Lyme Disease (Lyme Borreliosis) Due to Borrelia burgdorferi

Revised November, 2019

Causative Organism

The agents of Lyme borreliosis belong to the eubacterial phylum of spirochetes, which are vigorously motile, corkscrew-shaped bacteria. The spirochete cell wall consists of a cytoplasmic membrane surrounded by peptidoglycan and flagella and then by a loosely associated outer membrane ( Fig. 241.1 ). Of the Borrelia spp., B. burgdorferi is the longest (20–30 µm) and narrowest (0.2–0.3 µm), and it has fewer flagella (7–11). The complete genome of B. burgdorferi has been sequenced. B. burgdorferi strains have a small, linear chromosome (≈950 kilobases) and 17 to 21 linear and circular plasmids, which comprise about 40% of its DNA.

The remarkable aspect of the B. burgdorferi genome is the large number of sequences for predicted and known lipoproteins, including the plasmid-encoded outer-surface proteins (Osp) A through F. These and other differentially expressed outer-surface proteins presumably help the spirochete adapt to, survive in, and persist in markedly different arthropod and mammalian environments. In addition, during the disseminated phase of the infection, another surface-exposed lipoprotein, called VlsE, undergoes extensive antigenic variation. The organism has few proteins with biosynthetic activity and apparently depends on the host for much of its nutritional requirements. The genome contains no homologues for systems that specialize in the secretion of toxins or other virulence factors. The only known virulence factors of B. burgdorferi are surface-exposed lipoproteins that allow the spirochete to attach to mammalian cells.

The genus Borrelia currently includes 20 closely related species known collectively as Borrelia burgdorferi sensu lato ( B. burgdorferi in the general sense). However, only three pathogenic species commonly cause Lyme borreliosis. To date, all North American strains have belonged to the first group, B. burgdorferi sensu stricto ( B. burgdorferi in the strict sense), hereafter called B. burgdorferi. All three groups have been found in Europe, but most isolates there have been group 2 (Borrelia garinii) and 3 (Borrelia afzelii) strains. Only the latter two groups have been found in Asia. These differences may well account for regional variations in the clinical picture of Lyme borreliosis. B. burgdorferi grows best at 33°C in a complex liquid medium called Barbour-Stoenner-Kelly (BSK) medium.

Strains of B. burgdorferi have been subdivided according to several typing schemes, one based on sequence variation of OspC, a second based on differences in the 16S-23S ribosomal RNA (rRNA) intergenic spacer (IGS) region (or RST [ribosomal RNA intergenic spacer type]), and a third based on eight chromosomal housekeeping genes (multilocus typing). Among B. burgdorferi strains in the northeastern United States, the genes encoding OspC or the IGS are in strong linkage disequilibrium, suggesting a clonal structure of strains in this geographic region. From these typing systems, information is emerging concerning differential pathogenicity of strains of B. burgdorferi. , OspC type A (RST 1) strains, which account for 30% to 50% of infections in the northeastern United States, are particularly virulent. The OspC types of midwestern B. burgdorferi strains are more diverse than strains in the Northeast; OspC type H strains are most abundant (18%), and RST 1 strains account for only 3% of the infections there. B. burgdorferi strains in the United States represent distinct genotypes from B. burgdorferi strains in Europe. However, the clinical features of B. burgdorferi infection in Europe appear similar to those for B. afzelii and B. garinii infection, the common Borrelia spp. in Europe, suggesting that strains within a particular regional environment accrue similar characteristics as other strains that share the same ecologic niche.

Vector of Transmission and Animal Hosts

The vectors of Lyme borreliosis are closely related ixodid tick species that are part of the Ixodes ricinus complex (also called the Ixodes persulcatus complex). In the northeastern and midwestern United States the deer tick, Ixodes scapularis (also called Ixodes dammini; Fig. 241.2 ), is the vector, and Ixodes pacificus is the vector in the West. In Europe the sheep tick, Ixodes ricinus, and in Asia, the taiga tick, Ixodes persulcatus, are the primary vectors.

Ixodid ticks have larval, nymphal, and adult stages, and they require a blood meal at each stage. The peak questing periods for adult I. scapularis are spring and fall; for nymphs, May through July; and for larvae, August and September. In the northeastern United States, from Maine to North Carolina and in the north central states of Wisconsin and Minnesota, a highly efficient, horizontal cycle of B. burgdorferi transmission occurs among larval and nymphal I. scapularis ticks and certain rodents, particularly white-footed mice and chipmunks. This cycle results in high rates of infection among rodents and nymphal ticks, and primarily nymphal tick bites cause many new human cases of Lyme disease during the late spring and summer months. White-tailed deer, which are not involved in the life cycle of the spirochete, are the preferred host of adult I. scapularis , and they seem to be critical for the survival of ticks.

