Chapter VI.28. Lyme Disease
Jennifer W. Sasaki, MD
October 2022

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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Judy Makowski Vincent, MD. This current third edition chapter is a revision and update of the original author's work as well as the second edition.


In the month of August, a 9-year-old boy is brought to the pediatric clinic with the chief complaint of a large, red circular rash on his left thigh. The rash has been present for two weeks and has been enlarging. His father states that three weeks ago, the family was visiting relatives at a farm in Connecticut, and one day after playing outside in the woods, the boy was found to have a tick attached to his thigh. His father removed the tick with tweezers; however, a red macule remained at the site where the tick had been attached. One week after the tick was removed, a red ring developed around the macule. This ring became larger by expanding outward, leaving an area of central clearing. The boy has had a mild headache and myalgias but has remained afebrile.

Exam: VS T 37.1, HR 90, RR 20, BP 100/70. He is alert and active, in no acute distress, and is overall non-toxic appearing. Over the anterior surface of his left thigh, there is an erythematous circular macular lesion, 10 cm in diameter, with central clearing, and a central brown-red macule that is 3 mm in diameter. The thigh is non-tender to palpation. All joints are noted to have full range of motion, no swelling, no warmth, and no overlying erythema. His neck is supple without lymphadenopathy or stiffness. The remainder of his exam is unremarkable.

The skin lesion is diagnosed as erythema migrans, and the patient is diagnosed with Lyme disease with an early localized infection. No laboratory tests are performed. He is treated with 10 days of oral doxycycline 4.4 mg/kg/day divided into two daily doses. His headache and myalgias resolve within one week of treatment, and the erythema migrans resolves completely by the end of the antibiotic course.


Lyme disease is a vector-borne zoonosis, caused by the spirochete Borrelia burgdorferi and transmitted by the Ixodes species of tick. Lyme disease commonly manifests as erythema migrans, which often resolves with treatment. However, it has the potential to progress to a multisystem, multistage disease, affecting not only the skin, but also the heart, joints, and nervous system (1).

A zoonosis is an infectious disease that is transmitted from animals to humans, and vice versa. A vector is a carrier that transfers an infectious agent from one host to another. Lyme disease is caused by the spirochete Borrelia burgdorferi and is transmitted by the Ixodes species of tick. More rarely, and recently discovered, Lyme disease can also be caused by Borrelia mayonii.

National surveillance of annual cases of Lyme disease first started in 1982. Since then, the number of reported annual cases have continued to rise. From 1993 to 1997, an average of 12,451 cases per year were reported by states. By 2019, there were a total of 34,945 cases of Lyme disease reported to the Centers for Disease Control and Prevention (CDC), both confirmed and probable, a 4% increase from 2018 (2). The number of actual cases may be as much as 10-fold greater, largely due to underreporting.

In the United States, Lyme disease is primarily localized to states in the northeastern, mid-Atlantic, and upper north-central regions. However, cases also occur on the west coast, particularly in Northern California. Transmission occurrence varies depending on the distribution of the infected tick vector. Obtaining a travel history to endemic areas is very important, particularly because some manifestations of Lyme disease, such as arthritis, can be a late manifestation months after the initial tick bite.

Ixodes scapularis (the black-legged or deer tick) is the main vector in the northeastern, north central, and mid-Atlantic regions of the United States. Ixodes pacificus (the western black-legged tick) is the most common vector in the western United States.

The 2-year life cycle of the Ixodes tick advances through four stages (egg, larva, nymph, adult), and is central in the transmission of B. burgdorferi. The nymph stage is the most aggressive stage of the life cycle. The majority of early localized and early disseminated disease will occur during spring and summer, related to the prime feeding time of the Ixodes tick (3).

Most cases of Lyme disease result from exposure to infected ticks during activities such as property maintenance, recreation, and leisure activity. Therefore, persons who live or work in wooded areas, or areas with overgrown brush infested with vector ticks, are at risk for acquiring Lyme disease.

