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 Lyme Disease

An Evidence-based Approach

2nd Edition
 Lyme Disease
An Evidence-based Approach
2nd Edition

Edited by

John J. Halperin, MD

Overlook Medical Center, New Jersey, USA

and

Sidney Kimmel Medical College at Thomas Jefferson University,

Philadelphia, USA
 CABI is a trading name of CAB International
CABI CABI
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photocopying, recording or otherwise, without the prior permission of the
copyright owners.
A catalogue record for this book is available from the British Library,
London, UK.

Library of Congress Cataloging-in-Publication Data

Names: Halperin, John J., editor. | C.A.B. International, publisher.
Title: Lyme disease : an evidence-based approach / edited by John J. Halperin.
Other titles: Lyme disease (Halperin)
Description: 2nd edition. | Wallingford, Oxfordshire, UK ; Boston, MA : CABI,
[2018] | Includes bibliographical references and index.
Identifiers: LCCN 2017060811 (print) | LCCN 2017061260 (ebook) | ISBN
9781786392084 (pdf) | ISBN 9781786392091 (ePub) | ISBN
9781786392077 (hardback : alk. paper)
Subjects: | MESH: Lyme Disease
Classification: LCC RC155.5 (ebook) | LCC RC155.5 (print) | NLM WC 406 |
DDC 616.9/246--dc23
LC record available at https://lccn.loc.gov/2017060811

ISBN-13: 9781786392077 (hbk)

9781786392084 (PDF)
9781786392091 (ePub)

Commissioning editor: Rachael Russell

Editorial assistant: Alexandra Lainsbury
Production editor: Tim Kapp

Typeset by SPi, Pondicherry, India

Printed and bound in the UK by CPI Group (UK) Ltd, Croydon, CR0 4YY
 Contents

Contributors vii
Preface to First Edition ix
Preface to Second Edition xi

PART I: BIOLOGICAL SUBSTRATE

1 Ticks: The Vectors of Lyme Disease 1

Robert P. Smith

2 Biology of the Lyme Disease Agents: A Selective Survey of Clinical and

Epidemiologic Relevance 29
Alan G. Barbour

3 Borreliella: Interactions with the Host Immune System 45

Kirk Sperber and Raymond J. Dattwyler

4 Diagnostic Testing for Lyme Disease 58

Paul G. Auwaerter

5 Global Epidemiology of Borreliella burgdorferi Infections 76

Paul S. Mead

PART II: CLINICAL ASPECTS

6 Antibiotic Therapy for Infection Caused by Borrelia burgdorferi Sensu Lato 93

Gary P. Wormser

7 Lyme Borreliosis: The European Perspective 105

Franc Strle, Gerold Stanek and Klemen Strle

8 Lyme Neuroborreliosis: A European Perspective 124

Rick Dersch

v
vi Contents

9 Medically Unexplained Symptoms and Lyme Neuroborreliosis – Not the

Same: A Study in an Endemic Area of Norway 139
Erlend Roaldsnes, Randi Eikeland and Dag Berild

10 Erythema Migrans 142

Robert B. Nadelman and Linden Hu

11 Lyme Carditis 168

Jonathan R. Salik and David M. Dudzinski

12 The Musculoskeletal Manifestations of Lyme Disease (Infection with

Borrelia burgdorferi) 180
Leonard H. Sigal

13 Nervous System Involvement 202

John J. Halperin

14 Lyme Disease in Children 216

Eugene D. Shapiro

15 The Psychology of ‘Post-Lyme Disease Syndrome’ and ‘Not Lyme’ 227

Afton L. Hassett and Leonard H. Sigal

16 Chronic Lyme Disease 247

Adriana Marques

17 Lyme Disease: The Great Controversy 262

John J. Halperin, Phillip Baker and Gary P. Wormser

Index 279
 Contributors

Paul G. Auwaerter, MD, MBA, Sherrilyn and Ken Fisher Professor of Medicine, Fisher Center for
Environmental Infectious Diseases, Division of Infectious Diseases, Department of Medicine, Johns
Hopkins University School of Medicine, 725 North Wolfe Street, Rm 231, Baltimore, MD 21205,
USA. E-mail: [email protected]
Phillip J. Baker, PhD, Executive Director, American Lyme Disease Foundation, Lyme, CT 06371,
USA.
Alan G. Barbour, MD, Professor of Medicine, Microbiology and Molecular Genetics, and Ecol-
ogy and Evolutionary Biology, University of California Irvine, Irvine, CA 92697, USA. E-mail:
[email protected]
Dag Berild, MD, PhD, Professor of Infectious Diseases, Department of Infectious Diseases, Oslo
University Hospital, Oslo University and Oslo Metropolitan University, Oslo, Norway. E-mail: dag.
[email protected]
Raymond J. Dattwyler, MD, Professor of Microbiology/Immunology and Medicine, New York
Medical College, Valhalla, NY 10595, USA. E-mail: [email protected]
Rick Dersch, MD, Department of Neurology, Medical Center – University of Freiburg, Breisacher
Str. 64, D-79106, Freiburg, Germany. E-mail: [email protected]
David M. Dudzinski, MD, JD, Director, Cardiac Intensive Care Unit, Division of Cardiology, Massa-
chusetts General Hospital, Boston, MA 02114, USA. E-mail: [email protected]
Randi Eikeland, MD, PhD, Director of the National Advisory Unit for Tick-borne Diseases, Depart-
ment of Neurology, Hospital of Southern Norway, Norway. E-mail: [email protected]
John J. Halperin, MD, Chair, Department of Neurosciences, Overlook Medical Center, 99 Beauvoir
Avenue, Summit, NJ 07902, USA and Professor of Neurology and Medicine, Sidney Kimmel
Medical College of Thomas Jefferson University, Philadelphia, PA, USA. E-mail: john.halperin@
atlantichealth.org
Afton L. Hassett, PsyD, Associate Research Scientist, Chronic Pain and Fatigue Research Center,
Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48106, USA. E-mail:
[email protected]
Linden Hu, MD, Professor and Vice Dean for Research, Tufts University School of Medicine, 136
Harrison Ave, Boston, MA 02111, USA. E-mail: [email protected]
Adriana Marques, MD, Laboratory of Clinical Immunology and Microbiology, National Institute
of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda,
MD 20892, USA. E-mail: [email protected]

