Fall and rise of Lyme disease and other Ixodes

tick-borne infections in North America and

Europe

Alan G Barbour

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Departments of Medicine and Microbiology & Molecular Genetics, University of California, Irvine,
California, USA

Lyme disease is a spirochaetal infection with acute and chronic manifestations.

Lyme disease and other infections transmitted by Ixodes species ticks are
increasing in temperate and Holarctic regions of the Northern hemisphere.
These zoonotic infections are most commonly acquired in suburban residential
areas and outdoor recreation areas close to cities. Different enzootic cycles,
which include a variety of large and small mammals as well as migratory birds,
maintain and distribute in nature the Borrelia species that cause Lyme disease.
The rise in cases of Lyme disease and the other Ixodes tick-borne infections is, in
part, the consequence of reforestation and the increase in deer populations in
developed countries.

What we now call 'Lyme disease' or 'Lyme borreliosis' was first

described earlier this century in Europe under a variety of other names,
such as 'erythema chronicum migrans' (ECM) or 'Bannwarth's
syndrome'1"4. Few practitioners now, even in Europe, use these other
terms, so complete and widespread has been ascendancy of a name that
stems from a town in the northeastern US. Ironically, the 17th century
founders of Lyme, Connecticut, originally took for their village the name
of an English seaside town.
The story of Lyme disease terminology is also a metaphor for the
evolution of the infection. At first this disease appeared to be restricted to
Europe; the first Americans reported to have ECM acquired their
infections in Europe and not in the US5. Later, Steere and colleagues
Correspondence to described the infection so comprehensively to leave little doubt that, if this
Dr Alan G Barbour,
Department of
disorder had occurred in North America previously, it had escaped the
Microbiology S general notice of generations of physicians3. After the aetiological agent of
Molecular Genetcs, B240 Lyme disease was discovered, first in the US and soon after in Europe,
Medical Sciences I, comparison of the isolates suggested that the infection had recently been
University of California
Irvine, Irvine
imported to North America from Europe6. More recent studies, however,
CA 92697-4025, USA indicate these organisms have been long established on both continents7"9.

British Medical Bulletin 1998,54 (No 3) 647-658 CThe Bntsh Council 1998
Resurgent/emergent infectious diseases

Whatever its geographical origins, Lyme disease is at present the most

common vector-borne disease in Europe and the US2-3. In the US,
approximately 10 000 cases are officially reported annually; the actual
incidence is likely to be 5 times as many10. Trailing Lyme disease in
numbers but transmitted by the same, or similar, ticks are the infections
erhrlichiosis, babesiosis, and viral encephalitis. While Lyme disease
rarely, if ever, is fatal, cumulative morbidity from untreated infection has
been considerable. Contributing to the popular concern about Lyme

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disease is the fact that the usual victims of the infection are suburban in
residence and middle class or higher in socio-economic status2111"15.
Although some of the increased incidence of Lyme disease can be
attributed to recent migrations of humans into previously uninhabited
areas, a more important factor has been a different kind of change in the
landscape: the return to forests of lands formerly used for agriculture or
industry2'16.

Biology
The cause of Lyme disease is a spirochaete in the genus Borrelta6.
Borreha species shuttle between an arthropod vector, which is usually a
tick, and a mammalian or avian reservoir. The other major human
disease caused by Borreha species spirochaetes is relapsing fever. For

Table 1 Vectors of Lyme disease Borreha species (underlined) and related species

Tick Distribution Borrelia spp

Ixodes nc/nus*,# Western & central Europe afzelit. burgdorfen. garinn.

valalsiana, group DN127
/. scapulans*,# Eastern & central US & Canada burgdorfen. qroup DN127
1. paaficus'.tt Far-western US & Canada burgdorfen. group DN127
1. persulcatus*,# Far-eastern Europe S Asia afzshl. garfniL miyamotoi
1 unae North 4 South Atlantic gannn
1 hexagonus Western & central Europe afzelii. burgdorfen
1. minor Southeastern US burgdorfen
1. affims* Southeastern US burgdorferi
1 dentatus Northeastern US anderzonii. burgdorfen
1 spimpalpis Western US Group DN127
1 ovatus Japan japonlca
1. granulatus China ahshi
1. tanuki Japan tanukll
1. turdus Japan turdae
1 mpponensis* Korea aizsiil gannn. valaisiana
Haemaphysalis spp. China gannn

•Member of the Ixodes nanui complex of species

•Frequent vectors of Lyme disease Borrelia species to humans

648 British Medical Bulletin 1998,54 (No 3)

 Fall and rise of Lyme disease

Deer and other

large mammals
*

Not infected *'

Tick eggs < Adult ticks ^

Ixodes ticks that frequently

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feed on humans in suburban
and rural areas o Humans
Q.