Ixodes ticks are small and their bite tends to be painless, often going unnoticed. Many patients with Lyme disease do not recall a tick bite. The incubation period for Lyme disease, from the tick bite to the onset of symptoms, ranges from 3 to 32 days, with a median time of 11 days (4).

There is no evidence to date of Lyme disease being transmitted through human milk. Additionally, there has been no documentation of Lyme disease causing a congenital infection (4).

Much like syphilis, which is also a spirochete infection, Lyme disease classically progresses through three stages: early localized (Stage 1); early disseminated (Stage 2); and late disease (Stage 3). These are summarized in table 1.

Early localized disease (Stage 1): This stage occurs days to weeks following a tick bite. The characteristic feature is erythema migrans, which is the most common manifestation of Lyme disease in the pediatric population (1). Erythema migrans starts as a red macule or papule that then expands (hence the name, migrans) outward from the initial lesion to form a large (often 5 cm or more in diameter), erythematous, annular lesion with a central clearing. The rash can take on various forms, sometimes raised and urticarial-like, or with a dusky coloration, or necrotic, or vesicular. It can be mistaken for drug reactions or cellulitis. The classic bullís eye (target) appearance describing concentric red rings is not always seen, making the diagnosis more challenging. The rash is commonly found in areas of tight clothing, such as the groin, thigh, or axilla. Systemic symptoms may also occur concomitantly, such as flu-like symptoms, including myalgia, headache, fatigue, and possibly fever.

Early disseminated disease (Stage 2): Dissemination of the spirochetes occurs days to months after the appearance of the initial erythema migrans lesion, primarily in those left untreated. In some patients, early disseminated disease may be the initial manifestation of Lyme disease. Commonly during this stage, patients develop secondary erythema migrans lesions, located apart from the site of the tick bite. These lesions are similar to the primary lesion but are usually smaller. They are often accompanied by the same constitutional symptoms as with primary erythema migrans, including fever, headache, and generalized achiness. Other systemic manifestations may occur, such as radiculitis, cardiac involvement (atrioventricular block, myocarditis, pericarditis), nerve palsies (often cranial nerve VII or Bellís Palsy) or lymphocytic meningitis.

Late disease (Stage 3): Late disease occurs in patients who were untreated or inadequately treated at an earlier stage of disease, manifesting months to years following the initial spirochete infection. The spirochetes can evade the immune system and persist in localized areas. In children, this classically manifests as arthritis, predominantly affecting the large joints, most commonly the knees. On exam, the joint may be tender, erythematous, and swollen. If the joint fluid is aspirated and sent for cell count, there will usually be white blood cells present. In comparison to bacterial arthritis, the swelling in Lyme arthritis is often more prominent than the pain or disability. Additionally, the erythrocyte sedimentation rate (ESR) and neutrophilia tend to be lower than in bacterial arthritis (4). More rare late findings of Lyme disease include encephalopathy or encephalitis, peripheral neuropathy, or ophthalmologic conditions (such as optic neuritis, uveitis, conjunctivitis, keratitis).

Table 1 Ė Clinical features of the three stages of Lyme disease
StageClinical Features
1 Ė Early localized diseaseErythema migrans, flu-like symptoms
2 Ė Early disseminated diseaseSecondary annular erythematous lesions, flu-like symptoms, carditis, nerve palsies (e.g., Bellís palsy), arrhythmias, radiculitis, meningitis.
3 Ė Late diseaseArthritis, more rarely encephalopathy, encephalitis, peripheral neuropathy, ophthalmic conditions

The diagnosis of Lyme disease primarily relies on recognizing the characteristic clinical features of the disease in a patient with a likely exposure history (1). In early Lyme disease, the diagnosis is made clinically based on the presence of erythema migrans in a patient with a plausible history of exposure to B. burgdorferi. This is sufficient to make a diagnosis and begin treatment. Less than 50% of children in the early localized stage (stage 1) will have a positive serology. Therefore, the diagnosis of early localized disease does not require laboratory confirmation, nor should it be relied upon. Patients with disseminated disease, either early or late, will often have a positive serology. To make a diagnosis of stage 2 or 3 Lyme disease, a patient must have consistent clinical features, a reasonable exposure history, and a positive serologic test.

