Clinical manifestations of Lyme disease in adults

INTRODUCTION — Lyme disease is a tick-borne illness, which is most commonly caused by one of three pathogenic species of the spirochete, Borrelia burgdorferi sensu lato. Based on recent phylogenetic analysis, some authors have proposed reclassifying Borrelia burgdorferi as a genus, Borreliella burgdorferi, but there remains debate. B. burgdorferi is the primary cause of the disease in the United States. All three pathogenic species, B. burgdorferi, B. afzelii, and B. garinii, occur in Europe and in Asia. Other species of Borreliella that have been recovered from humans include B. mayonii, B. spielmanii, B. bavariensis, B. valaisiana, B. lusitaniae, and B. bissettii. Lyme disease has a broad spectrum of clinical manifestations, and it also varies in severity due, in part, to differences in the infecting species.

Lyme disease was first described in 1977 as "Lyme arthritis" in studies of a cluster in Connecticut of children who were thought to have juvenile rheumatoid arthritis [1]. The multisystem nature of the infection became clear as involvement of other systems was subsequently identified [2,3].

An overview of the clinical manifestations of Lyme disease in adults will be reviewed here. Issues related to bacteriology, epidemiology, diagnosis, and treatment of Lyme disease, as well as more detailed discussions of the clinical manifestations of Lyme disease, are reviewed separately.

●(See "Microbiology of Lyme disease".)

●(See "Epidemiology of Lyme disease".)

●(See "Diagnosis of Lyme disease".)

●(See "Treatment of Lyme disease".)

●(See "Nervous system Lyme disease".)

●(See "Musculoskeletal manifestations of Lyme disease".)

●(See "Lyme carditis".)

●(See "Lyme disease: Clinical manifestations in children".)

CLINICAL STAGES — The clinical manifestations of Lyme disease can generally be divided into three phases: early localized, early disseminated, and late disease (table 1). However, the clinical features of each stage can overlap and some patients present in a later stage of Lyme disease without a history of prior signs or symptoms suggestive of earlier Lyme disease [4]:

●Early localized disease is characterized by the appearance of the characteristic skin lesion, erythema migrans (EM), with or without constitutional symptoms (picture 1 and picture 2). EM usually occurs within one month following the tick bite.

●Early disseminated disease is characterized by multiple EM lesions (that typically occur days to weeks after infection) and/or neurologic and/or cardiac findings (that typically occur weeks to several months after the onset of infection). Some of these patients have no history of antecedent early localized Lyme disease.

●In the United States, late Lyme disease is typically associated with intermittent or persistent arthritis involving one or a few large joints, especially the knee (sometimes preceded by migratory arthralgias), and/or certain rare neurologic problems, primarily a subtle encephalopathy or polyneuropathy. Late Lyme disease may develop months to a few years after the initial infection. Arthritis may be the presenting manifestation of the disease.

UNITED STATES VERSUS EUROPE — The basic features of Lyme disease are similar worldwide, but there are regional variations, primarily between the illness found in the United States and that found in Europe and Asia [5]. The following observations illustrate the range of findings:

●A prospective cohort study evaluated 204 patients with erythema migrans (EM), 119 due to B. burgdorferi sensu stricto in the United States and 85 due to B. afzelii in Slovenia [6]. American patients had higher rates of systemic symptoms (69 versus 51 percent), multiple EM lesions (13 versus 7 percent), and seropositivity (89 versus 31 percent), and a briefer duration of EM prior to presentation (4 versus 14 days).

●In another report, EM lesions in American patients who had B. burgdorferi infection expanded faster than lesions in Austrian patients who had B. afzelii infection [7]. The more rapidly growing EM lesions in American patients was associated with higher mRNA levels of chemokines and cytokines associated with macrophage activation.

●Some of the skin manifestations of Lyme disease such as borrelial lymphocytoma, acrodermatitis chronica atrophicans, and morphea-like lesions, seem to occur exclusively in Europe. In addition, B. garinii infection in Europe rarely causes the following late neurologic features: chronic encephalomyelitis (characterized by spastic paraparesis), cranial neuropathy, or cognitive impairment with marked intrathecal antibody production to the spirochete. (See 'Borrelial lymphocytoma' below and 'Cutaneous disease' below and 'Neurologic features' below.)

