Lyme Disease Update for Pharmacists

RELEASE DATE

April 1, 2020

EXPIRATION DATE

April 30, 2022

FACULTY

Kiran Panesar Anwer, BPharm (Hons),
MRPharmS, RPh, CPh, MPSK
Consultant Pharmacist, Medical Writer,
Public Health Specialist trainee
Lusaka, Zambia

FACULTY DISCLOSURE STATEMENTS

Dr. Panesar Anwer has no actual or potential conflict of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT

acpePharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

UAN: 0430-0000-20-034-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL

To educate pharmacists about the diagnosis, prevention, and treatment of Lyme disease based on newly updated draft guidelines.

OBJECTIVES

After completing this activity, the participant should be able to:

  1. Identify risk factors that can lead to Lyme disease.
  2. Recognize the signs and symptoms of Lyme disease.
  3. Review counseling points for patients on preventing tick bites in humans and how to safely remove ticks.
  4. Discuss the therapeutic options for the various stages and manifestations of Lyme disease.

ABSTRACT: Lyme disease, a vector-borne bacterial infection, is a growing burden in the United States. It is spread by the black-legged tick that thrives living on the white-footed mouse and deer. If left untreated, Lyme disease can develop to late manifestations, affecting the joints, nervous system, or the heart. Pharmacists and healthcare professionals have a major role to play in raising awareness of Lyme disease, particularly in areas where it is less common. To that end, an updated Lyme-disease guideline has been drafted by the Infectious Diseases Society of America, the American Academy of Neurology, and the American College of Rheumatology. Pharmacists and their teams can recognize the signs and symptoms of Lyme disease and provide advice on prevention and management.

Lyme disease is a vector-borne, zoonotic infection caused by bacteria species Borrelia, particularly the Borrelia burgdorferi and rarely, Borrelia mayonii.1 The bacteria are transmitted from infected ticks of the genus Ixodes to humans via tick bites.2

Two types of ticks are responsible for transmitting Lyme disease bacteria (B burgdorferi) to humans: the blacklegged ticks (Ixodes scapularis, also known as deer ticks) in the New England and Great Lakes areas, and the western black-legged tick (Ixodes pacificus) in the West.3

In the United States, the white-footed mouse is the primary animal reservoir for Lyme disease. While other mammals, including dogs, can develop Lyme disease, they cannot directly transmit it to humans.3 Likewise, Lyme disease is rarely transmitted from person to person but rather is vector-borne.4

Ticks are the only vectors for Lyme disease; fleas, flies, and mosquitoes cannot carry the bacteria.3 Ticks cannot jump or fly—they wait in a position known as questing, whereby they hold onto leaves and grass by their third and fourth pair of legs with their first pair of legs outstretched, waiting to climb onto the host.5,6 If a host brushes against the spot where the tick is waiting, the tick quickly attaches to the host.

I scapularis ticks generally live for 2 years, during which time they go through four life stages: egg, larva, nymph, and adult.7 At each of these stages, the ticks need a new host for a blood meal in order to survive. Black-legged ticks can feed from mammals, birds, reptiles, and amphibians.

Nymphal and larval forms of the Ixodes tick thrive off the white-footed mouse, while adult ticks feed on deer.3 When counseling patients on identifying the ticks, it is useful to note that Ixodes ticks are much smaller than common dog ticks. Ticks in the larval and nymphal stages are only a few millimeters in diameter; adult ticks are larger. Since it takes about 36 hours after a bite for the spirochetes to migrate from the tick gut to the salivary glands, infection can usually only be transmitted after feeding for 36-48 hours, although the minimum time may be as little as 24 hours.3

History

In the early 1900s, a rash, now known as erythema migrans (EM), that was both erythematous and migrating and occurred after tick bites was noted by physicians in Europe. In the 1940s, this rash was found to be associated with a systemic illness thought to have been caused by the spirochete-like bacteria isolated from skin specimens of the EM lesions. Subsequently it was shown that penicillin could be used to successfully treat this tick-borne illness.3

