HISTORY

Lyme disease is a zoonosis discovered after a strange outbreak of illness in children in Lyme, Connecticut. These children were experiencing rashes, joint swelling, headaches, and fatigue. The outbreak led researchers to describe the syndrome as Lyme in the mid-1970s. It was not until the 1980s that Dr. Burgdorfer, a researcher, found the spirochete that caused this disease was transmitted by the deer tick. This was eventually named Borrelia burgdorferi and has led to an awareness of the most common vector-borne illness in the United States. It has been a prominent public health issue and a nationally notifiable condition since 1991. It is estimated that 300,000 new cases occur annually in the United States.

CAUSES AND SYMPTOMS

Lyme borreliosis is an acute inflammatory syndrome caused by infection with the Borrelia species. Borrelia burgdorferi is the primary agent in North America. Still, Borrelia afzelii and Borrelia garinii are also causative agents, particularly in Europe and Asia. Ixodes ticks transmit these spirochetal bacteria in their nymphal or adult life stages. A human must have a tick attached for thirty-six to forty-eight hours to contract Borrelia. Nymphs are often much more successful at transmitting due to their small size because they remain undetected. Mice are a primary reservoir for the spirochetes and often transmit Borrelia to nymphs at their initial blood feeding. Transmission typically occurs between May and October because of the feeding cycles of ticks.

Symptoms can generally be separated into three phases: early localized disease, early disseminated disease, and late disease. The early localized disease occurs a few days to a month after the tick bite. A hallmark of this phase is erythema migrans (EM), a rash that is widely known to resemble a bullseye. It is present in up to 80 percent of cases. Though the central clearing is a widely known characteristic, it must expand before this diagnosis is considered. Therefore, clinicians must carefully evaluate rashes at the bite site. Additional symptoms of this phase include fatigue, mild headache, muscle aches, joining pains, lymph node swelling, malaise, and neck stiffness.

Early disseminated disease can occur anywhere from weeks to months after the tick bite occurs. Because Lyme disease is caused by a bacterial infection transmitted via the bloodstream, this phase represents the spread of the bacteria throughout the body. This phase may be evidenced by multiple EM lesions, migratory arthralgias, generalized lymphadenopathy, liver disease, kidney disease, carditis, and inflammatory changes of the eye. The inflammatory changes of the eye can include iritis, conjunctivitis, vitreous, or retinitis. Neurologic manifestations include lymphocytic meningitis, cranial or peripheral neuropathy, myelitis, or encephalitis. Cranial neuropathies often present as Bell’s palsy and can be bilateral. Early disseminated disease is often mistaken for alternative chronic rheumatological conditions such as multiple sclerosis (MS).

Months to years after the initial tick bite, the late disseminated disease can occur if Lyme remains untreated. The late disease consists of peripheral neuropathies or encephalomyelitis and musculoskeletal symptoms. The musculoskeletal symptoms primarily consist of intermittent monoarticular, oligoarticular arthritis, or persistent monoarthritis.

A few symptoms are specific to European countries, including borrelial lymphocytoma, which is a bluish-red swelling that typically occurs near the EM. Common areas include the earlobe and the areola. When biopsied, these lesions typically demonstrate dense lymphocytic infiltration of the skin. In late disease, skin manifestations unique to Europe include acrodermatitis chronica atrophicans, bluish-red swellings that enlarge and then atrophy, leaving swollen tissues surrounding the lesions and prominent veins underlying the lesion. These cutaneous markings are characteristic of B. afzelii, which is transmitted in Europe.

POSTTREATMENT LYME DISEASE SYNDROME

There are various definitions from the Infectious Diseases Society of America (IDSA) and the Swiss Society of Infectious Diseases of posttreatment Lyme disease syndrome. Up to 15 percent of patients have subjective symptoms, including fatigue, myalgias, or cognitive difficulties that persist for months after successful treatment and resolution of objective symptoms. These symptoms usually resolve for patients within a year. However, some advocacy groups suggest this can be a part of chronic Lyme disease. This particular syndrome is poorly defined and is largely unrecognized by medical groups as having a causal link to Borrelia burgdorferi.