vii
viii Contributors

Paul S. Mead, MD, MPH, Bacterial Diseases Branch, Division of Vector-borne Diseases, National
Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention
(CDC), 3156 Rampart Road, Ft Collins, CO 80521, USA. E-mail: [email protected]
Robert B. Nadelman, Professor of Medicine, Department of Medicine, Division of Infectious
Diseases, New York Medical College, Valhalla, NY, USA.
Erlend Roaldsnes, MD, Department of Acute Medicine, Oslo University Hospital, Kirkeveien 166,
0450, Oslo, Norway. E-mail: [email protected]
Jonathan R. Salik, MD, Division of Cardiology, Massachusetts General Hospital, 55 Fruit St,
Boston, MA 02114, USA. E-mail: [email protected]
Eugene D. Shapiro, MD, Professor of Pediatrics, of Epidemiology and of Investigative Medicine,
Yale University, Department of Pediatrics, PO Box 208064, 333 Cedar Street, New Haven, CT
06520-8064, USA. E-mail: [email protected]
Leonard H. Sigal, MD, FACP, FACR, Clinical Professor, Department of Medicine, Division of
Rheumatology, RUTGERS – Robert Wood Johnson Medical School, PO Box 301, Stockbridge, MA
01262, USA. E-mail: [email protected]
Robert P. Smith, MD, MPH, Director, Division of Infectious Disease, Maine Medical Center,
Portland, ME, USA; and Director, Vector-borne Disease Laboratory, Maine Medical Center Re-
search Institute, Portland, ME, USA; and Professor of Medicine, Tufts University School of
Medicine, 81 Research Drive, Scarborough, ME 04074, USA. E-mail: [email protected]
Kirk Sperber, MD, Associate Professor of Medicine, New York Medical College, Valhalla, NY 10595,
USA. E-mail: [email protected]
Gerold Stanek, MD, Professor, Medical University of Vienna, Institute for Hygiene and Applied
Immunology, Kinderspitalgasse 15, 1095 Vienna, Austria.
Franc Strle, MD, PhD, Professor of Infectious Diseases, Department of Infectious Diseases, Univer-
sity Medical Center Ljubljana, Japljeva 2, 1525 Ljubljana, Slovenia. E-mail: [email protected]
Klemen Strle, PhD, Assistant Professor of Medicine, Massachusetts General Hospital/Harvard
Medical School, Room 8301 (CNY149), 55 Fruit St, Boston, MA 02114, USA. E-mail: kstrle@
mgh.harvard.edu
Gary P. Wormser, MD, Chief, Division of Infectious Diseases, Vice Chairman, Department of Medi-
cine, Medical Director and Founder of the Lyme Disease Diagnostic Center, Professor of Medicine,
Microbiology and Immunology, and Pharmacology, New York Medical College, 40 Sunshine Cot-
tage Rd, Valhalla, NY 10595, USA. E-mail: [email protected]
 Preface to First Edition

Spirochetal infections somehow seem to take on larger-than-life roles. ‘The French disease’, a.k.a.
syphilis, assumed almost mythic proportions. Initially brought back from the New World to the
Old, perhaps as divine retribution for measles, smallpox and myriad other curses visited on North
America’s aboriginal populations by European conquerors, neurosyphilis affected so many his-
toric personalities as to give it a legitimate claim as a moulder of history. Even early in the 20th
century, a lack of understanding of the pathophysiology of many other diseases led to the attribu-
tion of all manner of disorders to this infection, often by default, because nobody could come up
with a better explanation.
Early in the history of Lyme disease, many latched on to the syphilis parallel, asserting that this
new spirochetosis, like its cousin, could masquerade as innumerable other ailments. However, the
greatest similarity between the two has been the tendency to inappropriately attribute unrelated, but
otherwise not readily explained, disorders to the unjustly accused spirochete.
The past decade or two has seen medicine move broadly and strongly toward the requirement
for evidence-based support for its conclusions and actions. For those of us over a certain age, al-
though this is certainly intellectually satisfying, it produces a distinct cognitive dissonance. When I
was a resident, the truth was what the professors said and wrote in textbooks. The evidence basis at
best consisted of case series and anecdotal observations. Unfortunately, even the most brilliant
minds, individuals who led medicine for decades, were often proved wrong as new technologies –
imaging, biochemical assays, DNA analysis or whatever – provided more powerful tools to answer
questions.
The Lyme disease ‘debate’ is this tension writ large. On the one hand, there is a group, consisting
largely of family practitioners and other primary care providers, who see large numbers of patients
suffering with medically unexplained symptoms. They struggle (quite legitimately) to understand
the causes of these patients’ suffering, and draw on whatever technologies appear applicable – often
accepting the test results uncritically. They then accept responsibility for treating these patients and
actually try things! This earns them the sincere gratitude of patients who have been struggling both
with chronic disabling symptoms and the inability of mainstream medicine to provide them with
satisfying answers. Patients and treaters then provide each other with strong reinforcement.
In contrast, other physicians, often with more advanced specialty-oriented training, have
adopted the more rigorous, scientific approach. This group looks critically at all efforts to under-
stand, diagnose and treat this disorder, and would rather say ‘I don’t know’ than make assertions
felt not to be based on sound science. They demand that all conclusions, diagnostic approaches
and treatments meet current standards of evidence-based medicine. This culture clash fuels the