EARLY LOCALIZED DISEASE — Early localized disease includes erythema migrans (EM) and nonspecific findings that resemble a viral syndrome.

Erythema migrans — EM is a rash that appears at the site of the tick bite, usually within 7 to 14 days after the bite (range 3 to 30 days) [4,8,9]. While early erythema at the tick bite site is common due to a reaction to antigens in the tick saliva, this early allergic reaction must be differentiated from EM, which requires at least several days before slow expansion of the lesion begins. (See "Insect and other arthropod bites", section on 'Ticks'.)

EM occurs in approximately 80 percent of patients [10]. Approximately 25 percent of patients with early, localized Lyme disease recall a tick bite [11].

EM lesions typically have the following characteristics (picture 1 and picture 2) [12]:

●They are often found in or near the axilla, inguinal region, popliteal fossa, or at the belt line.

●They are not particularly painful, although EM lesions may occasionally burn or itch, and are hot to the touch.

●They typically expand slowly over the course of days or weeks, often with central clearing, and may reach a diameter of more than 20 cm [11,13]. During the first days, EM lesions may be uniformly red. As they expand, some central clearing often develops, and they may have a more complex target or bull's eye appearance.

Although central clearing is considered classic for EM, it often requires considerable expansion of the lesion and is usually not yet present in the first days of illness. In an observational cohort study of 118 cases of EM in which B. burgdorferi infection was confirmed by culture or polymerase chain reaction (PCR), the EM lesion was homogeneous in 59 percent, had central erythema in 32 percent, and central clearing in 9 percent [14]. The patients sought medical care at a median of three days following the appearance of the rash.

●EM lesions rarely have necrotic or vesicular centers (picture 3).

●Histologic examination reveals evidence of vascular endothelial cell injury (picture 4A-B).

Multiple EM lesions are a sign of early disseminated disease, not multiple tick bites. (See 'Multiple erythema migrans' below.)

It is important to note that a skin lesion indistinguishable from EM occurs in Southern tick-associated rash illness (STARI), an illness principally found in the southeast and south-central regions of the United States, although it has also been seen in more northern states (eg, New York, Pennsylvania, and Maine) as well (picture 5). (See "Southern tick-associated rash illness (STARI)".)

Other manifestations — During the first days or weeks of infection, patients with early, localized, or disseminated Lyme disease often also have nonspecific signs and symptoms resembling a viral syndrome, though high fever is uncommon in Lyme disease. Patients from the United States are more likely to have constitutional symptoms than patients in Europe [15]. In a prospective study of 79 patients with culture-confirmed EM, common clinical manifestations included the following [11]:

●Fatigue - 54 percent

●Anorexia - 26 percent

●Headache - 42 percent

●Neck stiffness - 35 percent

●Myalgias - 44 percent

●Arthralgias - 44 percent

●Regional lymphadenopathy - 23 percent

●Fever - 16 percent

Upper respiratory and gastrointestinal signs and symptoms are uncommon in Lyme disease [16]. Their presence should suggest an alternate diagnosis, such as a viral infection.

A study of patients enrolled in a Lyme vaccine trial addressed the question of the prevalence of early Lyme disease in patients lacking an EM lesion. Forty-two of 269 (16 percent) patients with definite or possible Lyme disease had systemic symptoms without EM; 18 of these had laboratory evidence of accompanying anaplasmosis, or babesiosis and possible Lyme disease, leaving 24 patients (9 percent) with laboratory-defined Lyme disease alone [16].

Symptoms in these 24 patients included arthralgias in 17, headache in 13, and neck stiffness in 10. While fever and chills were present in two-thirds of these patients, these symptoms were neither sustained nor prominent [16]. Lyme disease was confirmed in all 24 patients either by B. burgdorferi serologies (IgG variable major protein-like sequence-expressed sixth invariant region peptide enzyme-linked immunosorbent assay [VlsE C6 ELISA] and/or sonicate Western blot) or a positive polymerase chain reaction for B. burgdorferi DNA in the blood. Although standard serologic tests for Lyme disease may be negative during the first several weeks of infection, one would expect to see seroconversion after that time if the patient has persistent infection. Moreover, a clinical picture of persistent or recurrent flu-like symptoms after antibiotic treatment in a seronegative patient is unlikely to be due to B. burgdorferi infection. (See "Diagnosis of Lyme disease".)

