1424 PART 5 Infectious Diseases

would be positive. The results of current GlpQ-based assays cannot be

used to differentiate between different Borrelia species as to etiology.

■ DIFFERENTIAL DIAGNOSIS

Depending on the patient’s history of residential, occupational, travel,

and recreational exposures, the differential diagnosis of relapsing

fever includes one or more of the following infections that feature

either periodicity in the fever pattern or an extended single febrile

period with nonspecific constitutional symptoms: Colorado tick fever,

Rocky Mountain spotted fever and other rickettsioses, ehrlichiosis,

anaplasmosis, tick-borne viral infection, rat bite fever, and babesiosis

in North America, Europe, Russia, and northeastern Asia. Elsewhere

in the Americas and Asia and in most of Africa, malaria, typhoid fever,

typhus and other rickettsioses, dengue, and leptospirosis may also be

considered. There may be co-infections of malaria, typhus, or typhoid

with TBRF or LBRF. B. miyamotoi infection may coexist with Lyme

disease, anaplasmosis, or babesiosis in North America.

TREATMENT

Relapsing Fever

Penicillin and tetracyclines have been the antibiotics of choice

for relapsing fever for several decades. Erythromycin and chloramphenicol have been long-standing alternative choices. There

is no evidence of acquired resistance to these antibiotics. Borrelia

species are also susceptible to second- and third-generation cephalosporins. These spirochetes are also relatively resistant to rifampin, sulfonamides, and aminoglycosides. Spirochetes are no longer

detectable in the blood within a few hours after the first dose of an

effective antibiotic.

Under conditions of limited resources or in the midst of an

epidemic, a single dose of antibiotic usually suffices for successful

treatment of LBRF (Fig. 185-3). For adults, a single dose of oral

tetracycline (500 mg), oral doxycycline (200 mg), or intramuscular penicillin G procaine (800,000 units) is effective. The corresponding doses for children are oral tetracycline at 12.5 mg/kg,

oral doxycycline at 5 mg/kg, and intramuscular penicillin G procaine at 200,000–400,000 units. When an adult patient is stuporous

or nauseated, the intravenous dose of tetracycline is 250–500 mg.

Tetracyclines are contraindicated in pregnant and nursing women

and in children <9 years old; for individuals in these groups who are

allergic to penicillin, oral erythromycin (500 mg for adults and 12.5

mg/kg for children) is an alternative. While there is little reported

experience with other macrolides, such as azithromycin, these are

likely to be as effective as erythromycin.

But there are shortcomings of single-dose therapies for LBRF.

With penicillin alone, recurrence may occur in up to 20% of

patients, and the frequency of JHR was higher after tetracycline

than penicillin. For treatment of LBRF in adults in Ethiopia, a

regimen that reduces rates of both recurrence and JHR has been a

single dose of 400,000 units of intramuscular penicillin G procaine

FIGURE 185-2 Photomicrograph of tick-borne relapsing fever spirochete (Borrelia

turicatae) in a Giemsa-Wright–stained thin blood smear. Included in the figure are a

polymorphonuclear leukocyte and two platelets.

Oral

therapy

Sequential

therapy

Intravenous ceftriaxone 2 g qd

or Na penicillin G, 5 million U

q6h for 14 days

First choice

 Age ≥9 years, not pregnant:

 doxcycline, 100 mg bid

 Age <9 years: erythromycin,

 12.5 mg/kg per day

Second choice

 Age ≥9 years, not pregnant:

 tetracycline 500 mg qid

Third choice

 Age ≥9 years: erythromycin,

 500 mg qid

Duration: 10 days

First choice

 Single dose of penicillin G procaine IM

 800,000 U adults

 200,000–400,000 U children

 then (4–12 h later)

 Age ≥9 years, not pregnant

 doxycycline, 100 mg bid or

 tetracycline 500 mg qid

 Age <9 years or pregnant

 erythromycin, 12.5 mg/kg per day

 or 500 mg qid

Duration: 7 days

Second choice (penicillin allergy):

 erythromycin, 500 mg qid ≥9 years

 or 12.5 mg/kg/ per day <9 years

Duration: 7 days

Meningitis/encephalitis

Tick-borne relapsing fever Louse-borne relapsing fever

FIGURE 185-3 Algorithm for treatment of relapsing fever. If it is not known whether the patient has tick-borne or louse-borne relapsing fever, the patient should be treated

for the tick-borne form. The dashed line indicates that central nervous system invasion in louse-borne relapsing fever is uncommon.

