Lyme disease is the most commonly reported vector-borne disease in the United States.1 It is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans and animals that have been bitten by infected deer ticks, also called black-legged ticks (Ixodes scapularis).1,2 Deer ticks feed on the blood of three different hosts: white-footed mice, deer, and humans.
Once an infected deer tick has bitten its human host, the transmission of the bacterium can take anywhere from a few hours to more than a day. Deer tick bites frequently go undetected in humans because of the deer tick's extremely small size. Larval and nymphal deer ticks are typically no larger than the head of a pin, and a bite may be evident only with careful examination. (See Deer ticks or black-legged ticks.) If left untreated, the bacterium will travel through the bloodstream of the host and integrate itself into different areas of the body, causing a variety of mild to severe symptoms.
Lyme disease was first discovered in Old Lyme, Connecticut, in 1975 when a cluster of patients presented with uncommon arthritic symptoms. By 1977, the first 51 cases of “Lyme arthritis” had been described and I. scapularis was linked to the transmission. B. burgdorferi was identified in 1982, and serologic testing was available in 1984.3 From that initial cluster of patients in 1975, Lyme disease has risen to endemic proportions in the northeast and upper midwestern United States.
The CDC identifies 14 states as having the highest prevalence of Lyme disease, accounting for 96% of all reported cases: Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, and Wisconsin.4 National surveillance of both confirmed and probable reported cases of Lyme disease by state from 2006 to 2016 supports identification of these states. These areas of the United States are home to large populations of deer and white-footed mice, the deer tick's preferred hosts, and place B. burgdorferi close to highly developed areas populated with humans.
In addition to the CDC's efforts, research on Lyme disease is supported by many organizations within the National Institutes of Health, such as the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.5
More than 30,000 cases of Lyme disease are reported each year in the United States from health departments in every state and the District of Columbia; however, it is suspected that up to 10 times as many cases go unreported.6 Additional research estimates that 296,000 to 376,000 individuals filed medical claims based on a diagnosis of Lyme disease with a large U.S. insurance company annually.6
Regardless of the discrepancy between Lyme disease cases that are reported to the CDC and the number of individuals diagnosed each year, experts agree that the incidence rests between an estimated 300,000 and 329,000 cases annually.6,7
Lyme disease can affect individuals of any age, and signs and symptoms are reported as acute or chronic. Lyme disease is most prevalent in children because of their proximity to the ground and their increased likelihood to play in grassy areas where ticks may reside.7
The economic impact of Lyme disease on healthcare costs in the United States has not been widely researched. After initial antibiotic treatment for patients with Lyme disease, ongoing symptoms that may occur may have considerable long-term impact on healthcare costs.
Annual healthcare cost per individual diagnosed with Lyme disease is approximately $2,968, bringing the total direct medical costs attributable to Lyme disease and posttreatment Lyme disease syndrome (PTLDS) to be between $712 million and $1.3 billion annually.8 Because the number of Lyme disease and PTLDS cases continues to increase each year, healthcare costs can be expected to increase exponentially.
The saliva from an infected tick of the I. scapularis genus transmits B. burgdorferi into the skin while feeding. Once the saliva containing spirochetes enters the bloodstream, it can interrupt the normal protective immune response. The disrupted immune response allows the spirochetes to establish themselves locally. Once localization is established, the spirochetes multiply and spread outward to the dermis, causing the Lyme disease hallmark symptom of the bull's eye rash (erythema migrans [EM]), which is a reaction to the immune system's initiation of the inflammatory response to the invading organism. (See Erythema migrans.)
Neutrophils typically respond during the inflammatory response to eliminate the bacteria from the dermis but fail to do so, leaving the spirochetes to proliferate and survive. The neutrophils cannot mobilize to the affected area to eliminate the bacteria. Failure of the neutrophils to protect the host is due to the protein plasmin of the spirochete that allows it to hide from the immune system.
In addition, the protein plasma of B. burgdorferi and the production of spirochetes reduce or alter the receptor sites of surface proteins that are normally targeted by antibodies, inactivating the complement system and allowing the bacteria to be deposited in the extracellular matrix. Because the bacteria are deposited in the extracellular matrix, this makes it difficult for the immune system cells to reach the bacteria essentially persevering in the body for years without causing symptoms.9-11
Lyme disease clinical presentation
The early signs and symptoms of acute Lyme disease can be subtle and are often overlooked. The diagnosis of Lyme disease should be made based on presenting symptoms, reported tick bite, and history of being in a tick-abundant area. Serologic testing can often give false-positive results if performed within the first month after initial infection.1 If a positive Lyme titer is noted, Lyme disease is usually treated with antibiotics.