Laboratory abnormalities — In the prospective study of 79 patients with early Lyme disease and culture-confirmed EM cited above, the following laboratory abnormalities were identified [11]:

●Erythrocyte sedimentation rate more than twice the upper limit of normal (24 percent).

●Less frequent laboratory abnormalities included elevated serum creatine phosphokinase (12 percent), leukocytosis (5 percent), leukopenia (4 percent), anemia (3 percent), and thrombocytopenia (1.5 percent).

●Mildly elevated serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) was observed in 37 percent of patients. However, this study was performed before the appreciable incidence of coinfection with Anaplasma, Babesia spp, and/or Borrelia miyamotoi was recognized. Anaplasmosis may cause elevated aminotransferases, which could raise the incidence above that seen in patients who have Lyme disease alone. (See 'Coinfection with other tick-borne pathogens' below and "Human ehrlichiosis and anaplasmosis" and "Babesiosis: Clinical manifestations and diagnosis" and "Borrelia miyamotoi infection".)

Lyme serologies and other diagnostic tests are discussed separately. (See "Diagnosis of Lyme disease".)

EARLY DISSEMINATED DISEASE — Early disseminated Lyme disease usually occurs weeks to several months after the tick bite and may be the first manifestation of Lyme disease.

Neurologic manifestations — Neurologic features of early disseminated Lyme disease may include [15,17]:

●Lymphocytic meningitis

●Unilateral or bilateral cranial nerve palsies (especially of the facial nerve)

●Radiculopathy (Bannwarth syndrome)

●Peripheral neuropathy

●Mononeuropathy multiplex

●Cerebellar ataxia (rarely)

●Encephalomyelitis (rarely)

The classic triad of acute neurologic abnormalities is meningitis, cranial neuropathy, and motor or sensory radiculoneuropathy, although each of these findings may occur alone [18-20].

Although the facial nerve is the most commonly affected cranial nerve, other nerves such as the abducens nerve may be involved [21]. Lyme disease is one of the few causes of bilateral cranial nerve palsies. Other causes include tuberculosis, sarcoidosis, and trauma. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults" and "Central nervous system tuberculosis: An overview" and "Clinical manifestations and diagnosis of sarcoidosis".)

A detailed discussion on the neurologic manifestations of Lyme disease is found elsewhere. (See "Nervous system Lyme disease".)

Carditis — Cardiac manifestations of Lyme disease include fluctuating degrees of atrioventricular heart block, sometimes with myopericarditis, which is usually mild when it occurs. On rare occasion, sudden cardiac death attributable to Lyme disease has also been reported [22,23]. Chronic cardiomyopathy with heart failure has been linked to Lyme disease in Europe, but not in the United States. Lyme carditis is discussed in detail elsewhere. (See "Lyme carditis".)

Ocular manifestations — A variety of ocular manifestations have been associated with Lyme disease, including conjunctivitis, keratitis, iridocyclitis, retinal vasculitis, choroiditis, optic neuropathy, and uveitis [24,25]. Except for conjunctivitis, which occurs in about 10 percent of patients early in the infection, all of the other manifestations are rare and described only in case reports in which validation of B. burgdorferi infection was sometimes limited.

Cutaneous findings

Multiple erythema migrans — Multiple erythema migrans (EM) lesions can be seen in patients with early disseminated disease, and they are a sign of spirochetemia, not multiple tick bites (picture 6 and picture 7) [26]. In an early report of 314 patients describing the clinical manifestations of Lyme disease, almost half developed multiple EM lesions [9]. In contrast, later series in which patients with early disease were treated promptly with antibiotic therapy found multiple EM lesions in only 10 to 18 percent [6,11].

Borrelial lymphocytoma — In Europe, borrelial lymphocytoma is a rare cutaneous manifestation of Lyme disease that usually occurs during the early phase of infection [24,27-30]. It presents as a single bluish-red swelling with a diameter of up to several centimeters, which usually occurs later and lasts longer than erythema migrans (EM), but resolves spontaneously. It is most commonly located on the earlobe in children and near the nipple in adults, and often occurs near a previous or concurrent EM lesion. Pathology reveals a dense lymphocytic infiltration of the cutis and subcutis.