1425CHAPTER 186 Lyme Borreliosis

followed several hours later or the next day by doxycycline (100 mg

orally twice daily) or tetracycline (500 mg or 12.5 mg/kg orally

every 6 h) for 7 days.

The accumulated anecdotal reports on TBRF therapy indicate a

recurrence rate of ≥20% after single-dose treatment, plausibly due

to the propensity of some tick-borne species to invade the CNS.

Accordingly, multiple antibiotic doses are recommended. The preferred treatment for adults is a 10-day course of doxycycline (100 mg

twice daily) or tetracycline (500 mg or 12.5 mg/kg orally every 6 h).

When tetracyclines are contraindicated, the alternative is erythromycin (500 mg or 12.5 mg/kg orally every 6 h) for 10 days. If

a β-lactam antibiotic is given and CNS involvement is confirmed

or suspected, it is preferably administered intravenously rather

than orally. For adults, the regimen is penicillin G (5 million units

IV every 6 h) or ceftriaxone (2 g IV daily) for 10–14 days. Under

conditions of limited resources or when CNS involvement is not

suspected, oral penicillin V potassium (500 mg or 12.5 mg/kg every

6–8 h) for 10 days is used.

The JHR during treatment of relapsing fever can be severe and

may end in death if precautions are not in place for close monitoring for at least 24 h and with provision of parenteral cardiovascular

and volume support as needed. Apprehension, rigors, fever, and

hypotension occur within 1–3 h of initiation of antibiotic treatment

and may be accompanied by a further decrease in the platelet count.

The incidence of the JHR is 20–60% in LBRF after the first antibiotic dose. JHR may also be encountered when a patient with unsuspected relapsing fever is treated with other types of antibiotics, such

ciprofloxacin, that have suboptimal effects.

Experience with the treatment of B. miyamotoi infection is limited, but this organism likely has the same antibiotic susceptibilities

as other Borrelia species. Therapy for B. miyamotoi disease follows

the guidelines for Lyme disease. This would include parenteral

therapy for CNS involvement. In absence of contraindications,

doxycycline (100 mg twice daily) is the preferred choice for uncomplicated B. miyamotoi infection, because of the antibiotic’s efficacy

for anaplasmosis and Lyme disease. If JHR occurs, it is generally

milder than is observed in relapsing fever.

■ PROGNOSIS

The mortality rates for untreated LBRF and TBRF are in the ranges

of 10–70% and 4–10%, respectively, and are largely determined by

coexisting conditions, such as malnutrition, dehydration, or another

infection. With prompt antibiotic treatment, the mortality rate is 2–5%

for LBRF and <2% for TBRF. Features associated with a poor prognosis include concurrence with malaria, typhus, or typhoid; pregnancy;

stupor or coma on admission; diffuse bleeding; poor liver function;

myocarditis; and bronchopneumonia. The mortality rate from the

JHR in LBRF, in the absence of adequate monitoring and resuscitation

measures, is ~5%. Relapsing fever during pregnancy frequently leads

to abortion or stillbirth, but congenital malformations have not been

reported. Although spirochetes or their remnants may persist in the

CNS or other sequestered sites after bacteremia has resolved, posttreatment sequelae and prolonged disability have not been not documented

for relapsing fever or B. miyamotoi disease. Partial immunity against

reinfection seems to develop in residents of areas with perennial elevated risk.

■ PREVENTION

There is no vaccine for LBRF, TBRF, or B. miyamotoi disease. Reduction

of exposure to lice and ticks is the key strategy for prevention. LBRF

can be prevented through improved personal hygiene, reduction of

crowding, better access to hot water (≥60° C) for clothes washing, and

selected use of pesticides. Clothing is an important factor in maintaining the human body louse. The risk of TBRF can be reduced by construction of houses with concrete or sealed plank floors and without

thatched roofs or mud walls. Houses and cabins in forested areas pose

a risk in western North America when rodents nest in the roof, attic,

or wall spaces or under the structure. Buildings infested with Ornithodoros ticks can be treated with pesticides and then rodent-proofed.