Shortly thereafter, physicians in New England found that the children in an area around Lyme, Connecticut, had an unusual rash and associated arthritis. Further investigation of the clinical symptoms and the demographic background suggested that the children were suffering from the same disease that was most likely transmitted by a tick. In 1977 the condition was labeled Lyme disease, and in 1982, researchers found B burgdorferi spirochetes related to the illness in the intestinal tract of the adult deer tick Ixodes dammini (also known as the black-legged tick and currently referred to as I scapularis).3 The CDC began surveillance for Lyme disease at this point, and in 1991 Lyme disease was classified as a nationally notifiable disease.8

As a notifiable disease, clinicians and laboratories report possible cases of Lyme disease to local and state health departments, which then conduct case investigations to classify cases according to the national surveillance case definition. Those that qualify as confirmed or probable cases of Lyme disease are reported to the CDC through the National Notifiable Disease Surveillance System (NNDSS). A number of notable revisions have been made to the case definition of Lyme disease, with the most recent one occurring in 2017.9

Epidemiology and Economic Burden of Disease

Lyme disease is the most commonly occurring vector-borne disease and the sixth most commonly reported notifiable infectious disease, with estimates showing that approximately 300,000 people may get Lyme disease each year in the U.S.1

The CDC recorded a total of 42,743 confirmed and probable cases of Lyme disease in 2017. This was 17% higher than for 2016. It is thought that these figures may be conservative, given underreporting estimates of eightfold to tenfold in the U.S.10

Furthermore, data from the NNDSS have shown that areas associated with a high incidence of Lyme disease are growing and that the number of counties with an incidence of 10 or more confirmed cases per 100,000 persons increased from 324 in 2008 to 454 in 2017.1 The greatest risk of Lyme disease tends to be in the Northeast, mid-Atlantic, and upper Midwest, with pockets of lower risk along the West Coast. High-risk areas are directly associated with a greater presence of the white-footed mouse and white-tailed deer, both important hosts in the life cycle of the Ixodes tick.3,11

The increase in Lyme disease cases has been attributed to a range of factors. Climate change has contributed to the expansion of tick-habitable environments, leading to the increase in geographical areas where Lyme disease is noted.12 Additionally, environmental factors, such as human encroachment into habitats favorable to ticks and their hosts, deforestation, and increased human outdoor activities have a role to play in the growing number of Lyme disease cases. As such, the World Health Organization has made Lyme disease a priority.13

Although most patients with Lyme disease fully recover with prompt diagnosis and treatment, untreated Lyme disease can develop into debilitating sequalae, including arthritis, carditis, and neurologic and ocular manifestations.14

All these factors put together mean that Lyme disease results in the excessive use of healthcare services and imposes a burden on the U.S. economy, with estimated healthcare costs of up to $1.3 billion per year, and rising.15,16

Ticks can also cause other conditions, such as tickborne encephalitis; human granulocytic anaplasmosis; babesiosis, as a single infection or coinfection; and potential allergies to tick saliva.12,17

Risk Factors

Lyme disease affects people of both sexes equally, with the highest number of cases occurring in children aged 5 to 14 years and adults aged 55 to 70 years.3 Variables associated with increased probability of tickborne disease include deer abundance, landscapes interspersed with herbaceous and forested habitat, low human population density, gardens, pet ownership, participating in recreational outdoor activities such as walking, off-road cycling, and horseback riding, as well as certain occupational activities, such as outdoor work. Bite risk is higher in pet owners.18

Signs and Symptoms

The signs and symptoms of Lyme disease progress as the disease advances, and in many cases they may not be typical, making diagnosis difficult. There are three stages in Lyme disease: early localized disease, early disseminated disease, and late disease.