Reports from Europe have suggested a link between borrelial lymphocytoma caused by B. afzelii and primary cutaneous B cell lymphoma. However, this remains controversial and has been contradicted by studies from Asia and North America. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)", section on 'Disease associations' and "Primary cutaneous follicle center lymphoma", section on 'Pathogenesis'.)

LATE DISEASE — Late Lyme disease occurs months to a few years after the onset of infection and may not be preceded by a history of early localized or disseminated Lyme disease. In the United States, arthritis in one or a few joints is the most common feature of patients with late Lyme disease, but neurologic manifestations, such as a subtle encephalopathy or polyneuropathy can also occur. In Europe, patients may develop a chronic skin condition called acrodermatitis chronica atrophicans, but this manifestation has not been identified conclusively in the United States.

These features are less common now since the majority of patients are diagnosed and treated during the early phase of Lyme disease.

Arthritis — Lyme arthritis is characterized by intermittent or persistent arthritis in a few large joints, especially the knee [31]. In the late 1970s, before the cause of Lyme disease and the role of antibiotics in its treatment were known, the natural history of articular manifestations of Lyme disease was described in a cohort of 55 patients followed prospectively from the onset of disease with erythema migrans (EM) through later manifestations of the illness [31].

Months after the onset of infection, about 60 percent of patients developed joint swelling and pain. A few small joints or periarticular sites (tendons or bursae) were also affected, primarily in early attacks. The number of patients who continued to have recurrent attacks decreased each year. However, in a small percentage of cases, involvement in large joints (usually one or both knees) became chronic and sometimes led to erosion of cartilage and bone. (See "Musculoskeletal manifestations of Lyme disease".)

In patients with late-stage disease who develop arthritis, a small percentage have persistent symptoms after appropriate treatment. The basic pathogenetic feature of post-infectious Lyme arthritis is the development of an excessive, dysregulated proinflammatory immune response during the infection, which persists in the post-infectious period. This is described in detail elsewhere. (See "Musculoskeletal manifestations of Lyme disease", section on 'Post-infectious Lyme arthritis'.)

Neurologic features — The neurologic manifestations of late Lyme disease are different from those in early disseminated disease. (See 'Neurologic manifestations' above.)

The clinical features include confluent mononeuropathy multiplex, a subtle sensory axonal peripheral neuropathy [32,33], encephalomyelitis [34], and possibly a subtle encephalopathy [32,33]. With appropriate antibiotic therapy for early Lyme disease, late neurologic findings have almost disappeared; however, these manifestations of late Lyme disease are rare even in untreated patients.

A detailed discussion of the neurologic manifestations of Lyme disease is presented elsewhere. (See "Nervous system Lyme disease".)

Cutaneous disease

Acrodermatitis chronica atrophicans — In Europe, acrodermatitis chronica atrophicans is the cutaneous manifestation of late Lyme disease that may appear years following primary infection (range 0.5 to 8 years) [24,34-36]. This condition is primarily due to B. afzelii and has not been described convincingly in the United States.

Acrodermatitis chronica atrophicans is most common in women >40 years of age, but it may occur in younger people. It is typically located on the extensor surfaces of the hands and feet.

In its early stages, acrodermatitis chronica atrophicans has a slight bluish-red discoloration with associated swelling [24]. These lesions subsequently may slowly enlarge over months to years, and surrounding edema often resolves as atrophy develops. As a result, the underlying veins become prominent. Acrodermatitis chronica atrophicans usually begins as a unilateral lesion, but lesions may become bilateral over time.

In Europe, fibrous induration or nodules (over bony prominences such as elbow or patella) may also develop in patients with late Lyme disease [24,35,36]. Sclerotic lesions develop in other patients. These lesions can lead to peripheral nerve and/or joint damage. Histologic examination of such lesions reveal lymphocytic and plasma cell infiltrates in the dermis and sometimes the subcutis, with or without atrophy.

Other — In Europe, morphea-like skin lesions have also been described as a rare manifestation of late Lyme disease [37]. Histologic examination of these lesions typically reveals interstitial granulomatous dermatitis with histiocytic pseudorosettes.

POST-TREATMENT LYME DISEASE SYNDROME AND CHRONIC LYME DISEASE — Post-infectious pain and fatigue symptoms are a well-known complication of acute infection with a variety of viral, bacterial, parasitic, or fungal infections. In Lyme disease, this complication, which may follow any manifestation of B. burgdorferi infection, is called post-treatment Lyme disease syndrome (PTLDS) or chronic Lyme disease. This differs from those who have late-stage infection, usually Lyme arthritis, and develop persistent arthritis after the completion of antibiotic therapy, as described above. (See 'Arthritis' above.)