If residing in a high-risk environment, individuals should not sleep on

the floor, and beds should be moved away from the wall. Individuals

with recreational or occupational exposure to caves, where mammals,

including bats, may reside, merit advice about the risk of TBRF. Following exposure at a site of TBRF risk, treatment with doxycycline (either

a single dose of 100 mg or 200 mg on day 1 followed by 100 mg/d for

4 days) was efficacious in preventing infection in a placebo-controlled

trial. Recommendations for preventing B. miyamotoi infection follow

those for reducing risk of Lyme disease from exposure to the vector

hard ticks (Chap. 186).

■ FURTHER READING

Barbour AG, Schwan TG: Borrelia, in Bergey’s Manual of Systematics

of Archaea and Bacteria. WB Whitman et al (eds). John Wiley & Sons,

Inc., 2018, pp 1-22.

Binenbaum Y et al: Single dose of doxycycline for the prevention of

tick-borne relapsing fever. Clin Infect Dis 71:1768, 2020.

Butler T: The Jarisch-Herxheimer reaction after antibiotic treatment

of spirochetal infections: A review of recent cases and our understanding of pathogenesis. Am J Trop Med Hyg 96:46, 2017.

Christensen J et al: Tickborne relapsing fever, Bitterroot Valley,

Montana, USA. Emerg Infect Dis 21:217, 2015.

Gugliotta JL et al: Meningoencephalitis from Borrelia miyamotoi in

an immunocompromised patient. N Engl J Med 368:240, 2013.

Isenring E et al: Infectious disease profiles of Syrian and Eritrean

migrants presenting in Europe: A systematic review. Travel Med

Infect Dis 25:65, 2018.

Krause PJ et al: Borrelia miyamotoi infection in nature and in humans.

Clin Microbiol Infect 21:631, 2015.

Moran-Gilad J et al: Postexposure prophylaxis of tick-borne relapsing fever: Lessons learned from recent outbreaks in Israel. Vector

Borne Zoonotic Dis 13:791, 2013.

Nordmann T et al: Outbreak of louse-borne relapsing fever among

urban dwellers in Arsi Zone, Central Ethiopia, from July to November

2016. Am J Trop Med Hyg 98:1599, 2018.

Salih SY, Mustafa D: Louse-borne relapsing fever: II. Combined

penicillin and tetracycline therapy in 160 Sudanese patients. Trans R

Soc Trop Med Hyg 71:49, 1977.

Schwan TG et al: Tick-borne relapsing fever and Borrelia hermsii,

Los Angeles County, California, USA. Emerg Infect Dis 15:1026, 2009.

Telford SR et al: Blood smears have poor sensitivity for confirming

Borrelia miyamotoi disease. J Clin Microbiol 57:e01468, 2019.

von Both U, Alberer M: Images in clinical medicine. Borrelia recurrentis infection. N Engl J Med 375:e5, 2016.

Warrell DA: Louse-borne relapsing fever (Borrelia recurrentis infection). Epidemiol Infect 147:e106, 2019.

Wormser GP et al: Borrelia miyamotoi: An emerging tick-borne

pathogen. Am J Med 132:136, 2019.

■ DEFINITION

Lyme borreliosis is caused by a spirochete, Borrelia (also called Borreliella) burgdorferi sensu lato, that is transmitted by ticks of the Ixodes

ricinus complex. The infection usually begins with a characteristic

expanding skin lesion, erythema migrans (EM; stage 1, localized infection). After several days or weeks, the spirochete may spread to many

different sites (stage 2, disseminated infection). Possible manifestations

of disseminated infection include secondary annular skin lesions,

meningitis, cranial neuritis, radiculoneuritis, peripheral neuritis, carditis, atrioventricular nodal block, or migratory musculoskeletal pain.

186 Lyme Borreliosis

Allen C. Steere

1426 PART 5 Infectious Diseases

Months or years later (usually after periods of latent infection), intermittent or persistent arthritis, chronic encephalopathy or polyneuropathy, or acrodermatitis may develop (stage 3, persistent infection). Most

patients experience early symptoms of the illness during the summer,

but the infection may not become symptomatic until it progresses to

stage 2 or 3.

Lyme disease was recognized as a separate entity in 1976 because

of a geographic cluster of children in Lyme, Connecticut, who were

thought to have juvenile rheumatoid arthritis. It became apparent

that Lyme disease was a multisystemic illness that affected primarily

the skin, nervous system, heart, and joints. Epidemiologic studies of

patients with EM implicated certain Ixodes ticks as vectors of the disease. Early in the twentieth century, EM had been described in Europe

and attributed to I. ricinus tick bites. In 1982, a previously unrecognized spirochete, now called Borrelia burgdorferi, was recovered from

Ixodes scapularis ticks and then from patients with Lyme disease. The

entity is now called Lyme disease or Lyme borreliosis.