Larval ticks Nymphal ticks *

Infected

' Rodents, other small

^ mammals, and birds

Nymphal ticks Larval ticks

Infected
3
o Ixodes ticks that rarely
feed on humans I1
Adult ticks -»• Tick eggs

Fig. 1 This diagram shows the life cycles of Ixodes species ticks that frequently or rarely
bite humans (Table 1) and the reservoir animals for Lyme disease Borrelia species that they
may have in common 'Infected' means that in the change from the one stage to another
the infection is acquired, passed on, or is lost. For instance, larval ticks acquire the
infection after feeding on infected reservoir mammals or birds, but infected adult ticks do
not pass the infection on to their progeny through the eggs. Humans are inadvertent
hosts and not critical for maintaining the ticks in nature On the other hand, the small
mammals, bird, and a large mammal, usually a deer, are critical.

most Borrelia spp. humans are inadvertent hosts and transmission dead-
ends for the infecting spirochaete population. This means that to
understand the epidemiology of this infectious agent we need to know
its epizootology, that is, what happens in nature among animals.
Species of Borrelia that cause Lyme disease have been found in a variety
of ticks (Table I)9-17"24. With the exception of two species of Haema-
physalis in China, the tick vectors of these Borrelia spp. are in the genus
Ixodes, a type of hard ticks. Table 1 lists several different types of Ixodes

Bntah Medical Bulletin 1998,54 (No 3) 649

Resurgent/emergent infectious diseases

ticks. Only those of the I. rianus complex of ticks are known to transmit
the infection to humans. The vector species in this complex are I. ricinus
(sheep tick), /. scapulans (deer or black-legged tick), I. paaficus (western
black-legged tick), and /. persulcatus (taiga tick). The other species listed
in Table 1 seldom bite people. Yet species, such as /. uriae, I. hexagonus,
and /. spinipalpis, are important for maintaining the Lyme disease agents
in nature by transmitting the Borrelta spp. among animals and by carrying
them from one location to another (Fig. 1). For example, I. uriae ticks are

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the Borrelia vectors for a cycle involving seabirds that migrate north and
south between subarctic and subantarctic regions23.
The types of Borrelia presently known to cause Lyme disease are
classified into three species: B. burgdorferi, which occurs in North
America and western Europe; B. afzelii, which occurs in western and
central Europe and parts of Russia; and B. garinii, which occurs in
Europe, across Russia, and in northern Asia16-17*24-15. These Borrelia
species can be found in more than one Ixodes species (Table 1). For
instance, I. ricinus ticks have been found to carry at least four different
species, sometimes two or more at a time. Table 1 also lists species of
Borrelta, such as B. andersontt in North America, B. valatsiana in
Europe, and B. japonica in Asia, that are not established disease agents
for humans20-26"28. This is because they are associated mainly with ticks
that rarely feed on humans or because they are inherently non-infectious
or non-virulent for people. Some Borrelia strains, such as DN127 and
similar isolates, have not been given a separate species name yet.
The geographic areas providing a risk for Lyme disease can be
predicted by understanding the tick vectors, the hosts for the ticks, and
the reservoir for the spirochaetes2'16'17'25. I. ricinus complex ticks
proliferate and survive between temperatures of -10°C and +35°C, and
then only tolerate the extremes for short periods. The relative humidity
in the atmosphere should be 80% or greater, and the soil should be near-
saturated with water. These ticks flourish in areas with forests and damp
soil covered by a dense layer of undergrowth. They also do well in moist
bushy and tall grassy areas that border forested lands.
One of the characteristics of ticks that transmit Lyme disease to
humans is that they feed on a variety of hosts, including large and small
mammals, birds, and reptiles (Fig. \)1W7<15. In general, the immature
stages of larva and nymph feed on small mammals, ground feeding
birds, and lizards29. The adults usually feed on large or medium-sized
mammals and, less frequently, on birds. Some ticks are closely associated
with only one type of host by reason of anatomy, physiology, or
behaviour. But /. ricinus complex ticks are less discriminating in their
tastes. The 'preferred' hosts may be those animals that are both
abundant in the area and not very efficient at grooming themselves.