●Post-treatment Lyme disease syndrome – The term "post-treatment Lyme disease syndrome" is often used to describe nonspecific symptoms that may persist for months or years after treatment of Lyme disease [38-40]. For the majority of patients, these symptoms improve gradually over six months to one year. The proportion of patients who develop post-treatment Lyme disease syndrome ranges from 5 to 15 percent [41].

The Infectious Diseases Society of America (IDSA) proposed a definition of post-treatment Lyme disease syndrome in 2006 [15]. Criteria for this syndrome include a prior history of Lyme disease treated with an accepted regimen and resolution or stabilization of the objective manifestations of Lyme disease. In addition, the onset of subjective symptoms (eg, fatigue, widespread musculoskeletal pain, complaints of cognitive difficulties) must have occurred within six months of the diagnosis of Lyme disease and persist (continuously or relapsing) for at least six months after completion of antimicrobial therapy. There are also several exclusion criteria (table 2).

The Swiss Society of Infectious Diseases proposed a definition of post-treatment Lyme disease syndrome in 2005 and reaffirmed it in 2016 [42]. They proposed the following diagnostic criteria: documented clinical and laboratory evidence of previous infection with B. burgdorferi, a completed course of appropriate antibiotic therapy, symptoms including fatigue, arthralgia, myalgia, cognitive dysfunction or radicular pain persisting for >6 months, a plausible timely association between documented B. burgdorferi infection and onset of symptoms (ie, persistent or recurrent symptoms that began within six months of completion of a recommended antibiotic therapy for early or late Lyme borreliosis), and exclusion of other somatic or psychiatric causes of symptoms.

The cause of persistent, nonspecific symptoms after treatment for Lyme disease remains an area of uncertainty. Although there are data from animal models suggesting that remnants of B. burgdorferi can persist after antibiotic therapy [43-45], a link to PTLDS in humans has not been established. In addition, available evidence does not support the hypothesis that persistent infection with B. burgdorferi is the cause of chronic subjective symptoms that may occur after recommended courses of antibiotic therapy for Lyme disease since five double-blind studies that found no sustained difference between antibiotic and placebo-treated groups [15,42,46]. These data are discussed separately. (See "Treatment of Lyme disease", section on 'Role of additional antibiotics'.)

●Chronic Lyme disease – Chronic Lyme disease is a term that is used by some practitioners and patient advocacy groups. This term has not been clearly defined and can include post-treatment Lyme disease syndrome, as well as illnesses and symptom complexes for which there is no convincing scientific evidence of any relationship to B. burgdorferi infection [15,41]. These patients may have other recognizable syndromes or diagnoses. In one case series, for example, three patients who were diagnosed as having chronic Lyme disease had an underlying malignancy [47]. Among patients with nonspecific symptoms of fatigue and myalgias, these subjective symptoms are sometimes accompanied by tender points of fibromyalgia [48]. Since fibromyalgia is common in the general population, the association of Lyme disease and fibromyalgia may sometimes be by chance alone [15,49,50]. (See "Musculoskeletal manifestations of Lyme disease", section on 'Post-treatment Lyme disease syndrome'.)

REINFECTION — Reinfection with B. burgdorferi is possible following the successful treatment of early Lyme disease. Reinfection typically presents as erythema migrans at a different location on the skin [50,51].

In a study of 17 patients who received a diagnosis of erythema migrans between 1991 and 2011 and who had 22 paired episodes of erythema migrans, molecular typing of the B. burgdorferi gene encoding outer surface protein C (ospC) was performed using B. burgdorferi strains that were detected in cultures of skin or blood specimens [52]. The ospC genotype was found to be different at each initial and second episode of erythema migrans, demonstrating that repeat episodes of erythema migrans in appropriately treated patients were due to reinfection rather than relapse.