ix
x Preface to First Edition

debate – a debate that, if it were based just on scientific evidence, would have disappeared long ago
due to the totally one-sided nature of the observations.
However, the debate has not ended and many physicians in practice continue to see patients
who are convinced that their symptoms are due to a chronic infection with Borrelia burgdorferi.
Not only do these patients fear that they have a chronic, debilitating and difficult-to-treat infec-
tion, but they have been told that this infection will damage their nervous system and lead to inev-
itable irreparable brain damage. These frightened patients often come armed with reams of almost
plausible-sounding material downloaded from the internet, and are only too happy to debate the
contents with their physicians.
The goal of this book is to present the relevant evidence so that practicing physicians can better
understand the arguments being made and use the best information available to help their patients.
The intent is to cover the areas most often identified as ‘controversial’ and to provide perspective,
clarifying the debate. It is the hope of all the authors that this will help calm some of the anxiety
(among both physicians and patients) about this disorder, and allow physicians to provide their pa-
tients with the most appropriate treatment.
Before diving into the substance of the debate, it is essential that I acknowledge those who
have made this work possible. First, I thank the patients who freely share not only their stories but
also their insights and their fears, teaching me daily about the reality of their illnesses. Secondly,
I am grateful to the numerous colleagues – many of whom graciously agreed to contribute to this
volume – who have gone through the ‘Lyme wars’ with me over the years, educating me, debating
with me, together contributing to the maturation of the knowledge base regarding this illness.
Thirdly, I am forever grateful to the mentors of my formative years – the innumerable college and
medical school faculty who taught me the importance of thinking critically and analytically about
complex issues. At the apex of these were the three ultimate exemplars of what my son calls
‘eminence-based medicine’ – Raymond Adams, C. Miller Fisher and E.P. Richardson – three of the
greats of 20th-century neurology, with whom I had the privilege of working. Long before there
was evidence-based medicine, these giants made it crystal clear that truth would be found not in
the pronouncements of the giants but in a meticulous analysis of the data.
I owe a very special thank you to the American Lyme Disease Foundation, which graciously
provided funding to allow the publication of the colour illustrations in this volume. And finally, and
most importantly, I thank my son, for being a never ending source of pride, joy, inquisitiveness and
intellectual rigor, and my wonderful bride of three dozen years – who gamely puts up with my long
hours, battle stories and innumerable imperfections, yet is always there as the supportive anchor of
my universe, making it all possible.

John J. Halperin
 Preface to Second Edition

It has been 7 years since the writing of the first edition of this book – 7 years that have seen signifi-
cant advances in our understanding of the disorders collectively referred to as Lyme disease or
Lyme borreliosis. In this update, each author has built on the solid foundation of the first edition,
incorporating the meaningful advances in the field.
Several major changes deserve emphasis. The first comes from the world of microbiology.
As detailed by Dr Barbour, new members of the borreliosis family have been identified – Borrelia mi-
yamotoi, B. mayonii, B. bavariensis among others. As the family tree has expanded so too has our
knowledge of these spirochetes’ genomes – leading to the introduction of a new genus, Borreliella
(‘Borrelia-like’), subsuming the former Borrelia burgdorferi sensu lato, and distinguishing these from
the relapsing fever-like pathogens, which retain the genus name Borrelia. Like most changes to a
long-established order, this reclassification has not met with universal enthusiasm. In most of this
volume the new names have been adopted. A few remain with the resistance – identifying them will
be left as an exercise for the careful reader.
Diagnostics are improving. The two-tier testing paradigm, so important in standardizing diag-
nostics for more than two decades, may soon be updated, incorporating newer and simpler tests. Our
epidemiology colleagues stirred the pot several years ago when they estimated how many patients are
actually being diagnosed with and treated for Lyme disease in the USA, going beyond the precise case
definitions used for epidemiologic purposes – and, as Dr. Mead discusses, estimating that ten times as
many patients are being treated for Lyme disease as are reported as meeting case definitions. The al-
ternative-fact universe immediately saw this as evidence of a longstanding cover-up. Those who see
patients who have been diagnosed with Lyme disease saw it as evidence of overtesting, overtreatment
(including retreating because the serology is positive after treatment) and of the self-evident fact that
a symptomatic patient in the real world with a positive test would usually prefer to be treated with oral
antibiotics for a likely but not absolutely certain infection. Importantly, evidence continues to accrue
that simple oral antibiotic regimens are effective in most instances – including for most patients with
neuroborreliosis. At the same time, there has been ever more evidence that prolonged treatment con-
fers no added benefit while subjecting patients to considerable risk.
Several different perspectives are provided regarding ‘post-treatment Lyme disease syndrome’
(PTLDS). Whether these non-specific, highly prevalent symptoms are causally related to Lyme dis-
ease, or whether this reflects anchoring bias, remains to be resolved. Regardless, given the wide
prevalence of these symptoms, and their substantial impact on quality of life in individuals experien-
cing them, gaining a better understanding of their pathophysiology clearly remains an important