■ ETIOLOGIC AGENT

B. burgdorferi, the causative agent of Lyme disease, is a fastidious

microaerophilic bacterium. The spirochete’s genome is quite

small (~1.5 Mb) and consists of a highly unusual linear chromosome of 950 kb as well as 17–21 linear and circular plasmids. The most

remarkable aspect of the B. burgdorferi genome is that there are

sequences for more than 100 known or predicted lipoproteins—a larger

number than in any other organism. The spirochete has few proteins

with biosynthetic activity and depends on its host for most of its nutritional requirements. It has no sequences for recognizable toxins.

Currently, 20 closely related borrelial species are collectively referred

to as B. burgdorferi sensu lato (i.e., “B. burgdorferi in the general

sense”). The human infection Lyme borreliosis is caused primarily by

three pathogenic genospecies: B. burgdorferi sensu stricto (“B. burgdorferi in the strict sense,” hereafter referred to simply as B. burgdorferi),

Borrelia garinii, and Borrelia afzelii. B. burgdorferi is the major cause

of the infection in the United States; all three genospecies are found in

Europe, and B. garinii is the major cause in Asia.

Strains of B. burgdorferi have been subdivided according to several

typing schemes: one based on sequence variation of outer-surface

protein C (OspC), a second based on differences in the 16S–23S rRNA

intergenic spacer region (RST or IGS), and a third called multilocus

sequence typing. From these typing systems, it is apparent that strains of

B. burgdorferi differ in pathogenicity. OspC type A (RST1) strains seem

to be particularly virulent and may have played a role in the emergence

of Lyme disease in epidemic form in the northeastern United States in

the late twentieth century.

■ EPIDEMIOLOGY

The 20 known genospecies of B. burgdorferi sensu lato live in nature

in enzootic cycles involving 14 species of ticks that are part of the I.

ricinus complex. I. scapularis (Fig. 461-1) is the principal vector in

the eastern United States from Maine to Georgia and in the midwestern states of Wisconsin, Minnesota, and Michigan. I. pacificus is the

vector in the western states of California and Oregon. The disease

is acquired throughout Europe (from Ireland and Great Britain to

Scandinavia to European Russia), where I. ricinus is the vector, and

in Asian Russia, China, and Japan, where I. persulcatus is the vector.

These ticks may transmit other agents as well. In the United States, I.

scapularis also transmits Babesia microti; Anaplasma phagocytophilum;

Ehrlichia species Wisconsin; Borrelia miyamotoi; Borrelia mayonii; and,

in rare instances, Powassan encephalitis virus (the deer tick virus) (see

“Differential Diagnosis,” below). In Europe and Asia, I. ricinus and I.

persulcatus also transmit tick-borne encephalitis virus.

Ticks of the I. ricinus complex have larval, nymphal, and adult

stages. They require a blood meal at each stage. The risk of infection

in a given area depends largely on the density of these ticks as well as

their feeding habits and animal hosts, which have evolved differently in

different locations. For I. scapularis in the northeastern United States,

the white-footed mouse and certain other rodents are the preferred

hosts of the immature larvae and nymphs. It is critical that both of the

tick’s immature stages feed on the same host because the life cycle of the

spirochete depends on horizontal transmission: in early summer from

infected nymphs to mice and in late summer from infected mice to

larvae, which then molt to become the infected nymphs that will begin

the cycle again the following year. It is the tiny nymphal tick that is

primarily responsible for transmission of the disease to humans, which

peaks during the early summer months. White-tailed deer, which are

not involved in the life cycle of the spirochete, are the preferred host

for the adult stage of I. scapularis and seem to be critical to the tick’s

survival.

Lyme disease is now the most common vector-borne infection in the

United States and Europe. Since surveillance was begun by the Centers

for Disease Control and Prevention (CDC) in 1982, the number of

cases in the United States has increased dramatically. More than 30,000

new cases are now reported each summer, but the actual number of

new cases is probably closer to 300,000 annually. In Europe, reported

frequencies of the disease are highest in the middle of the continent

and in Scandinavia.