EM, the most distinctive sign of Lyme disease, is a slowly expanding skin rash and is found in about 60% of cases. It first presents about 1 to 4 weeks after the bite and lasts up to several weeks. The rash often has a typical bull’s-eye appearance, a red ring around a clear area with a red center.18 The rash is not painful, itchy, hot, or scaly and can appear at different sites on the body and grow larger as the infection spreads.19 Patients who do not present with EM can be difficult to diagnose, especially since it is not easy to ascertain the history of a tick bite. It is thought that only 50% to 70% of individuals recall a tick bite.20 These patients may be misdiagnosed or receive a delayed response.21

EM, which is associated with intense inflammation and a systemic spread of the pathogen, seems more common in the U.S. than in Europe. It is thought that this may be because only one species of B burgdorferi sensu stricto is responsible, whereas in Europe, other species—Borrelia afzelii and Borrelia garinii, and recently Borrelia spielmanii—have been shown to cause Lyme disease.22

The early localized stage is characterized by flu-like symptoms, including fever and sweats, chills, malaise, myalgias, arthralgia, headache, and tender local adenopathy.2 As the disease progresses, the symptoms may include headache, fever, tender regional adenopathy, conjunctivitis, carditis, and neurologic manifestations such as meningitis and cranial nerve palsy.

The late phase of the disease, which can occur months to years after the bite, is characterized by arthritis in the U.S., mostly occurring in the large joints, especially the knee. In Europe, neurologic symptoms are more common than arthritis in the late phase, possibly due to the variation in the Lyme disease–causing bacteria.23 Arthritis may sometimes be confused with arthralgia; the distinguishing factors are the presence of warmth, swelling from effusion, and limited range of motion associated with arthritis.

Diagnosis

When assessing a patient for Lyme disease, healthcare providers should consider the likelihood that the patient has in fact been exposed to infected blacklegged ticks in addition to the presenting signs and symptoms. If the pretest probability of Lyme disease exceeds 80%, then laboratory testing is unnecessary and treatment may be initiated.

Laboratory tests may be ordered if the diagnosis is uncertain.1 Common laboratory tests do not reveal Lyme disease, and serologic tests for Lyme disease may support the diagnosis but are not always essential for the diagnosis.3 The CDC recommends a two-step process using the same blood sample that detects the presence of antibodies against B burgdorferi in a patient’s blood. The first step involves an enzyme immunoassay (EIA) or immunofluorescence assay (IFA)–total Lyme titer or immunoglobulin A and immunoglobulin M titers.1 This is followed by a more specific Western immunoblot test that is performed if the results of the first step are positive (or indeterminate). If the first step is negative, then no further testing is required. The EIA or IFA tests are sensitive but not necessarily specific; the Western immunoblot is more specific to Lyme disease. Therefore, the overall result is considered positive if both steps are positive.1

It is important to keep in mind that these tests are prone to false negatives and false positives. The EIA and IFA tests may not be as sensitive early in the disease since antibodies to B burgdorferi may not be present in the blood sample.3 This can potentially lead to a false-negative result. On the other hand, mononucleosis, autoimmune states, and Treponema pallidum infection can lead to false positives; therefore, testing is not recommended if the pretest probability of Lyme disease is lower than 20%.3 Additionally, since antibodies often persist in the blood for months or years, it may be difficult to distinguish an active infection from a past infection. The overall false-positive rate of Lyme disease testing is approximately 5%.3

In an attempt to streamline diagnosis, the FDA cleared tests with new indications in July 2019. In the new indications, two enzyme immunoassays are run concurrently or sequentially rather than in the two-step process described above.24 Clinical tests showed that this alternative approach is as accurate as the two-tiered process.24

In late phases of Lyme disease, other tests such as joint aspiration, cerebrospinal fluid analysis, and electrocardiogram (ECG) may be ordered. An ECG is recommended in patients with signs and symptoms consistent with Lyme carditis such as dyspnea, edema, lightheadedness, chest pain, and syncope.

Management

There is currently no vaccination on the market for the prevention of Lyme disease. Therefore prevention of a tick bite or chemoprophylaxis is important. If the infection is manifest, then treatment using antibiotics is required.