xi
xii Preface to Second Edition

goal, whether or not they have any relationship to Lyme disease. Importantly, there are now abun-
dant data that this state is not indicative of nervous system infection or inflammation.
One might have hoped that the ‘great controversy’ would have calmed down by now. Sadly, not
so much. Proponents of the ‘Lyme literate’ perspective have become ever more convinced that they
own the correct world view and have become adept at using the explosion of on-line for-profit ‘jour-
nals’ to assert that their conjectures are supported by published medical literature. Given the larger
environment in which we live – where facts, logical reasoning and a solid basis in science are under-
valued at best, it is hard to know how this will play out.
Once again, I am extremely grateful to my colleagues for contributing their time, knowledge and
effort to provide their chapters. I particularly valued our debates over various fine points – I certainly
learned a lot. Several new contributors graciously agreed to join the effort; to them a special thank
you and welcome. Several from the first edition have retired; I wish them all the best.
I must single out Dr. Robert Nadelman for particular thanks, who, despite being severely ill, con-
tributed importantly to the update of Chapter 10 on erythema migrans. Sadly, Dr Nadelman passed
away in March 2018, as this volume was undergoing final preparation. In addition to being an as-
tute clinician and scholarly clinical scientist, Rob was a truly honourable gentleman, and a good
friend. He will be sorely missed.
As with everything we do in medicine and science this volume presents a perspective at a point
in time. I do not pretend that what we describe is carved in stone. Our effort has been to summarize
the best science available today. I’m sure 7 years from now much that is here will remain accurate;
some, undoubtedly will fall by the wayside. Hopefully, more of the former.
As before, I am grateful to my mentors, my colleagues and my students, all of whom inspire a
passion to sort fact from fiction, to advance our understanding of human biology and to help our
patients. A special thank you to my colleagues on the Guideline Development and Dissemination
Committee of the American Academy of Neurology, who continue to teach me about evidence-based
medicine. I am particularly grateful to my patients for sharing their very personal stories and
perspectives.
And most important of all, my undying gratitude to my bride of 43 years, for always putting up
with my long hours and way too many meetings, to my wonderful son and daughter-in-law, and to
the greatest invention ever – my two absolutely delightful grandchildren, who can put a smile on my
face no matter what!

John J. Halperin
 1 Ticks: The Vectors of Lyme Disease

Robert P. Smith1,2
1
Division of Infectious Disease, Maine Medical Center, Portland, ME, USA;
2
Vector-borne Disease Laboratory, Maine Medical Center Research Institute,
Scarborough, ME, USA

1.1 Introduction for the majority of human bites by ticks in the

north-east US (Falco and Fish, 1988; Rand et al.,
Lyme disease, human granulocytic anaplasmosis, 2007) where 10–30% of nymphs and 20–70%
babesiosis and a febrile illness caused by the re- of adult I. scapularis ticks carry Borreliella burg-
lapsing fever group bacterium Borrelia miyamo- dorferi (Feldman et al., 2015). In the south-east
toi are diseases transmitted in temperate zones US, however, juvenile I. scapularis ticks rarely
around the northern hemisphere by Ixodes ticks. parasitize humans (Felz et al., 1996) and, due to
In Eurasia, the same ticks also transmit the viral differences in preferred hosts, are infected with
agents of tick-borne encephalitis, while in North the agent of Lyme disease <2% of the time (Oli-
America they cause infection with a related fla- ver et al., 2003; Rosen et al., 2012). Tick quest-
vivirus known as Powassan virus (lineage 2) or ing behavior in southern sites differs from those
deer tick virus (Telford, 1997; Ebel et al., 2000; in the north-east and Midwest, with the south-
Tavakoli et al., 2009). Most disease transmission ern clade of I. scapularis nymphal ticks questing
to humans in North America and Eurasia is due beneath rather than above the leaf litter (Arsnoe
to bites from four species of ticks (I. scapularis, I. et al., 2015; Ginsberg et al., 2017). As a conse-
pacificus, I. ricinus and I. persulcatus) that are quence of limited human contact and low infec-
grouped in the Ixodes ricinus species complex tion rates, locally acquired Lyme disease in most
(Keirans et al., 1999). southern states is a rare event, despite the wide
These four species serve as bridge vectors of range of the potential vector.
disease from ancient cycles in nature to humans. Lyme disease is transmitted by I. scapularis
They are ‘generalist species’ that during their ticks in the eastern and Midwestern US and
multi-year life cycles feed on diverse hosts that south-central and eastern Canada, and by
may include species of mammals, birds or rep- I. pacificus (western black-legged tick) in the
tiles. Their importance as vectors of human dis- coastal Pacific states. Ixodes ricinus, the castor
ease varies with the disease agent, species of bean or sheep tick, causes Lyme disease in
tick, vertebrate host community, geographic ­Europe and far-western Asia, and I. persulcatus,
­region and local ecologic factors. As an example, the taiga tick, is its vector in eastern Europe and
I. scapularis (the black-legged tick, commonly central Asia (Fig. 1.1). In addition, other species
known as the ‘deer tick’) is present throughout of Ixodes ticks maintain Lyme disease in ‘silent’
the eastern US from Florida to Maine (Dennis ­enzootic cycles but do not serve as a vector of the
et al., 1998; Diuk-Wasser, 2006) and the Mid- disease to humans. For example, in the western
western US from Texas to Minnesota. It accounts US, I. spinipalpis is a vector of enzootic B. burgdorferi

