infection includes cultivation of the spirochete and PCR
detection of its specific DNA, which are very specific but often
not sensitive enough, particularly in extracutaneous manifestations
of LB. Thus, a combination of various diagnostic techniques may be
necessary in a given patient. The histopathologic picture of the
various manifestations of DB is not diagnostic per se, but in most
cases characteristic enough to represent a very helpful adjunct to
the clinical diagnosis, especially in BL and ACA.
Serology
Results of serum anti-Bb IgG and IgM antibody testing must
always be interpreted with caution and in context with the clinical
picture for several reasons. (i) In EM, false-negative results
occur in roughly 50% of patients, particularly in those with
shorter disease duration and/or a single lesion [3, 83, 109, 113,
142], since seroconversion has not taken place at the time of
diagnosis. Only by convalescence, weeks later, antibodies to
Bb are detectable in at least two thirds of patients [3,
102, 109, 113, 131]. In ACA, on the contrary, a significantly
elevated IgG antibody titer is characteristically found in all
patients [10, 11, 156], a positive IgM titer in only 25% [11].
Sensitivity of serologic testing in BL patients is 70-90% [14, 155,
156]. (ii) False positive results may be caused by cross reactions
in patients with other infections (e.g. Epstein-Barr virus
infection or syphilis) or autoimmune diseases (e.g. lupus
erythematosus or rheumatoid arthritis) [e.g. 117, 165].
Seroprevalence in residents of LB endemic areas, due to
asymptomatic infection, ranges from 10-30% [e.g. 23, 39], which
also contributes to false positive results. (iii) Serology results
cannot accurately distinguish between active or past infection.
(iv) Serologic tests have still not been standardized, causing a
poor correlation of results from different assays and laboratories
[56]. Because of the ambiguity of serologic results, a two-tier
protocol, employing a sensitive enzyme-linked immunosorbent assay
(ELISA) as a first step, followed by Western immunoblotting of
ELISA-equivocal or positive specimens should be performed in all
undecided clinical situations [32, 124]. Current guidelines for
interpretation of immunoblot results in the U.S.A. are those
recommended by the Centers for Disease Control and Prevention (CDC)
[32]. In Europe, no generally applicable interpretation criteria
exists so far [124].
Significantly immunogenic and diagnostically relevant antigens
of Bb include proteins of the following molecular weight
(kDa): 17-18 (outer surface protein (Osp) 17), 19 (OspE), 21 (p21),
22-25 (OspC, a very heterogeneous antigen [117]), 26 (OspF), 30
(p30), 31 (OspA), 34-36 (OspB), 37, 39 (borrelia membrane protein
(BmpA) or p39), 41 (flagellin or p41) or a 14kDa internal, non
cross-reactive fragment of the flagellum protein (p41int), 43
(p43), 45 (p45), 58 (p58), 60, 66, 83-100 (p83/100) [e.g. 21, 93,
167]. Humoral immune responses to OspC and flagellin, and to Osp17,
p21, and BmpA, when they occur together with OspC, are
characteristic for early LB. EM sera also often react to OspF and a
37kDa protein in the acute phase and to additional antigens, p58,
p83/100, and to 60- and 66kDa proteins in the convalescence phase
[3]. Sera of late stage LB (e.g. ACA) recognize particularly Osp17,
p21, p30, OspB, BmpA, p43, p45, p58, and p83/100, and also OspA
[21]. A recently tested Bb antigen is the 35-kDa
surface-exposed lipoprotein Variable major protein-like sequence,
expressed (VlsE), which undergoes antigenic variation, an effective
strategy of a microorganism to avoid immune destruction. VlsE
contains two invariable domains and a central variable one that
includes six variable and six invariable regions (IRs), which are
conserved among strains and genospecies of Bb sensu lato
[79]. IR(6), the immunodominant and most conserved one, is a 26mer
peptide that is specific for Bb>90 in neuroborreliosis,
and up to 100% in late-phase LB, including ACA [17, 80]. Thus, this
test may be used rather universally as it detects infections with
all Bb strains at different stages of LB. Also recombinant
whole VlsE was very specific and at least as sensitive as earlier
generation assays in patients with diverse manifestations of LB in
ELISA and Westernblot tests [17].