Prevention

The vaccine to protect against Lyme disease, LYMErix, was discontinued by the manufacturer in 2002 due to low usage.24 Although there is no other vaccine on the market, the increase in Lyme disease cases has led to an increase in interest in the development of a replacement vaccine, since vaccination shows potential as the most effective way of preventing Lyme disease and reducing its economic burden.25,26

One of the new approaches is a vaccine that works by stimulating the immune system to make antibodies that can attack B burgdorferi and other types of Borrelia, the bacteria that cause Lyme disease.27 The other is an injection of a single antibody.27

VLA15: VLA15 uses similar approach to LYMErix in that both vaccines target the outer surface protein A (OspA) of B burgdorferi. OspA is one of the most dominant surface proteins expressed by the bacteria when present in a tick.28 VLA-15 is a multivalent subunit vaccine that contains six different serotypes.29 The FDA granted the VLA-15 program Fast Track designation in July 2017.28 It is currently undergoing phase II clinical development with interim phase II data to be announced in 2020.28

In an attempt to streamline diagnosis, the FDA cleared tests with new indications in July 2019. In the new indications, two enzyme immunoassays are run concurrently or sequentially. Clinical tests showed that this approach is as acurate as the two-tiered process.

Lyme PrEP: The University of Massachusetts Medical School is using a different approach in Lyme pre-exposure prophylaxis (Lyme PrEP). This delivers a single defensive antibody and, as such, is not a vaccine.27

Pharmacists should note that since the effects of LYMErix were short-lived, those who were vaccinated before the vaccine was discontinued are probably no longer protected. These patients should therefore be managed in the same way as patients who have never received the vaccine.1

Ticks live in grassy, brushy, or wooded areas and on animals and are most active during the warmer months, although tick exposure can occur all year round.1 When counseling patients on preventing tick bites, pharmacists should also keep in mind pet ownership and how to prevent ticks on animals as well as in the yard. TABLE 1 lists some tips on preventing tick bites.1,5,6

How to Remove Ticks Correctly

Aim to remove the tick promptly, without leaving any parts of the tick attached to the host, and prevent it from releasing additional saliva or regurgitating its stomach contents into the bite wound.

Do:

  • Use an approved tick-removal tool, fine-pointed tweezers, or if neither of these are available, a fine thread (cotton or dental floss)
  • Clean the tool or tweezers with antiseptic before using it
  • Using a fine-pointed tweezers, grasp the tick from the head or mouth (not the body) and pull the tick out without twisting it
  • If using a thread, tie a single loop around the tick’s mouthparts as close to the skin as possible, then pull upwards and outwards without twisting
  • Cleanse the bite site and the tool after tick removal
  • Keep the tick in a sealed container in case a doctor needs to refer to it
  • Wash hands thoroughly

Do not:

  • Squeeze the tick’s body, because this may cause the head and body to separate, leaving the head in the skin
  • Use your fingernails to remove a tick, because an infection can occur through any breaks in the skin
  • Crush the tick’s body, because it may regurgitate its infected stomach contents into the bite wound
  • Apply anything to kill the tick off, because any discomfort to the tick can cause regurgitation or saliva release

Antibiotic Prophylaxis

In areas where tick bites are extremely common, the risk of infection after a prolonged bite can be anywhere between 10% to 25%.30,31 Antibiotic prophylaxis should be administered to patients within 72 hours of removing a tick after a high-risk bite, but not after lower-risk bites. High-risk bites are those that are from an engorged Ixodes tick, in a highly endemic area, and have been attached for 36 hours or more. Since spirochetes need up to 36 hours after a bite to migrate from the tick gut to the salivary glands, there is no risk of transmission of B burgdorferi from an unengorged tick, and routine antibiotic prophylaxis is not recommended in such cases.32-34

A single dose of 200 mg doxycycline for adults and 4.4 mg/kg, up to a maximum of 200 mg, for children aged 9 years and older is typically recommended.35

Doxycycline has traditionally been contraindicated in children aged 8 years and younger, as well as pregnant women, due to possible staining of primary teeth, concerns that are largely based upon findings from tetracycline rather than doxycycline. More recent research suggests that doxycycline for up to at least 14 days is safe in young children, and there is a growing consensus on supporting the use of doxycycline in this group.35 There are not enough data on the safety of doxycycline in breastfeeding women, and therefore its use is not currently recommended.

Treatment

Most patients with Lyme disease recover rapidly and completely with appropriate antibiotic treatment. The choice of antibiotic, route of administration, and duration of therapy for Lyme disease depend upon the patient’s clinical manifestations, stage of disease, and the presence of any concomitant medical conditions or allergies.