650 British Medical Bulletin 1998,54 (No 3)

 Fall and rise of Lyme disease

There are numerous actual or potential reservoirs for Lyme disease

Borrelia spp. and closely related species (Table l)17.18-^.29-^. Indeed, this
group of Borrelia spp. is notable for its wide host range, which includes
a variety of small mammals and birds, but not reptiles. Most other
Borrelia spp. have more limited host ranges6. The ability of Lyme disease
Borrelia spp. to infect so many types of animals may explain in part its
current success in adapting to local and global environmental changes.
For the /. rictnus complex ticks to be maintained within an area and

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to spread to new areas, they need large free roaming animals as hosts. In
most areas of the world where Lyme disease is common, deer serve this
role33"35. Deer themselves are not suitable reservoirs for maintaining the
spirochaete in nature, but by providing the adult ticks with a meal, a
necessity before reproduction can occur, the presence of deer in an area
assures a new generation of ticks (Fig. 1).

Evolution
The increase of Lyme disease in North America has paralleled the
explosive growth of deer populations on that continent over the last
several decades2. The Lyme disease agent and vectors had probably been
present in North America when the first European settlers arrived but,
through hunting and clearing of the forests for agriculture and industry,
the numbers of deer and the ticks that parasitized were drastically
reduced. Forests and woodlots have return to regions of North America
and Europe where high technology parks and residential areas have
replaced farms and smokestack factories. Contributing to the increase in
deer herds in developed countries in the North has been an absence of
significant predators, other than the sports hunter.
The reduction of deer and their ticks in the northestern US probably
produced an evolutionary bottleneck for B. burgdorferi in that region.
Whereas other parts of North America, such as southern and the far-
western US, have B. burgdorferi strains of several different genetic types,
the strains of B. burgdorferi in /. scapularis ticks of New York,
Connecticut, and nearby states are more limited in diversity9. When deer
and tick populations increased again, the B. burgdorferi strains that
proliferated represented a few clones or a single clone. Curiously, B.
burgdorferi isolates of Europe have been found to be no more
genetically diverse than those of the northeastern US, a finding that
contrasts with the greater genetic variety noted among B. azelii and B.
garinii isolates of Europe and Asia8. If B. burgdorferi was imported from
North America to Europe, it was more than a century ago; museum

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Resurgent/emergent infectious diseases

specimens of European ticks from 1884 revealed the presence of both B.

garinii and B. burgdorfert7.

Pathogenesis and clinical manifestations of Lyme disease

Infection almost always begins with a tick bite36-37. Maternal-fetal trans-

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mission is rare among humans, and transmission by oral, faecal,
respiratory, urinary, or sexual routes or by fomites does not occur. The
biting ticks for humans are usually in the nymphal stage of their life
cycle (Fig. 1). Infected adult ticks also bite humans but this stage is less
important as a vector for humans38. For one thing, adults are more easily
detectable than the tiny nymphs. Moreover, in geographic areas far
enough north to have four seasons, the adults tend to feed in the Spring
and Fall when fewer people are active outdoors2'16'17*25.
In highly endemic areas, up to 70-80% of the ticks are infected with
B. burgdorfert or other species2'16'17"25. For the first 24-48 hours of
feeding, the spirochaetes already present in the tick's intestine remain
dormant39. As the intestine fills more with blood, the spirochaetes begin
to multiply and migrate through the intestinal wall into the body fluid
that bathes the internal organs. From there, the spirochaetes move to the
salivary glands of the ticks. With multiplication and this passage, the
predominant surface antigens change from one pair of lipoproteins,
OspA and OspB, to a single abundant lipoprotein, OspC40.
The spirochaetes enter the skin with the tick's saliva. Dissemination
through the skin or blood may occur a few days later3. It is possible that
spirochaetes also disseminate via lymph channels or peripheral nerves.
Whatever the route, the bacteria can be found in experimental animals
and in infected humans at sites distant from the tick bite within days to
weeks of the start of the infection. The infection can be roughly divided
as three stages: early localized; early disseminated; and late (Table 2).
At the tick bite, the majority of infected humans have erythema migrans,
the flat, nonpainful erythema often with central clearing or concentric ring
pattern1-41. This is early localized infection and may be accompanied by
mild constitutional symptoms or lymphadenopathy. As the spirochaetes
move peripherally, the rash expands over several days to a few weeks to
diameters of several centimeters. At one time, this localized skin rash was
considered synonymous with Lyme disease, but similar or identical rashes
can occur in the absence of B. burgdorferi transmission42. Another sign of
early localized infection in Europe, but not in North America, is a benign
lymphocytoma of ear lobe or nipple1. In Europe, the initial region of
invasion of the skin may become a chronic inflammatory condition
known as acrodermatitis chronicum atrophicans1.