Serologic testing for Lyme disease is performed in two stages. The initial test is an enzyme-linked immunosorbent assay (ELISA or EIA) or immunofluorescent (IFA) test. These tests have a high sensitivity but low specificity, therefore false positives are likely. Because of this, a positive or equivocal ELISA test must be followed with a Western immunoblot for confirmation. To be positive, a Western immunoblot requires at least 5 of 10 bands to be detected for IgG and 2 of 3 for IgM; fewer bands should be interpreted as negative. If the ELISA finding is negative, follow-up testing with Western immunoblot is not necessary. Lyme disease serology should be performed only in patients with high clinical and epidemiological suspicion of Lyme disease, and not used indiscriminately for unspecific symptoms (e.g., isolated fatigue, fever, etc.).

In patients with possible Lyme arthritis, serologic testing is preferred over polymerase chain reaction (PCR) or culture. However, in a patient who is seropositive, and the diagnosis of Lyme arthritis requires further confirmation, PCR testing of synovial fluid is recommended (5).

After treatment, it is not recommended to perform a test of cure as antibodies may persist for years. A positive test in a treated patient does not signify a lack of cure or persistence of infection. There are other clinical lab tests for Lyme disease that are not FDA approved and are not recommended diagnostic tests for Lyme disease. These tests include urine tests, CD57 assay, novel culture techniques, and other antibody panels different from those listed above (4).

The constitutional symptoms that commonly present in Lyme disease (headache, arthralgia, fatigue, fever) are also frequent clinical manifestations in many other illnesses, such as common viral illnesses. The southern tick-associated rash illness (STARI) is transmitted via the Lone Star tick; it has a similar clinical presentation to Lyme disease, but the tests for Lyme disease are negative. STARI has been reported in the south central and southeastern region of the United States and presents with mild flu-like symptoms as well as a rash similar to erythema migrans. Fortunately, STARI has not been found to develop any of the disseminated findings of Lyme disease (4,5).

The differential for erythema migrans is wide and includes but is not limited to urticaria, erythema marginatum, cellulitis, and tinea corporis. The differential for the arthritis that presents in Lyme disease includes juvenile idiopathic arthritis, acute rheumatic fever, and reactive arthritis. Lastly, other causes of Bellís palsy (cranial nerve VII) include herpes simplex virus 1, human immunodeficiency virus, and varicella zoster virus infections.

In 2020, the Infectious Diseases Society of America (IDSA) published clinical practice guidelines for the prevention, diagnosis, and treatment of Lyme disease (5). Treatment is dependent on the stage of disease as well as the disease category.

For stage 1 (early localized disease), erythema migrans (single lesion) is treated with doxycycline for 10 days, or amoxicillin or cefuroxime for 14 days. If a child is unable to take any of the above agents, for reasons such as drug allergy, side effect profiles or tolerance, the recommended next-line therapy is azithromycin.

For stage 2 (early disseminated disease), erythema migrans (multiple lesions) is treated with the same oral therapy as early localized disease. Children presenting with isolated Bellís palsy (cranial nerve VII), without clinical manifestations of Lyme meningitis, should be treated with doxycycline for 14 days. It is not recommended to treat facial palsy with corticosteroids. It should be noted that antibiotic treatment does not affect the resolution of facial palsy, rather the purpose of treatment is to prevent the development of late Lyme disease. For carditis or atrioventricular heart block, outpatient or inpatient antibiotic treatment for 14 to 21 days is based on the extent of the patientís cardiac involvement. When the patient has demonstrated clinical improvement, a transition to an oral antibiotic (as used for early localized disease) to complete the course is appropriate. Patients with Lyme meningitis can be treated with oral doxycycline or intravenous ceftriaxone, depending on clinical stability. Recent evidence indicates that for children with Lyme meningitis well enough to be treated as an outpatient, oral doxycycline is an effective alternative treatment to hospitalization and intravenous ceftriaxone.