© CAB International 2018. Lyme Disease: An Evidence-based Approach,

Second Edition (ed. J.J. Halperin) 1
 2
I. persulcatus

I. pacificus I. scapularis I. ricinus

R.P. Smith
Fig. 1.1. The geographical distributions of the primary vectors of Lyme borreliosis spirochetes. (Designed by B. Kaye.)
 Ticks: The Vectors of Lyme Disease 3

infection in woodrats in regions where Lyme dis- other tick species, the second includes I. ricinus,
ease is not endemic due to absence of a human and I. scapularis is in a third. The fourth clade
biting (or ‘bridge’) vector (Maupin et al., 1994). consists of two tick species not known to para-
The seabird tick, I. uriae, which is not a member sitize humans. As natural hybridization of I. rici-
of the I. ricinus group, maintains enzootic Borre- nus and I. persulcatus ticks has been reported
liella garinii infection in colonies of puffins, auks from an area in Eurasia where they are sympat-
and kittiwakes in both the northern and south- ric, evolutionary species history may not denote
ern hemisphere (Olsen et al., 1995). But humans absolute reproductive isolation (Kovalev et al.,
are rarely in contact with this tick, and docu- 2016). Other ticks in these clades include several
mented transmission of Lyme disease to humans enzootic vectors that maintain ‘silent cycles’ of
by I. uriae bites has not been reported. Borreliella burgdorferi (i.e. I. minor in the south-
Although these enzootic cycles between ern US), but do not parasitize humans (Xu et al.,
ticks and their hosts are ancient, the emergence 2003). Not all important tick vectors of enzootic
of Lyme disease over the past 50 years in both Borreliella in nature are in the I. ricinus complex.
North America and Europe highlights changes For example, I. hexagonus, a major enzootic vec-
in the range and abundance of these ticks, the tor in Europe, is not closely related to ticks in the
environment we share with them and in the I. ricinus complex. That these vectors are not
activities that put us at risk. Despite great strides monophyletic is evidence that the ability to trans-
in our understanding of these factors, efforts to mit and maintain borrelial spirochetes evolved
control these ticks and to prevent transmission multiple times.
of the diseases they carry have not yet had a Population genetics of North American
major impact when viewed on a large regional I. scapularis ticks indicate a bottleneck occurring
scale. Interventions at the small scale of an indi- at the time of the Pleistocene Ice Age around
vidual lot or neighborhood have had varying 12,000 years ago. As per Humphrey et al. (2010),
success. It is the purpose of this chapter to ‘the mitochondria in both the Midwestern and
review the existing evidence for our current northeastern I. scapularis populations are derived
understanding of the evolution of these vectors, from a single colonizing tick that originated in
their means of dispersal and the reasons for refugia to the south of the ice sheet’. These stud-
range expansion, the mechanisms they use to ies, using 16S mitochondrial DNA, suggest that
transmit disease and the effectiveness of inter- the Midwestern population is younger than the
ventions to bring about their control. northeastern population, and both are more
­recent than southeastern populations, a conclu-
sion also reached by others (Qiu et al., 2002;
Rosenthal and Spielman, 2004). The three tick
1.2 Evolution and Historical populations have distinct haplotype frequencies,
Biogeography of Ixodes Ticks with low genetic variation between the Midwest-
ern and northeastern population and more
Ticks and insects last shared a common ancestor ­diversity present in the older southeastern group
550 million years ago (Douzery et al., 2004). (Humphrey et al., 2010; Gulia-Nuss et al., 2016).
Based on 16SrDNA phylogenies, hard ticks may Spielman et al. (1979) described the north-
have evolved during the radiation of bird taxa ern population or clade of the black-legged or
50–100 million years ago (Black and Piesman, deer tick as a distinct species (i.e. I. dammini)
1994). However, reconstruction of the evolu- based upon differences in nymphal tick mor-
tionary history of these invertebrates is based on phology and questing behavior (with associated
a very limited fossil record (Klompen et al., 1996; differences in human parasitism). Subsequent
de la Fuente, 2003). genetic analyses differed on the separate species
Phylogenetic analyses of existing I. ricinus status of I. dammini, with differences in mito-
complex ticks delineate more recent evolution- chondrial DNA (Rich et al., 1995; Caporale et al.,
ary history. Using 16S ribosomal DNA of 11 spe- 1995; Norris et al., 1996) but not nuclear ribo-
cies, Xu et al. (2003) provided evidence for four somal DNA (Wesson et al., 1993; Norris et al.,
distinct clades within the I. ricinus group. One 1996; McClain et al., 2001) evident between
clade includes I. persulcatus, I. pacificus and four northern and southern populations. After
4 R.P. Smith

assimilation of conflicting evidence, including Unlike I. scapularis, I. ricinus may be maintained