Serologic follow-up examinations after antibiotic therapy of EM
did not show a consistent pattern of the development of
anti-Bb antibodies. Most authors have demonstrated a decline
of IgM and IgG antibody titers in many of their patients, but the
time until the drop of the titers is variable and unpredictable
[e.g. 11, 46, 57, 82]. IgG as well as IgM titers may persist for
many months to years [3, 46, 69, 82, 131]. On the other hand, many
patients remain seronegative during the whole follow-up period [51,
82]. Finally, antibody titers may also first develop or even rise
during or after therapy [3]. In ACA, antibodies to Bb show a
(trend to) decrease about one year after therapy, but remain
elevated for many years in the majority of patients [11, 13, 63,
82]. Importantly, serologic results do not correlate with the type
of treatment or clinical symptoms after therapy [63, 82]. In
summary, antibody titers are of limited value for the control of
therapy in EM and ACA. In case of persistent positive antibody
titers without attributable clinical manifestations, no further
antibiotic treatment is necessary.
Cultivation of B. burgdorferi
Direct detection of Bb sensu lato from lesional skin by
cultivation in artificial growth media is the only method capable
of demonstrating live spirochetes at the site of infection.
However, isolation is laborious and does not yield timely results.
Furthermore, sensitivity of Bb cultivation from EM skin
biopsies is only 22-79% (average, 40%) due to the paucity of
organisms in clinical specimens [e.g. 29, 77, 109, 113, 119, 174].
The rate of recovery of Bb from skin biopsies of ACA
patients is about the same as in EM patients [119, 166], but
Bb has been less frequently cultivated from BL lesions [90,
166]. The isolation rate of Bb from blood of European EM
patients is low (1-9%) [88, 89, 113]. In the U.S.A., Bb may
be isolated from the blood in 25-50% of EM patients [109, 170]. In
conclusion, cultivation of Bb cannot be recommended as
routine diagnostic method in DB.
Polymerase chain reaction
Detection of Bb-specific DNA by PCR in biopsy samples from
lesional skin has been clearly shown to be the most sensitive,
specific, and quickest diagnostic tool in early and late
manifestations of DB [78]. In direct comparisons, various PCR
assays for EM lesions have yielded sensitivities between 25-79%
(average, 55%) [29, 77, 109, 113, 119, 174] and were thus superior
to culture (22-50% [77, 113, 119, 174]) and serological testing
(31-53% [77, 113]). Success of PCR depends on the type of tissue
conservation; analysis of freshly frozen tissue gives an at least
20% greater sensitivity than that of paraffin-embedded tissue in EM
and ACA [29]. In terms of different PCR assays, Bb appears
to be better detectable using nested OspA instead of flagellin
primers [174]. To date, no standardized protocols exist regarding
DNA-isolation, selection of primers, and PCR-conditions. In recent
studies, quantitative real-time PCR techniques have been applied to
EM skin biopsy samples and have produced sensitivities of 80% and
above [81, 109]. From ACA and BL lesions, Bb-specific DNA
may be amplified by PCR to a similar percentage as in EM [29, 97,
119, 120, 150]. PCR testing of other patient samples, including
blood and urine, is generally less valuable and currently cannot be
recommended for routine diagnosis of DB [77, 113].
Histopathology
The most important finding in EM is a patchy perivascular
mononuclear infiltrate mostly in the superficial but also in the
deeper dermis. The infiltrate is composed predominantly of
lymphocytes and histiocytes with a variable admixture of plasma
cells. In early lesions, a small number of eosinophils may also be
present [37, 163], which can make the differentiation from
unspecific arthropod bite reactions difficult.
There are two histopathologic types of BL, with (follicular
type) or without (diffuse/nodular type) follicular structures
[163]. In the diffuse/nodular type, a dense infiltrate of mature
lymphocytes, lymphoid cells, plasma cells, and sometimes
eosinophils and multinucleated giant cells can be observed,
especially in the upper and mid dermis. In the follicular type, a
dense, nodular infiltrate in the deep dermis forms follicular
structures with germinal centers, which consist of the same cells
(polymorphic lymphoid cells) as in germinal centers of normal
lymphatic tissue, thus imitating secondary lymph node follicles.
The infiltrate between the follicular structures is predominantly
composed of small lymphocytes, plasma cells, some eosinophils, mast
cells, and histiocytes. It should be kept in mind that BL may
histologically simulate cutaneous lymphomas in some cases [53].