For stage 3 (late disseminated disease), Lyme arthritis should be treated with the same oral agents recommended for early localized disease, for a total 28-day course. Due to the longer treatment duration, for patients less than 8 years of age, consider an oral agent other than doxycycline (as there is limited safety data on the use of doxycycline for 21 days or longer in children less than 8 years of age). In patients with a partial response (i.e., mild residual swelling) following completion of the first course of oral antibiotic therapy, the guidelines make no concrete recommendation. A second oral course can be considered in patients in whom synovial proliferation is modest compared to joint swelling and for those who prefer repeating a course of oral antibiotics before considering intravenous therapy (5). In patients with little to no response after the first course of therapy, or for patients who experience worsening arthritis, a 14 to 28 day course of ceftriaxone is recommended. Dosing is 50 to75 mg/kg, intravenous, once daily, maximum dose 2 g/day.

Lyme disease in children and adolescents has an excellent prognosis and responds well when treated appropriately. The most common presentation of Lyme disease in children is erythema migrans, and once appropriate treatment is initiated, the lesion usually resolves within several days. Additionally, appropriate treatment will almost always prevent progression to later stages of Lyme disease.

Instances of treatment failure are uncommon. It is not recommended to treat patients with persistent symptoms following appropriate treatment with additional anti-microbial therapy. Most persistent symptoms will gradually resolve and respond well to symptomatic management. Some patients with Lyme arthritis experience persistent synovitis for months to years, sometimes requiring treatment with nonsteroidal anti-inflammatories or intra-articular corticosteroid injections. Other differential diagnoses should be considered as well.

Prevention is best achieved by avoidance of tick habitats. Whenever possible, persons should avoid areas that are likely to be infested with ticks, particularly during spring and summer months when nymphal ticks feed. Ticks favor environments that are shaded, wooded, brushy or overgrown with low-lying vegetation and leaves.

Persons who risk exposure to tick-infested areas should wear light-colored clothing so that ticks can be spotted more easily and removed before becoming attached. Wearing long-sleeved shirts and tucking pants into socks or boot tops can help keep ticks from reaching the skin.

To prevent tick bites, the following repellents are recommended: N, N-diethyl-meta-toluamide (DEET), picardin, ethyl-3-(N-n-butyl-N-acetyl) aminoproprionate, oil of lemon eucalyptus (OLE), p-methane-3,8-diol (PMD), 2-undecanone, or permethrin (5).

Examining a childís entire body for ticks and their prompt removal will help prevent infection. If a tick is discovered, it should be removed at once. This is best accomplished with tweezers, inserted as close to the skinís surface as possible, pulling upward slowly and firmly. It is not recommended to burn the tick, such as with a match, nor is it recommended to apply chemicals or petroleum products to the tick. The tick should be removed with appropriate technique. Testing the tick for spirochetal infection is not recommended.

Even in areas of high endemicity, the risk of Lyme disease following a tick bite is low (3%); however, it may be higher (25%) in high-risk bites (1). A high-risk tick bite is defined as: 1) the tick bite is from a known Ixodes spp. vector, 2) occurs in a high endemic area, and 3) the tick was attached for 36 hours or longer. In such circumstances, prophylactic antibiotic treatment is recommended. In all age groups, the recommendation is to administer a single dose of oral doxycycline within 72 hours of tick removal. The dose is 200 mg for adults and 4.4 mg/kg (up to a maximum dose of 200 mg) for children. Tetracyclines are contraindicated in pregnancy. If a tick bite does not meet criteria for a high-risk bite, prophylactic antibiotic therapy is not recommended. Rather, they should watch and wait and seek medical attention if signs and symptoms of Lyme disease develop (e.g., appearance of erythema migrans rash).