assortative mating studies (Oliver et al., 1993b), in the absence of deer. This tick exists from
I. dammini was relegated as a junior synonym of coastal western Europe and Scandinavia to cen-
I. scapularis (Wesson et al., 1993; Norris et al., tral Asia (50–60° longitude) and south to the
1996; Rosenthal and Spielman, 2004). Whether Atlas Mountains of North Africa (Gern, 2002).
a separate species or not, the vectors of most Habitats encompass moist coniferous forests and
cases of Lyme disease in the northeastern US grasslands as well as temperate deciduous for-
derive from a common post-glacial founding
­ ests (Gern, 2002). The ecological web support-
population (Rosenthal and Spielman, 2004; ing enzootic Lyme disease is also more complex
Humphrey et al., 2010). in Eurasia, with at least three (and probably six)
European colonization of North America separate genospecies of Borreliella causing Lyme
resulted in near extirpation of white-tailed deer disease (Kurtenbach et al., 2002). Only limited
by the end of the 19th century, creating another data exist on the phylogenetics of different popu-
bottleneck for I. scapularis tick populations lations of I. ricinus and I. persulcatus, but one
(­McCabe and McCabe, 1997; Piesman et al., study of I. ricinus populations from throughout
2002). The current emergence of Lyme disease Europe demonstrated homogeneity with no
in the northeastern US parallels the sharp evidence for phylogeographic structure (Casati
increase in deer herd density and range (Spiel- et al., 2008).
man et al., 1993). Only a few remote or isolated It might be postulated that geographic evo-
refugia for deer remained in the northeastern US lutionary patterns in I. scapularis would be
by the early 20th century (Spielman et al., 1993; ­reflected in the pathogen as well, as evidence
McCabe and McCabe, 1997; Piesman et al., suggests that B. burgdorferi sensu strictu (ss),
2002). One such site, Naushon Island, located with the possible exception of one recently intro-
off the coast of Massachusetts, maintained a duced subtype, has been present in North Amer-
deer herd in a private hunting reserve, and ica for many thousands of years (Margos et al.,
­museum collections document I. scapularis ticks 2008; Qiu et al., 2008; Gatewood Hoen et al.,
from areas near this location in the 1920s (Spiel- 2009a; Walter et al., 2017). Reflecting the evo-
man et al., 1993). Although I. scapularis was first lutionary history of its vector, Brisson et al.
described in the US in 1821 (Say, 1821), an (2010) noted a greater degree of overlap of
authoritative review of Ixodes ticks (Cooley and B. burgdorferi ss subtypes within the northeast
Kohls, 1945) listed only 21 records of this tick, and Midwestern tick populations when com-
all in the southern US, while citing a report of pared to subtypes from the southeastern US.
one isolated population in Cape Cod, Massachu- Others (i.e. Gatewood Hoen et al., 2009b; Walter
setts (Piesman et al. 2002). Nineteenth-century et al., 2017) also document ancient phylogenetic
museum specimens of formalin-preserved mice relatedness of northeast and Midwestern US
from this area reveal the presence of B. burgdor- populations of B. burgdorferi ss, with evidence
feri DNA (Marshall et al., 1994). Return of deer of more recent genetic divergence within each
herds, sometimes to overabundance, presuma- of these regions. Geographic distribution of
bly led to the recent expansion of the range of B. burgdorferi ss subtypes suggests independent
I. scapularis in the northern US (Spielman et al., emergence in the northeast and Midwest from
1985, 1993; Piesman et al., 2002). separate relict foci, but with more rapid expan-
In Europe, where the erythema migrans sion of B. burgdorferi ss in the northeast US
rash of Lyme disease was first described nearly a (Gatewood Hoen et al., 2009a). Phylogenetics
century ago, it is unclear if post-Pleistocene pop- and migration rate analyses support ancient
ulation bottlenecks have occurred, as landscape genomic diversity with extensive gene flow of
features have been more stable, as has deer herd B. burgdorferi ss across North America, likely
management (Zonneveld and Foreman, 1990). facilitated by bird dispersal (Walter et al., 2017).
Nevertheless, deer herd densities are reported to A phylogeographic comparison of the diversity
have increased in many areas after World War II, of tick 16S mitochondrial haplotypes of I. scapu-
parallel with increasing abundance of I. ricinus laris in northeast, Midwestern and southeast
in some locations (Matuschka and Spielman, regions did not demonstrate similar patterns of
1986; Rizzoli et al., 2009; Medlock et al., 2013). genetic structure in populations of the vector
 Ticks: The Vectors of Lyme Disease 5