ACA is basically characterized by a patchy to band-like
mononuclear infiltrate within the entire dermis [25, 37, 38, 163].
The infiltrate is pronounced in the superficial dermis and
concentrated around blood vessels, which are often dilated, but
also extends between collagen fibers. It is composed of
lymphocytes, histiocytes, and plasma cells in greater numbers than
in EM. With progression of the lesion, the severity of the
infiltrate declines and atrophy of the epidermis with thinning and
loss of rete ridges develops. Another frequent finding in ACA is an
increased number of fibroblasts and fibrosis that begins already
early during the disease. In the late stage, degeneration and
marked reduction of collagen and elastic fibers can be seen.
Elastic fibers are regularly surrounded by macrophages and
multinucleated giant cells with elastophagocytosis, which may
explain the loss of elastic fibers [38].
Therapy (Table II)
( Table II )Antibiotic treatment
has to be performed as quickly as possible in all stages and for
all manifestations of LB. Therapy is most effective early in the
course of the disease. Advanced stages of the illness, in
particular neurologic or rheumatic manifestations are more
difficult to treat and may not respond to antibiotics.
Erythema migrans
EM is clinically self-limited in many cases [12, 156, 161, 162],
but Bb can persist in the skin after spontaneous recovery
from EM [74]. As a consequence, the infection may disseminate and
lead to a late manifestation of LB. Antibacterial treatment must
therefore be performed in any case of clinically definite EM,
regardless whether the diagnosis has been proven microbiologically
and/or serologically, because the response is particularly good
when therapy is administered early after onset [20, 131].
Oral doxycycline (100mg b.i.d.) [20, 35, 36, 84, 92, 101, 108,
131, 140, 143, 172], amoxicillin (500 mg t.i.d.) [35, 83, 92, 131],
and cefuroxime axetil (500 mg b.i.d.) [84, 92, 101] have been shown
to be the first-line antibiotics in controlled studies. Doxycycline
is preferable because of superior penetration into the
cerebrospinal fluid, proven effectiveness in disseminated Bb
infection [36], and additional effectiveness against
Ehrlichia organisms [171]. It is generally well-tolerated
[36], although it may cause photosensitivity [84, 101, 143].
Azithromycin (usually 500 mg b.i.d. on the first day, followed by
500 mg once daily for the next four days) has also been tested in
(smaller) comparative trials and shown to be at least as effective
as doxycycline [20, 140, 143], more effective than phenoxymethyl
penicillin [140, 160], but less effective than amoxicillin [83].
Second-line antibiotics include phenoxymethyl penicillin [22, 27,
105, 136, 157, 159, 160] and minocycline [27, 95, 97]. The
efficiency of those drugs has been demonstrated in studies with a
lesser quality of evidence. Parenteral therapy with ceftriaxone (2
g once daily) should be reserved for disseminated or complicated
infections, where it is highly effective [36, 159]. In children,
doxycycline is relatively contraindicated. Amoxicillin, cefuroxime
axetil, azithromycin, and phenoxymethyl penicillin have all been
shown to be safe and efficient treatments for this age group in
controlled studies [7, 9, 44]. Pregnant women should be treated in
the same way as other patients, except for the use of tetracyclines
[87, 171]. Few studies have investigated the duration of therapy
required to cure EM patients. Whereas some authors believe that a
3-week treatment course is superior to a 2-week course [27],
similar success rates for 2- or 3-week courses of doxycycline or
amoxicillin have been demonstrated in other studies [108, 172]. We
currently recommend treating patients for three weeks in case of
longer disease duration before therapy and/or presence of
extracutaneous symptoms.
The clinical course following appropriate therapy is excellent.
The skin lesion will resolve within 1-4 weeks after initiation of
the antibiotic [7, 83, 110, 131, 135, 143]. Extracutaneous signs
and symptoms are rare, mild to moderate, intermittent, and
associated with more symptomatic illness at the beginning of the
disease [20, 22, 36, 83, 110, 131, 135, 143, 171, 172]. Late
clinical sequelae or persistent complaints during a follow-up
period of 1-8 years occur in a minority of patients only [7, 27,
36, 63, 143]. Persistence of subjective symptoms post treatment,
including fatigue, arthralgias, myalgias, and cognitive
dysfunction, are more often found following advanced stages of LB
than after EM. They are not caused by persistence of Bb and
cannot be influenced by repeated courses of antimicrobial therapy
[72]. The pathological mechanism underlying those chronic symptoms
is unknown.