The vector ecology of B. burgdorferi is different on the West Coast, where the frequency of Lyme disease is low. There, two intersecting cycles are necessary for the transmission of the disease, one involving the dusky-footed wood rat and Ixodes spinipalpus (also called Ixodes neotomae ) ticks, which do not bite humans and that maintain the cycle in nature, and the other involving wood rats and I. pacificus ticks, which are less often infected but do bite humans.

In the southeastern United States, immature I. scapularis ticks feed primarily on lizards rather than rodents, and lizards are not susceptible to B. burgdorferi infection. Therefore B. burgdorferi infection occurs rarely in that part of the country. Instead, in the southern United States, in the mid-Atlantic states, and now moving into northeastern states, a rash resembling erythema migrans, called southern tick-associated rash illness (STARI), has been associated with the bite of the Lone Star tick (Amblyomma americanum). Although a novel Borrelia spp. called Borrelia lonestari has been found in these ticks, it is not clear that they are the cause of the disease. STARI may be accompanied by nonspecific systemic symptoms, but it is not known to cause chronic infection (see Chapter 298 for further details).

In Europe there is still debate about the preferred animal hosts of I. ricinus . These ticks feed on more than 300 animal species, including small mammals, birds, and reptiles. Because the Borrelia species differ in their resistance to complement-mediated killing, small rodents are important reservoirs for B. afzelii, whereas birds are strongly associated with B. garinii.

Epidemiology

Since surveillance was begun by the Centers for Disease Control and Prevention (CDC) in 1992, the number of reported cases of Lyme disease has increased dramatically in the United States. Currently, more than 30,000 cases have been reported yearly, making Lyme disease the most common vector-borne infection in the United States. Moreover, the CDC estimates that the actual number of cases is closer to 300,000 annually. The disorder occurs primarily in three distinct foci: in the Northeast from Maine to North Carolina; in the Midwest in Wisconsin, Minnesota, and Michigan; and in the West, primarily in northern California. The infection has now spread to Canada. Lyme borreliosis also occurs in temperate regions of the Northern Hemisphere in Europe and Asia. There, the highest reported frequencies of the infection are in middle Europe, particularly in Germany, Austria, Slovenia, and also in Sweden.

During the past 40 years the infection in the United States has continued to spread, particularly in the Northeast. It has caused focal outbreaks in some coastal areas, and it now affects suburban locations near Boston, New York, Philadelphia, Baltimore, and Washington—the most heavily populated parts of the country. Within these areas the occurrence of Lyme disease is highly focal. In Connecticut, which has one of the highest reported frequencies of Lyme disease in the United States, cases have been noted in all parts of the state, but most of the cases are still clustered in two counties in the southeastern part of the state, where the original epidemiologic investigation took place in the town of Lyme. In a large, 2-year vaccine trial, the yearly incidence of the disease in such highly endemic areas was greater than 1 per 100 participants.

Why did Lyme disease emerge in the northeastern United States during the latter part of the 20th century? The infection has probably been in North America for thousands of years, but ecologic conditions were altered during the European colonization of North America. Woodlands were cleared for farming, and deer were hunted practically to extinction. However, during the 20th century, farmland reverted to woodland, deer proliferated, white-footed mice and other rodents were plentiful, and the deer tick thrived. Soil moisture and land cover, as found near rivers and along the coast, were favorable for tick survival. Moreover, these areas became heavily populated with both humans and deer, as more rural wooded areas became wooded suburbs in which deer were without predators and hunting was prohibited. Finally, the spread of a particularly virulent spirochetal strain, B. burgdorferi OspC type A, may have contributed to the rise in the incidence of the infection.

Pathogenesis

Update: Peptidoglycan from Borrelia burgdorferi in Synovium of Patients with Persistent Lyme Arthritis

To maintain its complex enzootic cycle, B. burgdorferi must adapt to two markedly different environments: the tick and the mammalian or avian host. The spirochete survives in a dormant state in the nymphal tick midgut during the fall, winter, and spring, where it expresses primarily OspA and certain other proteins. When the tick feeds during the late spring or summer, these proteins are downregulated, and another set of proteins, including OspC, is upregulated. OspC binds mammalian plasminogen and its activators present in the blood meal, which facilitates spreading of the organism in the tick. In addition, within the tick salivary gland, OspC binds a tick salivary gland protein (Salp 15), and coating of the spirochete in this tick protein is essential for initial immune evasion in the mammalian host. The spirochete, which has few proteins with biosynthetic activity, appears to meet its nutritional requirements by infection of a mammalian or avian host.