■ PATHOGENESIS AND IMMUNITY

To maintain its complex enzootic cycle, B. burgdorferi must adapt to

two markedly different environments: the tick and the mammalian

host. The spirochete expresses outer-surface protein A (OspA) in the

midgut of the tick, whereas OspC is upregulated as the organism travels

to the tick’s salivary gland. There, OspC binds a tick salivary-gland protein (Salp15), which is required for infection of the mammalian host.

The tick usually must be attached for at least 24 h for transmission of

B. burgdorferi.

After injection into the human skin, the spirochete downregulates

OspC and upregulates the VlsE lipoprotein. This protein undergoes

extensive antigenic variation, which is necessary for spirochetal survival. After several days to weeks, B. burgdorferi may migrate outward

in the skin, producing EM, and may spread hematogenously or in

the lymph to other organs. The only known virulence factors of B.

burgdorferi are surface proteins that allow the spirochete to attach to

mammalian proteins, integrins, glycosaminoglycans, or glycoproteins.

For example, spread through the skin and other tissue matrices may be

facilitated by the binding of human plasminogen and its activators to

the surface of the spirochete. Some Borrelia strains bind complement

regulator–acquiring surface proteins (FHL-1/reconectin, or factor H),

which help to protect spirochetes from complement-mediated lysis.

Dissemination of the organism in the blood is facilitated by binding to

the fibrinogen receptor (αIIbβ3

) on activated platelets and the vitronectin

receptor (αv

β3

) on endothelial cells. As the name indicates, spirochetal

decorin-binding proteins A and B bind decorin, a glycosaminoglycan

on collagen fibrils, and B. burgdorferi also binds directly to native type

1 collagen lattices. This binding may explain why the organism is commonly aligned with collagen fibrils in the extracellular matrix in the

heart, nervous system, or joints.

To control and eradicate B. burgdorferi, the host mounts both

innate and adaptive immune responses, resulting in macrophage- and

antibody-mediated killing of the spirochete. As part of the innate

immune response, complement may lyse the spirochete in the skin.

Cells at affected sites release potent proinflammatory cytokines,

including interleukin 6, tumor necrosis factor α, interleukin 1β, and

interferon γ (IFN-γ). Patients who are homozygous for a Toll-like

receptor 1 polymorphism (1805GG), particularly when infected with

highly inflammatory B. burgdorferi RST1 strains, have exceptionally

high levels of proinflammatory cytokines. The purpose of the adaptive

immune response appears to be the production of specific antibodies,

which opsonize the organism—a step necessary for optimal spirochetal

killing. Studies with protein arrays expressing ~1200 B. burgdorferi

proteins detected antibody responses to a total of 120 spirochetal

proteins (particularly outer-surface lipoproteins) in a population of

patients with Lyme arthritis. Histologic examination of all affected

tissues reveals an infiltration of lymphocytes, macrophages, and plasma

cells with some degree of vascular damage, including mild vasculitis

1427CHAPTER 186 Lyme Borreliosis

or hypervascular occlusion. These findings suggest that the spirochete

may have been present in or around blood vessels.

In enzootic infection, B. burgdorferi spirochetes must survive this

immune assault only during the summer months before returning

to larval ticks to begin the cycle again the following year. In contrast,

infection of humans is a dead-end event for the spirochete. Within several weeks or months, innate and adaptive immune mechanisms—even

without antibiotic treatment—control widely disseminated infection,

and generalized systemic symptoms wane. However, without antibiotic

therapy, spirochetes may survive in localized niches for several more

years. For example, B. burgdorferi infection in the United States may

cause persistent arthritis or, in rare cases, subtle encephalopathy or

polyneuropathy. Thus, immune mechanisms seem to succeed eventually in the near or total eradication of B. burgdorferi from selected

niches, including the joints or nervous system, and symptoms resolve

in most patients.

■ CLINICAL MANIFESTATIONS

Early Infection: Stage 1 (Localized Infection) Because of the

small size of nymphal ixodid ticks, most patients do not remember

the preceding tick bite. After an incubation period of 3–32 days, EM

usually begins as a red macule or papule at the site of the tick bite that

expands slowly to form a large annular lesion (Fig. 186-1). As the

lesion increases in size, it often develops a bright red outer border and

partial central clearing. The center of the lesion sometimes becomes

intensely erythematous and indurated, vesicular, or necrotic. In other

instances, the expanding lesion remains an even, intense red; several

red rings are found within an outside ring; or the central area turns

blue before the lesion clears. Although EM can be located anywhere,

the thigh, groin, and axilla are particularly common sites. The lesion

is warm but not often painful. Approximately 20% of patients do not

exhibit this characteristic skin manifestation.