Co-infections in patients with Lyme disease are due to the overlap in transmission amongst the Ixodes tick species. Along with B. burgdorferi, the I. scapularis tick can transmit six other infectious organisms, including Anaplasma phagocytophilum, Ehrlichia muris eauclairensis (also known as Ehrlichia muris-like agent), Babesia microti, B. miyamotoi, B. mayonii, and Powassan virus. The two most common co-infections are Anaplasma phagocytophilum and Babesia microti, which cause anaplasmosis and babesiosis, respectively. Co-infection should be suspected in those not responding to treatment as expected, or those presenting with high fevers or characteristic hematologic findings. Both anaplasmosis and babesiosis can cause thrombocytopenia, leukopenia, neutropenia, and/or anemia. Hemolysis is suggestive of babesiosis, with the blood smear revealing the characteristic Maltese cross pattern. Patients might have indirect hyperbilirubinemia, elevated lactate dehydrogenase and/or anemia (5).

Currently, there is no available vaccine for Lyme disease. In 1998, a Lyme disease vaccine was approved by the FDA, but was voluntarily withdrawn from the market in 2002 due to anti-vaccine actions and lawsuits, low public demand, and unfounded public concern for possible side effects. A new vaccine trial is underway in Europe.


Questions
1. Which of the following is specific to early disseminated disease?
   a. Arthritis
   b. Encephalitis
   c. Carditis
   d. Erythema Migrans

2. If testing is indicated, the standard testing method is:
   a. Urine test for B. burgdorferi
   b. PCR of serum
   c. ELISA with reflex to Western immunoblot
   d. CD57 assay

3. True/False: It is recommended that children with Bellís palsy should be treated with corticosteroids.

4. A 7-year-old female presents with a rash consistent with erythema migrans. On exam she is well appearing, non-toxic, the rash is singular, no other pertinent findings. Upon further history, the patient lives in New England and is often playing outdoors. You diagnose her with Lyme disease, early localized disease. What is the treatment?
   a. Oral doxycycline for a 21-day course
   b. Oral doxycycline for a 10-day course
   c. Intravenous Ceftriaxone for a 7-day course
   d. No treatment is indicated


References
1. Shapiro ED. (2014). Clinical Practice. Lyme disease. New Engl J Med. 2014;370(18):1724-1731. doi.org/10.1056/nejmcp1314325
2. Centers for Disease Control and Prevention [Internet]. Lyme Disease Data and Surveillance. [cited 2019 April 29]. Available at: https://www.cdc.gov/lyme/datasurveillance/recent-surveillance-data.html
3. Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012;379(9814):461-473. doi: 10.1016/S0140-6736(11)60103-7
4. Lyme Disease. In: Committee on Infectious Diseases, Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH (eds). Red Book: 2021-2024 Report of the Committee on Infectious Diseases, 32nd edition, 2021. American Academy of Pediatrics, Itasca, IL. pp:482-489.
5. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the prevention, diagnosis, and treatment of Lyme disease. Clin Infect Dis. 2021;72(1):1-8. doi: 10.1093/cid/ciab049


Answers to questions
1. c. Carditis in early disseminated disease usually manifests as atrioventricular block. Other manifestations of early disseminated disease include multiple erythema migrans lesions, cranial nerve palsies, meningitis, or radiculitis.
2. c. ELISA with reflex to Western immunoblot. Urine test, CD57 assay, or PCR of the blood are not recommended diagnostic tests for Lyme disease. PCR of synovial fluid may help in making a diagnosis of Lyme arthritis but is not the standard testing.
3. False. Corticosteroids are not recommended.
4. b. Oral doxycycline for a 10-day course. Alternatively, the patient could also be treated with amoxicillin or cefuroxime. Intravenous ceftriaxone is usually reserved for treating persistent arthritis, carditis or meningitis.


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