After injection of B. burgdorferi by the tick (and a clinical incubation period of 3–32 days), the spirochete usually first multiplies locally in the skin at the site of the tick bite. In most patients immune cells first encounter B. burgdorferi at this site. Dendritic cells isolated from the dermis readily engulf B. burgdorferi in vitro. During the initial infection B. burgdorferi induces potent proinflammatory and compensatory antiinflammatory responses in cells in EM lesions, and B. burgdorferi– stimulated peripheral blood mononuclear cells (PBMCs) produce primarily proinflammatory cytokines, particularly interferon (IFN)-γ. Thus both innate and adaptive cellular elements are mobilized to fight the infection.

Within days to weeks, B. burgdorferi strains in the United States often disseminate to many distant anatomic sites. During this period the spirochete has been recovered from blood and cerebrospinal fluid (CSF), and it has been seen in small numbers in specimens of myocardium, retina, muscle, bone, spleen, liver, meninges, and brain. To disseminate, B. burgdorferi adheres to integrins, proteoglycans, or glycoproteins on host cells or tissue matrices. As in the tick, spreading through the skin and other tissue matrixes may be facilitated by the binding of plasminogen and its activators to the surface of the spirochete. During dissemination, a 66-kilodalton (kDa) spirochetal protein binds the platelet-specific integrin α _IIb β ₃ and the vitronectin receptor (α _v β ₅ ). A 26-kDa glycosaminoglycan binding protein binds heparan sulfate and dermatan sulfate, which are expressed on endothelial cells. A 47-kDa fibronectin-binding protein (BBK32) binds fibronectin, a ubiquitous extracellular matrix protein. Finally, decorin-binding proteins A and B (DbpA and DbpB) of the spirochete bind decorin, a proteoglycan on the surface of collagen, which may explain the alignment of spirochetes with collagen fibrils in the extracellular matrix in the heart, nervous system, or joints.

All affected tissues show an infiltration of lymphocytes and plasma cells. Some degree of vascular damage, including mild vasculitis or hypervascular occlusion, may be seen in multiple sites, suggesting that spirochetes may have been in or around blood vessels. Although B. burgdorferi has been identified inside cultured cells in vitro, it has not been seen in intracellular locations in histologic sections of infected tissues from patients with Lyme disease.

Despite an active immune response, B. burgdorferi may survive during dissemination by changing or minimizing antigenic expression of surface proteins and by inhibiting certain critical host immune responses. Two linear plasmids (lps) seem to be essential, including lp25, which encodes a nicotinamidase, and lp28-1, which encodes the VlsE lipoprotein, the protein that undergoes extensive antigenic variation. In addition, the spirochete has a number of highly homologous, differentially expressed lipoproteins, including OspE/F paralogs, which further contribute to antigenic diversity. Finally, B. afzelii and, to a lesser degree, B. burgdorferi have complement regulator-acquiring surface proteins that bind complement factor H and factor H–like protein 1. These complement factors inactivate C3b, which protects the organism from complement-mediated killing.

Both innate and adaptive immune responses are required for optimal control of spirochetal dissemination. Membrane lipoproteins are mitogenic for B cells. The specific immunoglobulin M (IgM) response is often associated with polyclonal activation of B cells, including elevated total serum IgM levels, circulating immune complexes, and cryoglobulins. In murine B. burgdorferi infection, CD1d presentation of monogalactosyl diacylglycerol (MgalD, BbGL-II) to natural killer T cells may be important in the early innate immune response, possibly as an initial source of IFN-γ. CD1d-deficient mice do not control the infection as well as their wild-type counterparts.

In the human infection the adaptive IgG response develops gradually over weeks to months to an increasing array of spirochetal proteins and two borrelial glycolipids. Using protein arrays that expressed approximately 1200 or more B. burgdorferi proteins, antibody responses were detected to a total of more than 100 proteins in a population of patients with early or late Lyme disease, particularly plasmid-encoded outer-surface lipoproteins. Spirochetal killing seems to be accomplished primarily by bactericidal B-cell responses, which promote spirochetal killing by complement fixation and opsonization. As shown in mice, the primary purpose of B. burgdorferi– specific CD4 ⁺ Th1 cells, which secrete mainly IFN-γ, is to prime T-cell–dependent, B-cell responses. B. burgdorferi– specific CD8 ⁺ T cells and NK cells are other important sources of IFN-γ. In patients with EM a dichotomy was noted between Th1 and Th17 responses. High Th1-associated responses correlated with more effective immune-mediated spirochetal killing, whereas high Th17-associated immune responses correlated with post-Lyme symptoms.