Early Infection: Stage 2 (Disseminated Infection) In cases

in the United States, B. burgdorferi often spreads hematogenously to

many sites within days or weeks after the onset of EM. In these cases,

patients may develop secondary annular skin lesions similar in appearance to the initial lesion. Skin involvement is commonly accompanied

by severe headache, mild stiffness of the neck, fever, chills, migratory

musculoskeletal pain, arthralgias, and profound malaise and fatigue.

Less common manifestations include generalized lymphadenopathy or

splenomegaly, hepatitis, sore throat, nonproductive cough, conjunctivitis, iritis, or testicular swelling. Except for fatigue and lethargy, which

are often constant, the early signs and symptoms of Lyme disease are

typically intermittent and changing. Even in untreated patients, the

early symptoms usually become less severe or disappear within several

weeks. In ~15% of patients, the infection presents with these nonspecific systemic symptoms.

Symptoms suggestive of meningeal irritation may develop early in

Lyme disease when EM is present but usually are not associated with

cerebrospinal fluid (CSF) pleocytosis or an objective neurologic deficit.

After several weeks or months, ~15% of untreated patients develop

frank neurologic abnormalities, including meningitis, subtle encephalitic signs, cranial neuritis (including bilateral facial palsy), motor

or sensory radiculoneuropathy, peripheral neuropathy, mononeuritis

multiplex, cerebellar ataxia, or myelitis—alone or in various combinations. In children, the optic nerve may be affected because of inflammation or increased intracranial pressure, and these effects may lead to

blindness. In the United States, the usual pattern consists of fluctuating

symptoms of meningitis accompanied by facial palsy and peripheral

radiculoneuropathy. Lymphocytic pleocytosis (~100 cells/μL) is found

in CSF, often along with elevated protein levels and normal or slightly

low glucose concentrations. In Europe and Asia, the first neurologic

sign is characteristically radicular pain, which is followed by the

development of CSF pleocytosis (meningopolyneuritis or Bannwarth’s

syndrome); meningeal or encephalitic signs are frequently absent.

These early neurologic abnormalities usually resolve completely within

months, but in rare cases, chronic neurologic disease may occur later.

Within several weeks after the onset of illness, ~8% of patients

develop cardiac involvement. The most common abnormality is a

fluctuating degree of atrioventricular block (first-degree, Wenckebach,

or complete heart block). Some patients have more diffuse cardiac

involvement, including electrocardiographic changes indicative of

acute myopericarditis, left ventricular dysfunction evident on radionuclide scans, or (in rare cases) cardiomegaly or fatal pancarditis. Cardiac

involvement lasts for only a few weeks in most patients but may recur

in untreated patients. A few cases of mitral or aortic valve endocarditis

have been reported, in one case occurring years after acute cardiac

involvement of Lyme disease. Chronic cardiomyopathy caused by B.

burgdorferi has been reported in Europe.

During this stage, musculoskeletal pain is common. The typical

pattern consists of migratory pain in joints, tendons, bursae, muscles,

or bones (usually without joint swelling) lasting for hours or days and

affecting one or two locations at a time.

Late Infection: Stage 3 (Persistent Infection) Months after

the onset of infection, ~60% of patients in the United States who have

received no antibiotic treatment develop frank arthritis. The typical

pattern comprises intermittent attacks of oligoarticular arthritis in

large joints (especially the knees), lasting for weeks or months in

a given joint. A few small joints or periarticular sites also may be

affected, primarily during early attacks. The number of patients who

continue to have recurrent attacks decreases each year. However, in

a small percentage of cases, involvement of large joints—usually one

or both knees—is persistent and may lead to erosion of cartilage and

bone.

White cell counts in joint fluid range from 500 to 110,000/μL (average, 25,000/μL); most of these cells are polymorphonuclear leukocytes.

Tests for rheumatoid factor or antinuclear antibodies usually give

negative results. Examination of synovial biopsy samples reveals fibrin

deposits, villous hypertrophy, vascular proliferation, microangiopathic

lesions, and a heavy infiltration of lymphocytes and plasma cells.