652 Bntisb Medical Bulletin 1998,54 (No 3)

 Fall and rise of Lyme disease

Table 2 Clinical stages and manifestations of Lyme disease

Period Time from Manifestations Treatment

onset duration

Early localized 1-8 weeks Solitary erythema migrans 7-21 days

Regional lymphadenopathy
Lymphocytoma
Mild constitutional symptoms

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Early disseminated 3-26 weeks Multiple erythema migrans 14-30 days
Cranial neuritis
Memngoencephalitis
Radicuhtis
Polyarthritis
Cardttis

Late S 6-12 months Oligoarticular arthritis 21-60 days

Acrodermatitis chronicum atrophicans
Meningoencephalrtis
Peripheral neuropathy

Organs and tissues likely to be seeded with B. burgdorferi during

dissemination are the following: (i) the heart; (ii) large joints, such as the
knee; (iii) the peripheral and central nervous system; and (iv) distant
parts of the skin3-4-41. More likely than not, the affected limb in a case of
neuropathy or arthritis will be the same limb bitten by the tick.
Oligoarticular arthritis with frank joint swelling appears to be more
common with B. burgdorferi than with other species of Lyme disease
agents. On the other hand, certain strains of B. garinii are frequently
represented among isolates from the cerebrospinal fluid, and B. afzelii is
more likely to be confined to the skin than the other two species4344.
Spirochaetes have been few in number in whatever tissue they have been
found2-41. For instance, at the height of the blood infection, the number of
spirochaetes in a milliliter of blood is about 1000. Pathologists examining
histological preparations with a silver stain, such as Warthin Starry, or
immunofluorescence, may have to search many fields to find an organism
in the heart or skin. A consequence of this low bacterial burden and slow
progression is an infectious disease with low fever, low mortality, and a
course measured in weeks to years rather than days.
Spirochaetes express OspC during the early phase of the infection in
humans and experimental animals. IgM antibodies to OspC appear
beginning about 2 weeks after the start of infection45. Selection by the
immune systems of countless reservoir animals likely accounts for the
considerable strain-to-strain differences in OspC sequences and
epitopes. OspA, which is expressed within the tick and seldom if ever
within mice, shows less sequence variability between strains46.

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Resurgent/emergent infectious diseases

The surface proteins of the spirochaetes during late or latent infection

are not known but may be related to variable antigens of relapsing fever
Borrelia spp.47. The bacteria are even fewer in number than during acute
infection. The inflammation that occurs in a knee or patch of
acrodermatitis chronicum atrophicans is out of proportion to the numbers
of organisms present13. While some investigators have proposed a
predominantly intracellular location for the spirochaetes during late or
latent infection, the bulk of experimental evidence indicates that while the

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spirochaetes may be sequestered in immunologically protected locations,
such as brain and eye, the majority, if not all, remain extracellular6.
When infections are localized, oral antibiotics for 2—4 weeks are
sufficient to cure almost all patients2'3. After dissemination has occurred,
treatment is more difficult. The neurotropism and slow growth of the
Lyme disease Borrelia spp. mean that treatment with antibiotics that
penetrate the central nervous system and for durations of a few weeks
are needed. Successful therapy with pMactam antibiotics of these
infections is another indication that intracellular localization is not a
prominent feature of the pathogenesis of this infection.