Table II Treatment of choice for
dermatoborrelioses
|
Manifestation
|
Antibiotic
|
Daily dosage
|
Duration (days)
|
|
Erythema migrans
|
Doxycycline
|
2x100mg
|
14 (-20)
|
|
Amoxicillin
|
3x500mg
|
14 (-20)
|
|
Cefuroxime axetil
|
2x500mg
|
14 (-20)
|
|
Azithromycin
|
2x500mg + 1 x 500mg
|
1 + 4
|
|
Borrelial lymphocytoma
|
Doxycycline
|
2x100mg
|
20(-30)
|
|
Amoxicillin
|
3x500mg
|
20(-30)
|
|
Azithromycin
|
2x500mg + 1x500mg
|
1 + 4
|
|
Acrodermatitis chronica atrophicans
|
Doxycycline
|
2x100mg
|
30
|
|
Ceftriaxone
|
1x2g
|
14(-20)
|
|
Penicillin V
|
3x1500 Mio U
|
14(-20)
|
Borrelial lymphocytoma and acrodermatitis chronica
atrophicans
The optimal therapeutic regimen for BL and ACA has not yet been
determined. At present, patients with BL should be treated with the
same antibiotics as EM (doxycycline, amoxicillin, cefuroxime
axetil, azithromycin, phenoxymethyl penicillin, or ceftriaxone)
[62, 90, 144]. It appears that doxycycline and azithromycin perform
comparably well, whereas phenoxymethyl penicillin may be less
effective than the newer antibiotics [144]. The average time until
clearance of BL after initiation of therapy depends on duration of
the skin lesion and is 4-7 weeks [13, 90, 144, 156], but may expand
up to 40 weeks [90]. The long-term outcome is favorable in all
patients [90]. In some publications, a treatment period of two
weeks has been reported [90, 144]. We and other authors [161]
prefer a 3-4-week course because of the longer pre-treatment
disease duration than in EM.
Regarding ACA, few studies of limited numbers of patients [2,
10, 11, 71, 97, 114, 157] suggest that doxycycline, minocycline,
cefuroxime, cefotaxime, ceftriaxone, and oral or parenteral
penicillin are effective in the treatment of ACA. However, only
inflammatory changes of ACA will resolve within several months,
whereas atrophy, telangiectases, and neuropathy cannot be
influenced by the antibiotic [10, 71, 161]. It seems to be
important to treat patients for an extended period (at least
4 weeks), as persistence of the skin manifestation and
necessity of retreatment was most often seen after 2-3-week therapy
[2].
Prophylaxis
Prevention of tick-borne diseases can best be accomplished by
general methods, such as avoiding tick habitats, wearing of
protective clothing, usage of repellents, and prompt removal of
attached ticks. Two recombinant vaccines have been developed for
use in the U.S.A. based on the surface lipoprotein A (OspA) of
Bb[130, 137]. They have been demonstrated to be safe and
very effective (80-90%) in preventing LB in large,
placebo-controlled trials [130, 137]. One of those was marketed in
1998, but the company pulled it off the market again in 2002. In
Europe, a vaccine is currently being developed.
Antibacterial treatment after a tick bite (chemoprophylaxis) has
been shown to be a promising approach to reduce the risk of
developing LB. In a randomized, double-blind, placebo-controlled
trial [103] of 482 subjects who were given either a single 200
mg dose of doxycycline or placebo within 72 hours after a tick
bite, EM developed significantly less often in the doxycycline
group during a follow-up period of (only) six weeks. The efficacy
was calculated to be 87%. On the contrary, in a meta-analysis of
three earlier comparable clinical trials of a total of
600 patients [154], chemoprophylaxis was not found to have a
significantly superior effect. Therefore, it is not totally clear
whether antimicrobial treatment after a tick bite will prevent LB
effectively. Chemoprophylaxis is currently not recommended as
standard practice for some other reasons [129]. The infection rate
of ticks varies in different geographic areas and from season to
season. The infection rate in humans after a tick bite is
relatively low, and LB (at least in the early stages) is very well
treatable. Finally, costs and adverse effects of antimicrobial
prophylaxis must be considered.
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