Although most patients with Lyme arthritis respond well to antibiotic therapy, a small percentage in the northeastern United States

have persistent postinfectious (also called postantibiotic or antibioticrefractory) Lyme arthritis for months or even for several years after

receiving oral and IV antibiotic therapy for 2 or 3 months. Although

more often these patients are initially infected with OspA type A (RST1)

strains of B. burgdorferi, this complication is not thought to result from

persistent infection. Results of culture and polymerase chain reaction

(PCR) for B. burgdorferi in synovial tissue obtained in the postantibiotic

period have been uniformly negative. Rather, the basic pathogenetic feature of postinfectious Lyme arthritis is the development of an excessive,

dysregulated proinflammatory immune response during the infection,

characterized by exceptionally high IFN-γ levels, which persists in the

postinfectious period. Risk factors for excessively high IFN-γ responses

FIGURE 186-1 A classic erythema migrans lesion (9 cm in diameter) is shown near

the right axilla. The lesion has partial central clearing, a bright red outer border, and

a target center. (Courtesy of Vijay K. Sikand, MD; with permission.)

1428 PART 5 Infectious Diseases

include presentation of an epitope of B. burgdorferi OspA (OspA164-175)

by certain class II major histocompatibility complex molecules (particularly HLA-DRBI*

0401); a Toll-like receptor 1 polymorphism 1805GG

in patients who were infected with OspC type A (RST1) B. burgdorferi

strains; and an imbalance of the CD4+ T effector/regulatory cell ratio in

which the majority of CD4+CD25+ T cells, which are ordinarily regulatory T cells, become IFN-γ-secreting T effector cells.

The consequences of this excessive proinflammatory response in

Lyme synovia include vascular damage, autoimmune and cytotoxic

processes, and tumor-like fibroblast proliferation and fibrosis. An

important driver of innate immune responses may be persistence of B.

burgdorferi peptidoglycan in synovial fluid, which may be especially

difficult to clear. In addition, four autoantigens that are targets of T

and B cell responses in patients with Lyme disease, particularly those

with postinfectious arthritis, have now been identified: endothelial cell

growth factor, matrix metalloproteinase-10, apolipoprotein B-100, and

annexin A2, which may have a role in persistent inflammation.

Although rare, chronic neurologic involvement also may become

apparent from months to several years after the onset of infection,

sometimes after long periods of latent infection. The most common

form of chronic central nervous system involvement is subtle encephalopathy affecting memory, mood, or sleep, and the most common

form of peripheral neuropathy is an axonal polyneuropathy manifested as either distal paresthesia or spinal radicular pain. Patients with

encephalopathy frequently have evidence of memory impairment in

neuropsychological tests and abnormal results in CSF analyses. In cases

of polyneuropathy, electromyography generally shows extensive abnormalities of proximal and distal nerve segments. Encephalomyelitis or

leukoencephalitis, a rare manifestation of Lyme borreliosis associated

primarily with B. garinii infection in Europe, is a severe neurologic disorder that may include spastic paraparesis, upper motor neuron bladder dysfunction, and, rarely, lesions in the periventricular white matter.

Acrodermatitis chronica atrophicans, the late skin manifestation of

Lyme borreliosis, has been associated primarily with B. afzelii infection

in Europe and Asia. It has been observed especially often in elderly

women. The skin lesions, which are usually found on the acral surface

of an arm or leg, begin insidiously with reddish-violaceous discoloration; they become sclerotic or atrophic over a period of years.

The basic patterns of Lyme borreliosis are similar worldwide, but

there are regional variations, primarily between the illness found in

North America, which is caused exclusively by B. burgdorferi, and that

found in Europe, which is caused primarily by B. afzelii and B. garinii.

With each of the Borrelia species, the infection usually begins with

EM. However, B. burgdorferi strains in the eastern United States often

disseminate widely; they are particularly arthritogenic, and especially

OspC type A (RST1) strains may cause postinfectious arthritis. B.

garinii typically disseminates less widely, but it is especially neurotropic

and may cause borrelial encephalomyelitis. B. afzelii often infects only

the skin but may persist in that site, where it may cause several different

dermatoborrelioses, including acrodermatitis chronica atrophicans.

Post-Lyme Syndrome (Chronic Lyme Disease) Despite resolution of the objective manifestations of the infection with antibiotic

therapy, ~10% of patients (although the reported percentages vary

widely) continue to have subjective pain, neurocognitive manifestations, or fatigue symptoms. These symptoms usually improve and

resolve within months but may last for years. At the far end of the

spectrum, the symptoms may be similar to or indistinguishable from

chronic fatigue syndrome (Chap. 450) and fibromyalgia (Chap. 373).