Other emerging tickborne infections

The same Ixodes ticks that transmit Lyme disease to humans are vectors
for at least three other infectious agents: Ehrltchia phagocytophila,
Babesia microti, and tickborne encephalitis (TBE) virus. The same
factors in the increase in Lyme disease, that is, reforestation and growth
of deer populations, also explain changes in the incidence of infections
caused by these microorganisms14'16*31148. Co-infections with two or more
of these organisms are not uncommon in people living in or visiting the
endemic areas12'49*50.
Ehrlichiae are obligate intracellular Gram-negative bacteria related to
rickettsiae51. Only recently have the human pathogens been cultivated in
the laboratory. There are several different species of Ehrhchia. Represen-
tatives are found on different continents and associated with different
types of reservoir animals. In North America, E. phagocytophila, which is
transmitted by I. scapularis and /. pacificus ticks, causes human
granulocytic ehrlichiosis. The reservoir is the field mouse, Peromyscus
leucopus, that harbours B. burgdorferi. Human granulocytic ehrlichiosis is
suspected to also occur in Europe52. Two other ehrlichial diseases of
humans are human monocytic ehrlichiosis, which is caused by E.
chaffeensis and transmitted by other types of ticks in central and southern
US, and Sennetsu fever, which is caused by E. sennetsu in Japan and has

654 British Medical Bulletin 1998,54 (No 3)

 Fall and rise of Lyme disease

an as yet indecipherable transmission cycle. Features distinguishing

human granulocytic and monocytic ehrlichiosis from Lyme disease are
higher body temperature, leukopenia, and thrombocytopenia.
TBE is a spring-summer encephalitis caused by a flavivirus in the
temperate and sub-arctic regions of Eurasia14"53. It is one of the few
arboviral infections transmitted to humans by ticks, in this case /.
ricinus, I. persulcatus, and possibly /. ovatus. A TBE-like virus has
recently been identified in North America, where this type of tickborne

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infection had not been frequently observed54.
Babesiosis resembles malaria in many aspects55. The piroplasms that
cause babesiosis are intraerythrocytic parasites. Infected individuals have
fever and haemolytic anaemia. Those without spleens have more severe
courses and may die of the complications of acute infection. There are
many different species of Babesia, and the distribution of these infections
is worldwide. B. microti in North America and B. divergens in Europe are
the commonest agents of babesiosis for humans. The reservoirs for both
Babesia species are rodents. The vectors are /. scapularis for B. microti
and I. ricinus for B. divergens. Unlike ehrlichiosis, which usually is a
shortlived infection if the patient survives, babesiosis can cause a
persistent infection and may, in endemic areas, be another infectious risk
of blood transfusion.

Prevention
Lyme disease and the other infections are one of the costs we bear for
living close to nature and for the 're-greening' of parts of Europe and
North America2'16. These diseases are not spread from person-to-person
and, thus, can be prevented by avoiding exposure to ticks, or by taking
personal precautions against tick bites when in an endemic area. For
instance, a resident of New York City or Vienna has a very low to
nonexistent risk of getting Lyme disease, babesiosis, ehrlichiosis, or TBE.
If they go to the New Jersey seashore or the Vienna Woods, repellents can
be sprayed and light-coloured trousers and a long-sleeved shirt can be
worn. A nightly check for ticks can further reduce the odds of getting ill.
However, the suburban environment for the vector ticks means that
exposure may be unavoidable for those who on a daily basis work
outdoors or hve in the area2-16'56. Reduction of deer and tick populations
can be achieved but the current strategies for this, such as deer eradication
or community pesticide use, are not socially acceptable to one
constituency or another33'35'57'58. A vaccine has been available to prevent
TBE, and a recombinant vaccine based on the OspA protein59 has just
completed successful human trials in the US59-60.

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Resurgent/emergent infectious diseases

Acknowledgements
My laboratory's research on Lyme disease is supported by National
Institutes of Health grants AI24424 and AI37248.1 thank Guy Baranton
and Durland Fish for their helpful advice.

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