ticks and populations of B. burgdorferi ss mice (Schmidt et al., 1999). Recent blood meal
(Humphrey et al., 2010). Similarly, Walter et al. molecular studies suggest a greater proportion
(2017) found no genetic evidence of a geographic of ticks may feed on non-rodent hosts than earli-
linkage of I. scapularis ticks and B. burgdorferi ss er studies demonstrate (Brisson et al., 2008). It is
populations, consistent with active gene flow unclear if fluctuations in rodent populations (i.e.
between regional bacterial but not tick populations. mice) may also shift tick population host expo-
sure to other mammals or birds, giving rise to
temporal differences in pathogen prevalence in
the same locale (Rand et al., 1998; Schmidt et al.,
1.3 Life Cycles of I. ricinus 1999; Swei et al., 2012). Limited host choice
Complex Ticks may not limit establishment of this tick. On
Monhegan Island, Maine, where most mammal
1.3.1 Vertebrate hosts species including mice are absent, subadult ticks
feeding on Norway rats (and all stages feeding
Although there is great complexity of tick–host on deer) alone maintained the tick population
associations in this group, representing differing until deer were removed from the island (Smith
ecologic communities and species histories, et al., 1993; Rand et al., 2004a).
there are several features common to their life Adult ticks typically feed on medium sized
cycles. They are all ‘three host ticks’ that take a or larger mammals to the exclusion of rodents
blood meal once in each stage or instar (i.e. lar- and birds (Eisen and Lane, 2002). Deer are the
va, nymph, adult) on a vertebrate host before predominant definitive host for I. scapularis,
molting to the next stage (Keirans, 1999). Mated though adult ticks will feed on a variety of mam-
female ticks lay a single mass of eggs (n = 800– mals, including ungulates, black bear, coyotes,
3000) that hatch months later. The entire life raccoons, skunks, opossums, dogs, cats, livestock
cycle typically lasts 2 years for I. scapularis (range and humans (Piesman and Spielman, 1979;
2–4 years) and 3 years for I. pacificus, I. persulca- Fish and Dowler, 1989; Piesman, 2002). Ixodes
tus and I. ricinus (range 2–6) years. Subadult scapularis tick populations are associated with
ticks generally parasitize rodents or small mam- areas with co-existing deer populations (Piesman
mals, birds and reptiles, but will also feed on and Spielman, 1979; Wilson et al., 1985; 1990;
large mammals including deer. There may be Rand et al., 2003; Werden et al., 2014). Adventi-
marked geographical differences in host choice tious importation on birds may lead to occasional
for these subadults, even within a species, de- records of ticks from areas where a tick popula-
pending upon the regional composition of the tion is not established or maintained (Smith et al.,
host community. For example, I. scapularis ticks 1996; Ogden et al., 2008).
in the southeastern US feed preferentially on liz- Ixodes pacificus ticks parasitize over 100 ver-
ards, whereas northern populations feed pre- tebrate species (Castro and Wright, 2007). The
dominantly on small rodents (Piesman and primary hosts for subadult ticks are lizards
Spielman, 1979; Spielman et al., 1985; Oliver (western fence lizard, southern alligator lizard),
et al., 1993a; 2003). This difference in host feed- but many rodent and bird species are also para-
ing results in the marked differences seen in tick sitized (Eisen and Lane, 2002; Eisen et al., 2004;
infection by B. burgdorferi ss, Anaplasma phagocy- Salkeld et al., 2008; Newman et al., 2015). Infes-
tophilum and Babesia microti, all of which are tation of rodents increased, but did not surpass
transmitted by infected rodents – but not reptiles – lizards in more moist habitats such as redwood/
to I. scapularis ticks as they feed. On one island tanoak woodlands (Eisen et al., 2004). Western
site with limited mammalian biodiversity (Nan- gray squirrels are frequently parasitized by this
tucket Island, Massachusetts), Spielman et al. tick in oak woodland habitats (Lane et al., 2005;
concluded that over 90% of larval and nymphal Salkeld et al., 2008). Similar to I. scapularis, the
I. scapularis ticks fed on white-footed mice primary hosts for adult ticks in northern California
(­Spielman et al., 1985; Piesman, 2002). In Dutch- are deer (i.e. black-tailed), though they have been
ess County, New York, however, while white-­footed noted to feed on 29 mammal species (Westrom
mice hosted most larval ticks, eastern chip- et al., 1985; Castro and Wright, 2007). However,
munks hosted threefold more nymphs than unlike the single vector cycle present in the
6 R.P. Smith

northeastern US, sylvatic maintenance of enzo- and red foxes 2%’. A different situation exists in
otic B. burgdorferi in the western states involves the Far East, where 62% feed on cattle and 24%
not only I. pacificus but also I. spinipalpis and per- on red deer (Korenberg et al., 2002). In Japan,
haps I. jellisoni (Brown et al., 2006). Of these mice (Apodemus sp.), voles and shrews, along
three ticks, however, only I. pacificus is consid- with birds, are frequently parasitized by I. persul-
ered a bridge vector, transmitting infection to catus, while adult ticks primarily feed on sika deer
humans. and red foxes (Miyamoto and Matuzawa, 2002).
Life cycles for I. ricinus ticks are more varia- In contrast to I. scapularis and I. ricinus ticks,
ble reflecting the heterogeneity of the ecological only the adult stages of I. persulcatus commonly
situations in which they exist (Balashov, 1972; parasitize humans (Korenburg, 2001).
Gern and Humair, 2002). While they have been To what extent vertebrate host species
reported to feed on over 300 species of mammals diversity determines abundance of these ticks is
and birds, subadult ticks preferentially feed on an area of ongoing controversy. Ixodes scapularis
smaller mammals and birds, while adult ticks abundance may be higher in some environ-
feed on larger mammals such as deer (Gray et al., ments with less mammalian biodiversity, pro-
1992; TäLleklint and Jaenson, 1996). But unlike vided that Peromyscus mice are present (Allan
I. scapularis, deer do not appear to be essential to and Keesing, 2003; Werden et al., 2014). Due to
perpetuation of this tick. In a heavily grazed sheep high larval tick mortality associated with feeding
farming environment with a paucity of other on some hosts (i.e. opossums, squirrels), their
mammals, sheep were the predominant hosts of absence from the host community may increase
all stages of the tick (Ogden et al., 1997). On an tick abundance (Keesing et al., 2009). Increased
island off Sweden lacking large mammals, the feeding on competent reservoir hosts such as
I. ricinus population is maintained almost entirely mice, chipmunks and shrews may lead not only
by feeding on hares (Jaenson and Talleklint, to higher nymphal tick abundance, but to higher
1996). There is evidence of genetic structure of levels of nymphal and adult tick infection with
I. ricinis ticks removed from particular mammal, B. burgdorferi (Logiudice et al., 2003; Brisson et al.,
bird or reptile hosts, suggesting that while these 2008; Keesing et al., 2009; Werden et al., 2014).
I. ricinis ticks feed on many different types of ver- This occurrence is context-dependent however
tebrate hosts, there may be evolution of genetic (Ogden and Tsao, 2009). For example, a compar-
adaptations within this tick species to particular ison of nymphal infection rates in a species-poor
host types (Kempf et al., 2011). island community to a mainland area in Con-
The life history of I. persulcatus, which has a necticut revealed no difference, with higher tick
range in forests from the Far East to the Russian abundance on the mainland site (States et al., 2014).
northwest, is similar in its diversity of hosts to Given the diversity of hosts in any one site,
that of I. ricinus (Balashov, 1972; Grigoryeva and in different ecological settings, comprehen-
and Stanyukovich, 2016). However, while sub- sive field studies to determine host associations
adult I. persulcatus ticks may parasitize up to 50 of these ticks are difficult and may require exam-
species of small animals (Korenberg et al., 2002), ination of many species of mammals and birds.
there is a particular association of this tick with Techniques for identification of prior hosts from
voles (Clethrionomys sp.) and shrews (Sorex sp.) remnant blood in ticks provide a means to quan-
across its range. Subadults may frequently also tify tick feeding history in a particular popula-
feed on chipmunks and red squirrels, and tion, and to link this information to presence of
nymphs often feed on hooved animals (Koren- pathogen infection in the vector (Humair et al.,
berg et al., 2002). Birds are also frequently para- 2007). Using reverse line blots to target host
sitized. Hares are notable because all three stages mitochondrial DNA in ticks, researchers in
will feed on them, sometimes in large numbers Switzerland documented different host expo-
(Korenberg et al., 2002). Adult ticks parasitize sures in different populations of field-collected
most larger mammals, whether wild or domes- I. ricinus on north and south slopes of a single
tic. Korenberg and colleagues note that ‘in the mountain (Cadenas et al., 2007). In an Irish
southern taiga forests of the eastern East Euro- research site, blood meal analysis revealed birds
pean Plain, cattle are parasitized by 52% of to be a major reservoir host for I. ricinus ticks
adult I. persulcatus ticks, hares 34%, elks 4%, (Pichon et al., 2005).
 Ticks: The Vectors of Lyme Disease 7