The first symptom noticed by most patients and medical providers is EM. It usually migrates from the site of the tick bite and appears as a solid red expanding blotch or a central ringed spot (similar to a bull's eye). It will appear 3 to 30 days after the transmission of Lyme disease, and is an average of 5 to 6 inches in size. It will persist for about 3 to 5 weeks and may be warm to touch; it is usually not painful or pruritic.
Only 70% to 80% of individuals with Lyme disease present with EM.1,4 If early localized Lyme disease is not treated, patients may develop multiple secondary circular rashes as spirochetes spread throughout the body.
Other signs and symptoms of acute infection are flulike symptoms such as pyrexia, chills, and multiple edematous lymph nodes. Patients will present with extreme fatigue, cephalgia, migrating myalgia, and arthralgia. These symptoms may occur as early as 7 to 14 days after exposure but may take up to 30 days after the tick bite to present.
If treatment does not occur during the initial stages of Lyme disease (during the first 1 to 2 weeks and up to 30 days) when the patient is symptomatic with rash and flulike symptoms, neurologic complications can occur in the second stage or early disseminated stage of Lyme disease.5 The patient will experience parasthesia in the extremities, pain, and weakness. They may present with Bell palsy (paralysis of the facial muscles) or visual disturbances.4,5
Other neurologic complications include meningitis-type symptoms such as fever (100° F to 102° F [37.7° C to 38.8° C]), stiff neck, and severe headaches.1,5 Subtle cognitive difficulties may also occur at this stage. The patient may become forgetful or complain of problems with short-term memory. Encephalitis, encephalomyelitis, and subtle encephalopathy may occur.4
Cardiac manifestations may include conduction abnormalities such as atrioventricular (AV) heart block. In the disseminated stage of Lyme disease, patients may experience heart palpitations or dysrhythmia and develop myocarditis or pericarditis.4 Other manifestations may include conjunctivitis, keratitis, or uveitis. The patient may develop mild hepatitis or present with splenomegaly on exam.
During the second or disseminated stage of Lyme disease, when the infection is well established, serologic tests are almost always positive. There is a higher tendency for test results to show false-negatives within the first 30 days of infection. Most patients with Lyme disease respond well to treatment with antibiotics; the infection is almost always cured when treated early. Additional antibiotic treatment may be required for the small percentage of patients with a recurrence of symptoms.1,5
Although the etiology is unknown, PTLDS occurs in approximately 5% of patients treated successfully for Lyme disease.12 Patients with similar symptoms as those found in PTLDS, such as fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome, are also grouped in the chronic Lyme disease category.10 Many of these patients never underwent Lyme disease testing. Some researchers believe that their symptoms are the result of undiagnosed and subsequently untreated Lyme disease.
Following antibiotic treatment, many patients report persistent manifestations of Lyme disease. Posttreatment B. burgdorferi-positive cultures and polymerase chain reaction, which has a high sensitivity for Borrelia bacteria, support the diagnosis of a persistent infection. Clinical manifestations, serologic findings, and detection of infectious agents contradict each other.13,14 Approximately 20% of patients will continue to report recurrent symptoms after antibiotic treatment.15
Approximately 36% of patients report new-onset fatigue, approximately 20% report widespread pain, and approximately 45% report neurocognitive deficits.16 Patients without evidence of B. burgdorferi infection who present with a group of persistent symptoms are considered to have a chronic form of Lyme disease.17,18 According to the International Lyme and Associated Disease Society (ILADS), failure to fully eradicate the infection may result in the development of a chronic form of Lyme disease that may cause increased patient morbidity and costs.19
PTLDS has multiple causes, typically related to the survival mechanisms of the B. burgdorferi species. Theories include evasion of the immune response due to alterations in B. burgdorferi form, it can morph itself into cyst forms, spheroplasts, L-forms, and round bodies. The morphologic modifications allow the B. burgdorferi to be resistant to antibiotic treatment, requiring alternative treatments or dosing strategies.20
Altering the immune response is another theory of persistent infection with B. burgdorferi. It is thought that B. burgdorferi influences immunomodular response on host cells, altering neutrophil and macrophage response and dendrite functioning interfering with cell receptors, signaling Lyme disease at different times. It is thought that complement-mediated killing and altering cytokine and chemokine levels modify recognition of cells that direct the killing of pathogens that bypass the complement-mediated killing and are able to persist within the host.21,22