DIAGNOSIS

Testing or treatment should be considered in endemic areas or after a travel history confirms travel to endemic areas in patients with suspicious symptoms. Testing should not occur on asymptomatic individuals after a tick bite or in patients with no history of a tick bite with vague and nonspecific symptoms. Testing these groups increases the risk for false positives and unnecessary antibiotics. Serologic testing is not typically positive for at least one week.

In patients who live in or have traveled to endemic areas with a history of tick bite and early localized disease, clinical diagnosis and treatment are appropriate. Serologic testing, discussed below, should not be conducted in these individuals as the adaptive immune process is often not initiated, and false negatives can occur at this time. Serologic testing can be utilized if treatment is not prescribed. Still, if it is negative, it should be repeated in two to three weeks to ensure no false negative.

Polymerase chain reaction (PCR) testing can be conducted on local biopsies of skin lesions, but this is not done often because biopsies are not routinely performed. Most testing occurs in primary or urgent care centers where this isn’t largely available. Similarly, blood cultures can be done but are done rarely because of the lack of commercial availability of this testing.

SEROLOGIC TESTING

All testing is used in conjunction with clinical symptoms to diagnose a patient with Lyme disease. Testing is at high risk for both false-positive and false-negative results. Traditional two-tiered testing strategies can be utilized regardless of the suspected stage of Lyme disease. New modified two-tiered testing strategies have been developed to impact the sensitivity and specificity of testing in early disseminated disease. Unfortunately, experience with this strategy is limited and not as widely available.

Traditional two-tiered testing utilizes an enzyme-based immunoassay. If this test is positive, it is followed by a more specific IgM and IgG Western blot. Though Western blots are more specific, there is a high risk for false positives. If the enzyme-based immunoassay is negative, testing does not progress beyond this stage.

Modified testing utilizes two stages of enzyme-linked immunosorbent assay (ELISA) testing. One protocol moves from IgG and IgM testing on a major protein-like sequence to whole-cell ELISA testing. The second moves from whole-cell ELISA testing to a more specific C-6 ELISA testing. These tests can result in decreased specificity for certain strains of Borrelia. This type of testing requires a positive on both assays to diagnose Lyme disease.

In addition, special populations with arthritis or neurological symptoms can have testing conducted on cerebrospinal fluid (CSF) or synovial fluid. The decision to test these patients is made based on their presentation. Testing must be considered carefully along with the patient presentation and risk factors because it, unfortunately, cannot diagnose or rule out Lyme disease on its own.

TREATMENT AND THERAPY

There are various regimens based on the suspected stage of Lyme disease. It is, however, acceptable to initiate prophylaxis with doxycycline if the patient meets the following criteria: bite from a nymph or adult Ixodes species; the tick is attached for at least thirty-six hours; the bite occurs in an endemic area, and prophylaxis is initiated within seventy-two hours. Guidelines largely do not support prophylaxis with anything aside from doxycycline as a single dose.

EARLY LOCALIZED DISEASE

Since serologic testing is often negative at this time, treatment is initiated based on the patients’ clinical presentation and risk factors. With the presence of EM, treatment should be initiated with doxycycline, amoxicillin, or cefuroxime for ten to fourteen days. Though some protocols express a preference for amoxicillin for children, the American Academy of Pediatrics suggests that doxycycline is safe for children for less than twenty-one days. Azithromycin and Clarithromycin are acceptable alternatives for the suggested antibiotics. If uncertainty exists regarding the diagnosis of EM versus cellulitis in a patient with risk factors, augmentin, cefuroxime, or doxycycline should be used to treat the cellulitis to eliminate the risk of untreated Lyme disease.

EARLY DISSEMINATED DISEASE

Treatment in early disseminated disease is dependent upon patient presentation. Doxycycline, ceftriaxone (intravenous or intramuscular), or amoxicillin for fourteen to twenty-one days is appropriate in most patients. Doxycycline is preferred in patients with acute neurological manifestations due to higher central nervous system penetration. If a patient cannot tolerate doxycycline, intravenous or intramuscular therapy is preferable to oral amoxicillin. Steroids are not helpful with neurological manifestations like Bell’s palsy and aren’t recommended.