Reinfected patients may have a marked anamnestic immune response with rapid IgG isotype switching [50]. However, in patients who are treated during the early stages of disease, the initial immune response is directed against a smaller number of antigens which do not protect against reinfection, or variations in proteins expressed by different strains of B. burgdorferi may thwart protection from these previously developed immune responses. In contrast, patients who have had late-stage manifestations of Lyme disease often have expanded antibody responses to many additional antigens that protect against reinfection, and such responses typically persist for years, albeit at a low level after successful treatment of the infection. Reinfection has not been reported in patients who previously had Lyme arthritis, a late disease manifestation [53].

PREGNANCY AND BREAST FEEDING — Because Borrelia species are spirochetes, there has been concern about the possibility of congenital Lyme disease given the serious congenital disease that can result from maternal syphilis, another spirochetal disease. Available evidence suggests that there is no definable congenital Lyme disease syndrome. If adequately treated, Lyme disease occurring during pregnancy does not predispose to congenital anomalies or fetal demise. In addition, a woman who has a history of Lyme disease diagnosed and treated before the pregnancy has no reason for concern. The treatment of Lyme disease, including during pregnancy, is presented elsewhere. (See "Treatment of Lyme disease".)

Initially, several early case reports and small studies suggested a link between maternal Lyme disease and congenital malformations or fetal demise [54-58]. However, subsequent studies have not supported an association between Lyme disease in pregnancy and adverse fetal outcomes, congenital malformations, or cardiac malformations [59-63].

●In a prospective study, 2000 women residing in an endemic area had Lyme serology during their first prenatal visit and at delivery [60]. Neither a history of a tick bite nor serologic evidence of Lyme disease during pregnancy were associated with fetal death, decrease in infant birth weight, premature delivery, or congenital malformations.

●In a prospective study of pregnant women with erythema migrans treated during pregnancy with ceftriaxone, 51 of 58 (88 percent) delivered normal term babies [61]. Among the remaining seven pregnancies, there was one spontaneous abortion, five premature births, and one term baby with a urologic defect noted at seven months of age.

●A retrospective, case-control study of 1500 children, 796 with a congenital heart defect, showed no link between congenital heart disease and a history of maternal tick bite or maternal infection within three months of conception or during pregnancy [62].

●A survey of 162 pediatric neurologists from areas endemic for Lyme disease failed to identify a congenital neurologic Lyme disease syndrome [63].

Although these studies were fairly large, they were limited by the small number of women actually exposed to Lyme disease during pregnancy. Thus, while these data are reassuring, it is not clear that the power of the studies was sufficient to rule out a small increase in risk. What can be said, is that there is no accepted or well-described "congenital Lyme disease syndrome," in marked contrast with the classic syndrome of congenital syphilis.

For women who develop Lyme disease after delivery, there is no evidence that Borrelia species can be transmitted during breast feeding. (See "Epidemiology of Lyme disease", section on 'Transmission to humans'.)

COINFECTION WITH OTHER TICK-BORNE PATHOGENS — Patients with Lyme disease in endemic areas may be coinfected with another tick-borne disease. Other organisms transmitted by Ixodes ticks include: Anaplasma phagocytophilum, Powassan encephalitis virus (also called deer tick virus), and Babesia microti in the United States; tick-borne encephalitis virus in Europe [64-67]; and B. miyamotoi, a Borrelia species related to the agents of relapsing fever, which is found worldwide. (See "Human ehrlichiosis and anaplasmosis" and "Babesiosis: Clinical manifestations and diagnosis" and "Borrelia miyamotoi infection".)

Investigation for coinfection is warranted in patients with fever for more than 24 hours if they are receiving antimicrobial therapy for Lyme disease that does not have activity against possible coinfecting pathogens (eg, anaplasmosis is not treated with amoxicillin or cefuroxime and babesiosis is not treated with any of the preferred oral regimens) [15]. It is also reasonable to test for coinfection in those with unexplained leukopenia, neutropenia, thrombocytopenia, anemia, and/or elevated indirect bilirubin [8,15,64,65,67].

Reported rates of coinfection with babesiosis or anaplasmosis in endemic regions of the United States have typically ranged from about 2 to 10 and 2 to 12 percent, respectively [15], although higher numbers have also been reported [65].

The following observations illustrate the range of findings:

●Among 192 residents of areas with high rates of tick-borne infections (Block Island, RI; Nantucket, MA; southeastern Connecticut) who were diagnosed with a tick-borne disease, 75 (39 percent) were coinfected with more than one organism [65]. Lyme disease with babesiosis was responsible for 81 percent of coinfections, whereas 9 percent had Lyme disease with HGA, 5 percent had all three infections, and 4 percent had babesiosis with HGA.