Compared with symptoms of active Lyme disease, post-Lyme symptoms tend to be more generalized or disabling. They include marked

fatigue, severe headache, diffuse musculoskeletal pain, multiple symmetric tender points in characteristic locations, pain and stiffness in

many joints, diffuse paresthesias, difficulty with concentration, and

sleep disturbances. Patients with this condition lack evidence of joint

inflammation, have normal neurologic test results, and may exhibit

anxiety and depression. In contrast, late manifestations of Lyme disease, including arthritis, encephalopathy, and neuropathy, are usually

associated with minimal systemic symptoms. Currently, no evidence

indicates that persistent subjective symptoms after recommended

courses of antibiotic therapy are caused by active infection.

■ DIAGNOSIS

The culture of B. burgdorferi in Barbour-Stoenner-Kelly (BSK) medium

permits definitive diagnosis, but this method has been used primarily

in research studies. Moreover, with a few exceptions, positive cultures

have been obtained only early in the illness—particularly from biopsy

samples of EM skin lesions, less often from plasma samples, and occasionally from CSF samples. Later in the infection, PCR is greatly superior to culture for the detection of B. burgdorferi DNA in joint fluid;

this is the major use for PCR testing in Lyme disease. However, because

B. burgdorferi DNA may persist for at least weeks after spirochetal killing with antibiotics, detection of spirochetal DNA in joint fluid is not

an accurate test of active joint infection in Lyme disease and cannot

be used reliably to determine the adequacy of antibiotic therapy. The

sensitivity of PCR determinations in CSF from patients with neuroborreliosis has been much lower than that in joint fluid. With current

methods, there seems to be little if any role for PCR in the detection of

B. burgdorferi DNA in blood or urine samples, although this is an area

of active research. A potential drawback is that PCR must be carefully

controlled to prevent contamination.

Because of the problems associated with direct detection of B.

burgdorferi, Lyme disease is usually diagnosed by the recognition of a

characteristic clinical picture accompanied by serologic confirmation.

Although serologic testing may yield negative results during the first

several weeks of infection, almost all patients have a positive antibody

response to B. burgdorferi after that time when a two-test approach of

enzyme-linked immunosorbent assay (ELISA) and Western blot or a

protocol of two enzyme immunoassays (EIAs) is used. The limitation

of serologic tests is that they do not clearly distinguish between active

and inactive infection. After antibiotic therapy, the amount of antibody declines but the results of Western blot, a nonquantitative test,

do not change much (or very slowly). Thus, patients with previous

Lyme disease—particularly in cases progressing to late stages—often

remain seropositive for years, even after adequate antibiotic therapy.

In addition, ~10% of patients are seropositive because of asymptomatic infection. If individuals with past or asymptomatic B. burgdorferi

infection subsequently develop another illness, the positive serologic

test for Lyme disease may cause diagnostic confusion. According

to an algorithm published by the American College of Physicians

(Table 186-1), serologic testing for Lyme disease is recommended only

for patients with at least an intermediate pretest probability of Lyme

disease, such as those with oligoarticular arthritis. It should not be used

as a screening procedure in patients with pain or fatigue syndromes.

In such patients, the probability of a false-positive serologic result is

higher than that of a true-positive result.

For serologic analysis of Lyme disease in the United States, the CDC

recommends a two-step approach in which samples are first tested by

ELISA, and equivocal or positive results are then tested by Western

blot. This is called the conventional two-test approach. During the

first weeks of infection, both IgM and IgG responses to the spirochete

should be determined, preferably in both acute- and convalescentphase serum samples. Approximately 20–30% of patients have a

TABLE 186-1 Algorithm for Testing for and Treating Lyme Disease

PRETEST PROBABILITY EXAMPLE RECOMMENDATION

High Patients with erythema

migrans

Empirical antibiotic

treatment without

serologic testing

Intermediate Patients with

oligoarticular arthritis

Serologic testing and

antibiotic treatment if test

results are positive

Low Patients with nonspecific

symptoms (myalgias,

arthralgias, fatigue)

Neither serologic testing

nor antibiotic treatment

Source: Adapted from the recommendations of the American College of Physicians

(G Nichol et al: Ann Intern Med 128:37, 1998).