In patients presenting with carditis, observation in the hospital with electrocardiography (EKG) monitoring is appropriate until the PR interval is less than 300 milliseconds for at least twenty-four hours. A severe atrioventricular block may require a temporary pacemaker. In all patients admitted to the hospital, intravenous therapy is preferred. Upon discharge from the hospital, treatment can transition to oral doxycycline.

LATE DISSEMINATED DISEASE

Treatment of late disseminated disease is very similar to early disseminated disease. Patients presenting with arthritis are generally treated with oral doxycycline. If they cannot tolerate doxycycline, amoxicillin or cefuroxime are acceptable alternatives. Hospitalized patients can be given ceftriaxone or cefuroxime intravenously and transitioned to oral doxycycline. Treatment should be continued for thirty days, and if arthritis is mostly resolved, it should be discontinued. If arthritis persists but is partially resolved, the course should be extended for thirty days. If arthritis remains unresolved, intravenous therapy should be considered.

Late neurological manifestations should be treated with intravenous cefuroxime as it penetrates the central nervous system with the greatest efficacy. This should be continued for fourteen to twenty-eight days. An alternative to this regimen is ceftriaxone or doxycycline for fourteen to twenty-eight days. Adjusting the timeline of neurological treatment is much more difficult than adjusting arthritic treatment because neurological symptoms often take several months to resolve. Cutaneous manifestations are amenable to oral therapy with doxycycline, amoxicillin, or cefuroxime.

SPECIAL CONSIDERATIONS

Children and pregnant women should be given amoxicillin or cefuroxime before doxycycline. Doxycycline can be used in children for less than twenty-one days, but pregnancy is a contraindication for doxycycline administration. Lastly, posttreatment Lyme disease syndrome should not be treated with antibiotics unless objective manifestations persist. This condition is typically due to dysregulation of the immune system rather than the persistence of the infectious agent.

VACCINE

SmithKlein Beecham developed a Lyme disease vaccine in 1998 called “Lymerix.” It had a favorable safety profile, but clinicians raised concerns about the possibility of the immune response to the vaccine increasing the risk of autoimmune Lyme arthritis. Consequently, sales were extremely low, and the manufacturer discontinued production. A new vaccine is currently in trials in Europe and the United States using new technology that eliminates the epitope that raised concerns in the initial vaccine. Monoclonal antibodies are also being considered for preexposure prophylaxis.

PREVENTION

Prevention should be focused on as a primary measure to avoid infection. These measures include avoiding tick environments like long grasses, low-lying bushes, and wooded areas. If this is not possible, wearing protective clothing, including hats and permethrin-treated long-sleeved clothing, can be helpful. Consideration for wearing a bug repellant is also important. Diethyltoluamide (DEET) is the evaluated method for preventing tick bites. Though there are other popular suggestions, they have not been evaluated against DEET for efficacy.

After exposure to environments where ticks may be prevalent, removing clothes and placing them in the dryer, taking a bath within two hours, and carefully checking for and removing ticks on both humans and pets can help reduce the risk for Lyme disease.

There are also environmental interventions that have been attempted, but none are widely regarded as extremely effective. Attempts to control rodent and deer population infection were limited in efficacy. Though landscape management is very effective, it also carries a high labor and cost investment. However, when possible, managing long grass, shrubs, and the transition point between the woods and yard should be considered to reduce personal risk.

PERSPECTIVE AND PROSPECTS

Since its discovery in the 1970s, Lyme disease has progressed from a small cluster of outbreaks in Lyme, Connecticut, to one of the most prevalent vector-borne illnesses in North America and Europe. With infection rates estimated to exceed 400,000 cases annually, a great deal of research has uncovered the spirochete that causes this infection, ideal treatment regimens that eradicate the bacteria, and that seek to understand prevention and potentially eradication of this infectious risk.

Continued research on this topic is being invested into vaccines and monoclonal antibodies for prevention. Defining chronic Lyme versus posttreatment Lyme disease syndrome is also a potential consideration for ongoing research. Major organizations widely recognize the prominence of Lyme disease as a public health threat at this point. Greater awareness will likely improve understanding of this topic in the coming years.

See also: Patient safety and rights.