1.3.2 Questing behavior exhibiting a unimodal pattern of activity peak-

ing after dark (Madden and Madden, 2005). In-
These tick species all quest for hosts from vegeta- terestingly, temperature changes exerted a more
tion, waiting for vibration, heat or other signals predictable response in activity than did daylight
of the presence of a host as it passes (Balashov, (Madden and Madden, 2005).
1972; Eisen and Lane 2002; Tomkins et al.,
2014). This activity leads to a loss of energy and
water, so ticks will descend to resorb water in the 1.3.3 Phenology (seasonal cycle
litter zone as needed. A requirement for Ixodes development)
tick survival is access to microhabitats with high
humidity (>80–85%) at ground level (Stafford, While there are similarities in the life cycles of
1994).To varying degrees, all species of this these ticks, there are differences in tick phenolo-
group have evolved behaviors to limit water loss gy (seasonal cycle development) that have an
and maximize questing success (Balashov, 1972). impact upon transmission of enzootic patho-
Subadults of northern I. scapularis ticks (but not gens. The bimodal seasonal inversion of sub-
southern populations) often quest from the leaf adult stages of northeastern US populations of
litter or from low shrubs and grasses just above I. scapularis, with nymphal population peaks
the ground, while adult ticks often quest 1 m or (May to July) preceding larval peaks (August to
less from the ground in bushes and other forest September), increases infection transmission to
understory (Spielman et al., 1985; Arsnoe et al., hosts prior to larval contact (Spielman et al.,
2015; Ginsberg et al., 2017). Dessication stress 1985; Daniels et al., 1989). Regardless of the
is the proposed reason that southern subadult time of feeding, female I. scapularis ticks produce
I. scapularis ticks quest below the leaf litter (Gins- eggs in late spring leading to larval appearance
berg et al., 2017). Questing behavior for I. pacifi- in late summer (Yuval and Spielman, 1990).
cus ticks in northwest California is similar to that Based on field studies using confined ticks in
described for northern populations of I. scapula- their natural microhabitats, survival of different
ris (Lane et al., 2007). But unlike I. scapularis stages of unfed ticks could be determined, and
ticks, whose host seeking behavior varies with progression to the next developmental stage
temperature and relative humidity (Clark, 1995; could be timed in fed ticks (Yuval and Spielmen,
Vail and Smith, 1998; 2002), no such relation- 1990). Adult I. scapularis ticks survived the win-
ship has been observed in the diurnal behavior ter, whether fed or not, but did not survive the
of I. pacificus nymphs (Lane et al., 2007). Prior following summer. Larvae that feed in September
experimental studies of adult I. pacificus, however, overwinter as nymphs, while later feeders over-
have documented a positive association between winter as larvae. Unfed larvae survive less than
questing activity and relative humidity, and 1 year. Fed nymphs molt to adults that appear
lower nymph densities at mean daily tempera- in late autumn. Unfed nymphs may survive
tures >23°C (Loye and Lane, 1988; Eisen et al., through two seasons, so that annual cohorts
2002). Similarly, questing by I. ricinus primarily overlap (Yuval and Spielman, 1990). All stages
depends upon relative humidity and solar radia- of fed I. scapularis may enter diapause (dormancy),
tion (Jensen, 2000). Questing behavior, and but only larvae and adults appear to survive the
locomotor activities to move to a new site, may be winter.
decreased in dessicating environments (Balashov, This phenology is less evident in I. ricinus
1972). Computer-assisted video tracking of I. rici- populations, however, though bimodal popula-
nus ticks to measure locomotor activity under tion peaks (spring and autumn) are observed.
controlled climactic conditions documented Eggs laid before mid-July may hatch in August,
regulation of this activity by water saturation but many do not hatch until the following spring
deficit (Perret et al., 2003). Locomotor activity (i.e. (Gray, 1981; 1991). Randolph et al. (2002)
movement from one site to another) was primar- developed a quantitative framework for seasonal
ily nocturnal, serving also to reduce water loss. population dynamics of I. ricinus ticks that pre-
A similarly designed study of I. scapularis activi- dicted tick demographic processes using a tem-
ty revealed diurnal locomotor activity only for perature-dependent model and measurements
autumn adults, with spring adults and nymphs of tick fat content. This framework is consistent
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