Several groups have published Lyme disease guidelines. The most recent guideline has been drafted by the Infectious Diseases Society of America, the American Academy of Neurology, and the American College of Rheumatology. It was made available for public comments up until September 9, 2019, and a final guideline is yet to be published.36 The draft guidelines state that the aim of treatment is the “resolution of objective signs and symptoms of infection with prevention of relapsed active infection or new complications of infection.”35

B burgdorferi is susceptible to a range of antimicrobials, including doxycycline, penicillin, amoxicillin, cefuroxime, ceftriaxone, and azithromycin.1,35 Oral therapy is preferred over IV therapy where possible, due to ease of administration and tolerability.

In early localized or early disseminated Lyme disease associated with EM, the draft guidelines recommend doxycycline, amoxicillin, cefuroxime, or phenoxymethylpenicillin as first-line agents, and azithromycin as a second-line agent in patients who are not able to tolerate or have contraindications to the first-line agents.35 Some, but not all, studies show equal efficacy of azithromycin to first-line agents.

Children under age 8 years and pregnant or nursing women with early localized or early disseminated Lyme disease in whom doxycycline is contraindicated can be given amoxicillin or cefuroxime axetil.35

Patients presenting with Lyme disease with neurologic manifestations can be prescribed IV penicillin G, ceftriaxone, or cefotaxime or oral doxycycline, when not contraindicated.35

For treatment of Lyme arthritis, the draft guidelines recommend an oral course of antibiotics for 28 days. If there is a partial response, with mild residual joint swelling, retreatment with oral antibiotics may be required. For patients who do not respond to the initial course of antibiotics at all (moderate-to-severe joint swelling), IV ceftriaxone is proposed.35

Patients who do not respond to any of the above antibiotic regimens are said to have post-antibiotic Lyme arthritis (previously known as antibiotic-refractory Lyme arthritis) and should be referred to a rheumatologist. They may be managed using nonsteroidal anti-inflammatory drugs, intra-articular corticosteroids, disease-modifying antirheumatic drugs, biologic response modifiers, or synovectomy, depending upon their symptoms.35

Patients who develop Lyme carditis will require total antibiotic therapy for 14 to 21 days. Those who have significant PR prolongation, other arrhythmias, or clinical manifestations of myopericarditis such as symptoms of left ventricular dysfunction should be hospitalized and monitored continuously. IV ceftriaxone should be initiated until evidence of improvement, after which patients can be switched to oral antibiotics to complete treatment.35 Temporary pacing is recommended, rather than a pacemaker, for such individuals, as symptoms will improve within a few days.35

Patients with carditis who do not require hospitalization can be managed with the oral antibiotics doxycycline, amoxicillin, cefuroxime, or azithromycin.

TABLE 2 lists the recommended dosages for antibiotics used in the management of Lyme disease.

Role of the Pharmacist

Pharmacists and other healthcare practitioners, particularly those in areas of endemicity, should become familiar with the clinical manifestations and recommended practices for diagnosing and treating Lyme disease. Furthermore, they should be vigilant for patients presenting with EM over the summer months and for patients with flu-like symptoms at a time when seasonal flu is receding. Such patients should be advised to seek medical help as soon as possible.

In addition, pharmacists can provide advice on how to avoid ticks and prevent tick bites, how to check for ticks, and how to safely remove ticks, as well as counsel patients on treatment options, if necessary.

REFERENCES

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  34. Piesman J, Maupin GO, Campos EG, et al. Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method. J Infect Dis. 1991;163(4):895-897.
  35. [Guideline] Lantos P, Rumbaugh J, Bockenstedt L, et al. Draft clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2019 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. IDSA. idsociety.org/practiceguideline/Lyme-Disease-Guideline-Public-Comments/. June 27, 2019. Accessed December 1, 2019.
  36. Infectious Diseases Society of America. IDSA/AAN/ACR Draft Lyme Disease Guidelines. www.idsociety.org/practice-guideline/Lyme-DiseaseGuideline-Public-Comments/. Accessed November 30, 2019.