●In other reports from southern New England, coinfection with B. microti occurred in 2 percent of patients with erythema migrans [66], and 10 percent of those with serologic evidence of Lyme disease [67].

●In studies from New England and Wisconsin, 2 to 12 percent of patients with erythema migrans were coinfected with A. phagocytophilum [66,68,69].

●In a serosurvey, archived sera were examined using B. miyamotoi GlpQ enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) assays [70]. The seroprevalence of B. miyamotoi was 4 percent in 639 healthy individuals in Rhode Island or Massachusetts and 10 percent in 194 patients with early stage Lyme disease in Connecticut, Massachusetts, New York, or Rhode Island.

Coinfected patients tend to have more prolonged and more severe symptoms (particularly higher fever, sweats, and rigors) than are usually seen with Lyme disease alone [64,67,69]. However, this may be due in part to referral bias.

Although no clinical symptoms clearly identify patients with coinfection, standard blood counts may suggest the presence of another pathogen. Lyme disease, by itself, rarely causes abnormalities; in contrast, anemia and thrombocytopenia often occur in babesiosis, whereas leukopenia and/or thrombocytopenia may occur in anaplasmosis. Although anaplasmosis and babesiosis are usually asymptomatic infections, they are more of a problem in the very young or very old, or, in the case of babesiosis, in those without a spleen. (See "Human ehrlichiosis and anaplasmosis" and "Babesiosis: Clinical manifestations and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Tick-borne infections (Lyme disease, ehrlichiosis, anaplasmosis, babesiosis, and Rocky Mountain spotted fever)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Basics topic (see "Patient education: Lyme disease (The Basics)")

●Beyond the Basics topics (see "Patient education: Lyme disease symptoms and diagnosis (Beyond the Basics)" and "Patient education: Lyme disease treatment (Beyond the Basics)" and "Patient education: Lyme disease prevention (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Microbiology – Lyme disease is a tick-borne illness caused predominantly by three pathogenic species of the spirochete Borreliella (previously referred to as Borrelia burgdorferi sensu lato). (See 'Introduction' above.)

●Clinical phases of illness – The clinical manifestations of Lyme disease can generally be divided into three phases: early localized, early disseminated, and late disease (table 1). (See 'Clinical stages' above.)

•Early localized Lyme disease – Patients in the early localized phase have erythema migrans (EM) and nonspecific findings that resemble a viral syndrome. EM occurs in approximately 80 percent of patients, usually within one month following the tick bite. (See 'Early localized disease' above.)

•Early disseminated Lyme disease – Early disseminated disease manifests as acute cutaneous, neurologic, or cardiac involvement that usually occurs weeks to several months after the tick bite and may be the first manifestation of Lyme disease. (See 'Early disseminated disease' above.)

•Late Lyme disease – Late disease occurs months to a few years after the onset of infection and may not be preceded by a history of early localized or disseminated Lyme disease. In the United States, arthritis in one or a few joints is the most common feature of patients with late Lyme disease. Neurologic manifestations (eg, a subtle polyneuropathy, encephalomyelitis) may also occur, but these are rare. In Europe, patients may develop a chronic skin condition called acrodermatitis chronica atrophicans, but this manifestation has not been conclusively identified in the United States. (See 'Late disease' above.)

●Persistent symptoms – Nonspecific symptoms (such as headache, fatigue, and arthralgias) may persist for months after treatment of Lyme disease. There is no evidence that these persistent subjective complaints represent ongoing active infection or that repeated or prolonged courses of antibiotics provide any benefit. (See 'Post-treatment Lyme disease syndrome and chronic Lyme disease' above.)

●Pregnancy and breastfeeding – Current evidence suggests that there is no definable congenital Lyme disease syndrome. In addition, for women who develop Lyme disease after delivery, there is no evidence that Borrelia species can be transmitted during breastfeeding. (See 'Pregnancy and breast feeding' above.)

●Coinfections with other tickborne pathogens – Coinfection of B. burgdorferi with Babesia microti, B. miyamotoi, and/or Anaplasma phagocytophilum occurs in some patients since these organisms share the tick vector (Ixodes spp). (See 'Coinfection with other tick-borne pathogens' above.)