Late manifestations of Lyme disease
According to the 2017 CDC case definition, for purposes of surveillance, late manifestations include any of the following when an alternate explanation is not found:
- Attacks that are occurring over weeks or months with joint swelling developing into chronic arthritis in one or more joints
- Myalgia, arthralgia, or fibromyalgia alone do not meet criteria for musculoskeletal involvement
- If progressive arthritis is not preceded by an attack, it is not considered musculoskeletal involvement.23
- Lymphatic meningitis, cranial neuritis facial palsy, encephalomyelitis that cannot be explained by any other cause
- Headache, fatigue, parasthesia, and mildly stiff neck alone are excluded from the criteria.23
- Myocarditis associated with second-degree or third-degree AV heart block resolving in days
- Palpitations, bradycardia, bundle branch block, and myocarditis alone are excluded from the criteria.23
PTLDS clinical presentation
Common signs and symptoms of patients with PTLDS include complaints of fatigue, malaise, neck pain and stiffness, headache, generalized pain, and fever. If left untreated, the disease can progress with patients reporting having rheumatologic manifestations such as transient, migratory arthritis in one or more joints. Patients will most likely complain of intermittent or transient tendonitis, bursitis, and pain in their muscles and bones. If left untreated, arthritis can occur in the recurring joint or in different joints.4 Patients will experience arthritic pain and swelling in one or two large joints, most often the knees.1 A complete evaluation of the musculoskeletal system is indicated, including joint assessment for pain, swelling, and joint deformities.
A thorough neurologic exam is recommended. Patients will often complain of disorientation, confusion, and dizziness. Other symptoms include short-term memory loss and an inability to concentrate, which may negate their ability to work, drive, or perform simple tasks. Another complaint is often the inability to finish sentences or follow conversations. Patients often describe it as being in a mental “fog.”1 In addition to the cognitive symptoms, patients will also experience numbness of their arms and hands or legs and feet. This may be fleeting or migratory, lasting for undesignated amounts of time, or be continuous.
As neurologic involvement progresses, nuchal rigidity and sensorimotor disturbances may be seen as well as changes in the Mini-Mental State Exam for impaired problem resolution. EM as mentioned before, usually seen early in the disease, may return later in the disease as well.24 As the disease progresses, musculoskeletal changes tend to dominate; edematous joints are present and are usually painful to the touch. Neurologic abnormalities such as encephalopathy may produce gait changes.24
Irritability and sleep disorders are two other neurologic complications of disease progression.5 Irritability, mood disturbances, and sleep dysfunction are the result of mild-to-severe encephalopathy, polyneuropathy, and profound fatigue. Nerve and joint damage occurs in varying degrees for patients with late-stage Lyme disease and can be permanent.5
As the disease progresses, organ-specific physical abnormalities can be found on objective exam. Dysrhythmias and a prolonged PR interval are common cardiac findings, however, third-degree AV heart block is rare.25,26
Differential diagnosis of Lyme disease can be complex due to the nonspecific subjective findings. Infection with B. burgdorferi can impersonate signs and symptoms of other diseases, such as fibromyalgia, chronic fatigue syndrome, and amyotrophic lateral sclerosis. Dementia, Parkinson disease, and Guillain-Barré syndrome are neurologic and psychological diseases to consider.27
Controversy surrounds treatment considerations for patients with PTLDS. Some questions surrounding treatment of PTLDS and its underlying cause include the following: Is B. burgdorferi responsible for persistent symptoms that present after the customary course of antibiotic treatment for Lyme disease? Are the symptoms related to treatment failure?19,28
The ILADS has published evidence-based guidelines for practitioners to use to determine the effective use of antibiotic retreatment in patients with PTLDS. The ILADS guidelines use an evidence-based approach to decrease morbidity and increase the quality of life for patients with PTLDS, and adopt a patient-centered approach for decision making with risk/benefit assessment. Treatment excerpts are found below while the full evidence-based treatment guidelines can be found at https://doi.org/10.1586/14787210.2014.940900.