In the enzootic infection B. burgdorferi spirochetes must survive this immune assault for only the summer months before returning to the larval ticks to begin the cycle again the next year. In contrast, infection of humans is a dead-end event for the spirochete. Within several weeks to 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. B. burgdorferi , the sole cause of the infection in the United States, may cause persistent arthritis or, in rare cases, a subtle encephalopathy or polyneuropathy accompanied by minimal, if any, systemic symptoms. Patients with Lyme arthritis have high antibody responses to many spirochetal proteins that are suggestive of hyperimmunization due to recurrent waves of spirochetal growth. Even without antibiotic treatment, the number of patients who continue to have attacks of arthritis decreases by about 10% to 20% each year, and few patients have had attacks for longer than 5 years. Thus immune mechanisms seem to succeed eventually in the eradication of B. burgdorferi from selected niches, including the joints or nervous system.

Clinical Characteristics

As with other spirochetal infections, human Lyme borreliosis generally occurs in stages, with remissions and exacerbations and different clinical manifestations at each stage. Early infection consists of stage 1 (localized EM), followed within days or weeks by stage 2 (disseminated infection). Late infection, or stage 3 (persistent infection), usually begins months to years after the disease onset, sometimes following long periods of latent infection. In an individual patient, however, the infection is highly variable, ranging from brief involvement in only one system to chronic, multisystem involvement of the skin, nerves, or joints. In the United States about 10% of individuals have asymptomatic B. burgdorferi infection and seem to cure the infection without antibiotic therapy.

Early Infection: Stage 1 (Localized Infection)

In about 70% to 80% of patients EM develops at the site of the tick bite ( Fig. 241.3A and Table 241.1 ). However, because of the small size of nymphal I. scapularis , most patients do not remember the tick bite. During the first several days the lesion often has a homogeneous red appearance. In addition, the centers of early lesions sometimes become intensely erythematous and indurated, vesicular, or necrotic. As the area of redness around the center expands, most lesions continue to have bright-red outer borders (usually flat, but occasionally raised) and partial central clearing. In some instances migrating lesions remain an even, intense red; several red rings are found within the outside one; or the central area turns blue before it clears. Although the lesion can be located anywhere, the thigh, groin, and axilla are particularly common sites. If EM is on the head, only a linear streak might be seen to emerge from the hairline. The lesion is hot to the touch, and patients often describe it as burning or occasionally itching or painful.

TABLE 241.1

Manifestations of Lyme Disease by Stage ^a

From Steere AC. Lyme disease. N Engl J Med . 1989;321:586–596. Copyright © 1989, Massachusetts Medical Society. All rights reserved.

	EARLY INFECTION		LATE INFECTION
System b	Localized Stage 1	Disseminated Stage 2	Persistent Stage 3
Skin	Erythema migrans	Secondary annular lesions	Acrodermatitis chronica atrophicans
		Malar rash	Localized scleroderma-like lesions
		Diffuse erythema or urticaria
		Evanescent lesions
		Lymphocytoma
Musculoskeletal		Migratory pain in joints, tendons, bursae, muscle, bone	Prolonged arthritis attacks
		Brief arthritis attacks	Chronic arthritis
		Myositis c	Peripheral enthesopathy
		Osteomyelitis c	Periostitis or joint subluxations below acrodermatitis
		Panniculitis c
Neurologic		Meningitis	Chronic encephalomyelitis
		Cranial neuritis, facial palsy	Spastic paraparesis
		Motor or sensory radiculoneuritis	Ataxic gait
		Subtle encephalitis	Subtle mental disorders
		Mononeuritis multiplex	Chronic axonal polyradiculopathy
		Pseudotumor cerebri
		Myelitis c
		Cerebellar ataxia c
Lymphatic	Regional lymphadenopathy	Regional or generalized lymphadenopathy
		Splenomegaly
Heart		Atrioventricular nodal block
		Myopericarditis
		Pancarditis
Eyes		Conjunctivitis	Keratitis
		Iritis c
		Choroiditis c
		Retinal hemorrhage or detachment c
		Panophthalmitis c
Liver		Mild or recurrent hepatitis
Respiratory		Nonexudative sore throat
		Nonproductive cough
Kidney		Microscopic hematuria or proteinuria
Genitourinary		Orchitis c
Constitutional systems	Minor	Severe malaise and fatigue	Fatigue

a The staging system provides a guideline for the expected timing of the different manifestations of the illness, but this may vary in an individual case.

b The systems are listed from the most to the least commonly affected.

c Because the inclusion of these manifestations is based on one or a few cases, they should be considered possible but not proven manifestations of Lyme disease.

In Europe EM is often an indolent, localized infection, whereas in the United States, the lesion is associated with more intense inflammation and signs and symptoms that suggest dissemination of the spirochete. In one US study spirochetes were cultured from plasma samples in 50% of patients with EM. In a recent study the EM skin lesions of B. burgdorferi– infected US patients expanded faster, were associated with more symptoms, and had higher messenger RNA levels of macrophage-associated chemokines and cytokines than did EM lesions of B. afzelii– infected Austrian patients.