ILADS recommends three components to the treatment approach:19
Patients with continuing manifestations of Lyme disease should be given information about antibiotic retreatment during a clinical visit. Treatment options such as common adverse reactions to antibiotics should be discussed with the patient. A common adverse reaction of antibiotics is Clostridium difficile; this may require an addition of probiotics to the treatment plan.19
The original Lyme disease diagnosis must be reevaluated and assessed for other causes of continued disease manifestations. Included in the reevaluation is the investigation of any other tick-borne illness.19 Jointly with their clinician, patients should be involved in the therapeutic treatment plan specific to this clinical episode. The initial retreatment course of antibiotics is 4 to 6 weeks. Individualized treatment options are available and extensive based on specific patient variations.19
Once the course of antibiotics is completed, clinicians must reevaluate for treatment effectiveness and assess for any needed adjustments to the treatment plan. In cases of severe disease and treatment risk, it may be necessary to reevaluate more frequently. A multidisciplinary individualized care is the focus of treatment. Educational information should be provided to the patient about symptoms and symptom management, support groups, and the need for psychological evaluation if indicated.19 (See Resources.)
The best prevention for Lyme disease is to avoid tick-infested areas, particularly areas where deer and mice thrive, such as shady and moist areas with tall grass, brush, low tree branches, or shrubs. Gardens and lawns, especially areas at the edge of woods or bordering stone walls, are also high-risk areas.
Precautions can be taken if spending time in these areas. Individuals visiting high-risk areas should wear lightweight, light colored, long-sleeved shirts and long pants. Tuck the pants into closed-toe shoes or boots to prevent ticks from climbing up legs. The light color makes it easier to see ticks against the fabric.
Use an insect repellent containing diethyltoluamide (also known as DEET).2 Wear clothing that has been treated with permethrin, or spray shirt collars and pant and shirt cuffs with insect spray. Pull back long hair, or cover hair with a hat for protection. Do not sit on the ground while outside. After returning home, check for ticks thoroughly. Carefully inspect areas such as armpits, behind the knees, in the hair, and in the groin. Shower or bathe as soon as possible after spending time outdoors. Wash clothes and place them in the dryer on high heat to kill any remaining ticks.2
An infected tick cannot normally begin to transmit the spirochete to its host until it has been attached for 36 to 48 hours.29 Therefore, examining oneself daily and removing any ticks before they become engorged with blood is in itself a preventive measure.
After a recognized tick bite, the Infectious Diseases Society of America does not recommend antimicrobial treatment for the prophylaxis of Lyme disease. Yet, a single dose of doxycycline may be offered to adult patients who are not pregnant and to children older age 8 years in highly endemic areas when all of the following circumstances are present:29
- The patient does not have an allergy to the drug and there are no other contraindications to doxycycline.
- The attached tick can be identified as an adult or nymphal I. scapularis tick.
- The estimated time of tick attachment is longer than 36 hours; this is determined based on the degree of engorgement of the tick or the estimated time of tick attachment.
- Prophylaxis can be started within 72 hours of tick removal.
- Lyme disease is common in the county or state where the patient lives or has recently traveled.
Lyme disease is a multifaceted illness in which patients may experience both acute and chronic persistent signs and symptoms. Understanding the course of Lyme disease and the history of chronic symptoms is key to management. Early acknowledgment of Lyme disease sequelae can help in managing the disease and reducing symptoms. Practitioners and patients must work collaboratively to increase positive outcomes.
The Lyme Disease Association: www.lymediseaseassociation.org/resources
LymeLight Foundation: www.lymelightfoundation.org
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20. Lantos PM, Auwaerter PG, Wormser GP. A systematic review of Borrelia burgdorferi
morphologic variants does not support a role in chronic Lyme disease
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. J Inflamm Res
. 2016;9:91–102. doi:10.2147/JIR.S104790.
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24. Oczko-Grzesik B, Kępa L, Puszcz-Matlińska M, Pudło R, Żurek A, Badura-Głąbik T. Estimation of cognitive and affective disorders occurrence in patients with Lyme borreliosis. Ann Agric Environ Med
. 2017;24(1):33–38. doi:10.5604/12321966.1229002.
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. 2014;8:15–26. doi:10.2147/IJGM.S75825.
27. Lantos PM. Chronic Lyme disease
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28. Bogdos M, Giannopoulos S, Kosmidou M. The conflict on posttreatment Lyme disease syndrome
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