Chapter VI.27. Lyme Disease
Jennifer W. Sasaki
November 2013

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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 second edition chapter is a revision and update of the original author's work.


In the month of August, a 7 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 2 weeks and has been enlarging. His father states that 3 weeks ago, the family was visiting relatives at a rural 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 had 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, and then the ring appeared to grow larger by expanding outward, leaving an area of central clearing. The boy has had a mild headache and myalgia, but has been afebrile.

Exam: VS T37.1, P90, RR 20, BP 100/70. He is alert, active, in no distress, and is non-toxic. Over the anterior surface of his left thigh, there is a red ring, 20 cm in diameter, with central clearing, and a central brownish-red macule that is 3 mm in diameter. The thigh is non-tender, as are all of the joints. There is now swelling to the joints either. His neck is supple without lymphadenopathy. The remainder of his exam is unremarkable.

No laboratory tests are performed. The skin lesion is diagnosed as erythema migrans, and thus the child is given the diagnosis of Lyme disease with an early localized infection. He is treated with amoxicillin 50 mg/kg/day by mouth divided into three daily doses for 14 days. His headache and myalgia resolve within one week, and the erythema migrans resolves completely by the end of amoxicillin treatment.


Lyme disease was first described in the early 20th century but was only first recognized as a distinct disease in 1975, following an epidemiologic investigation of a group of children in Old Lyme, Connecticut, diagnosed as having "juvenile rheumatoid arthritis". Lyme disease is a multisystem, multistage, inflammatory illness affecting primarily the skin, nervous system, heart and joints (these affected systems are identical to those affected in rheumatic fever). It is the most common vector-borne zoonosis in the United States.

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 transmitted by the Ixodes species of tick. Ixodes scapularis (the black-legged or deer tick) in the northeastern, north central, and mid-atlantic regions of the United States, while I. pacificus (the western black-legged tick) is the vector in the western United States (1,2). Ixodes ricinus and Ixodes persulcatus are also capable of transmitting the disease and are found in Europe and Asia, respectively.

Epidemiology

The number of cases reported annually has increased significantly since national surveillance was begun in 1982 (1). During 1993-1997, a mean of 12,451 cases were reported by states annually to the CDC. In 2009, the number of confirmed cases in the United States reached a high of 29,959. In 2011, the number of confirmed cases was 24,364, and the number of probable cases was 8,733. In the United States, while the disease is primarily localized to states in the northeastern, mid-Atlantic, and upper north-central regions, it has been reported in all states apart from Hawaii. In 2011, 96% of cases were reported from 13 states—Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Vermont, Virginia and Wisconsin. (3)

Etiology

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. In the spring of the first year, the adult tick lays eggs, from which larvae emerge. In the summer, the larvae feed on reservoir-competent hosts, including the white-footed mouse, and become infected with the spirochete. The larvae remain dormant during the fall and winter, molting into nymphs in the spring. The nymph stage is the most aggressive stage of the life cycle. The nymphs feed predominantly in the spring and summer, biting animals or humans, and infecting them with the spirochete. Hence, the majority of cases are reported between May and August. In the fall and winter, the nymphs grow to be adult ticks, attaching to a host mammal (particularly the white-tailed deer) in order to feed and mate. The adult ticks are not involved in the life cycle of the spirochete. In the western United States, Lyme disease occurs sporadically, due to the fact that the I. pacificus nymph prefers to feed on lizards, which are resistant to infection. A small number of larvae and nymphs feed on wood rats, which are susceptible to infection and capable of transmitting the spirochetes.

Transmission

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.

Experimental conditions have shown that in order for the infected ticks to transmit B. burgdorferi spirochetes, they must feed on its host for 24-36 hours. However, studies have shown that the incidence of disease is much higher when the tick is attached to its host for greater than 72 hours, even though most cases are less than 24 hours.

Ixodes ticks are smaller than dog ticks; and as a result, their bite tends to be painless, often goes unnoticed and, thus, puts individuals at greater risk of acquiring Lyme disease (2). The majority of patients with Lyme disease do not recall a tick bite (1). If a tick is discovered, it should be removed at once. This is best accomplished with tweezers, pulling slowly and firmly near the mouth of the tick (not the body) until it relinquishes its grasp (2).

The incubation period from infection to onset of symptoms is 7 to 14 days, with a range of 3 to 30 days. B. burgdorferi spreads locally through the skin from the site of the tick bite, resulting in a single erythema migrans lesion in approximately two-thirds of patients who become symptomatic. Days to weeks later, the spirochete may disseminate via lymphatic or blood-borne routes to other areas of the skin, causing multiple erythema migrans lesions; and to the eye, muscle, bone, synovial tissue, central nervous system and heart (1,4,5).

Clinical Features

Much like syphilis, which is also a spirochete infection, Lyme disease classically progresses through three stages: Early localized (Stage 1); Disseminated (Stage 2); and Late disseminated (Stage 3).

Early Localized (Stage 1):
This stage occurs 3 to 32 days following a tick bite. The characteristic feature is erythma migrans (also known as erythema chronicum migrans), which is a slowly expanding skin lesion, spreading from the central bite lesion. Erythema migrans appears as an erythematous, flat, or slightly raised rash, in the shape of a ring or concentric rings; commonly called a ‘bulls eye’ lesion. The rash tends to expand over days (hence the name, migrans), with an average size of 15 cm. It is commonly found in areas of tight clothing, such as the groin, thigh or axilla. Erythema migrans is present in 70-80% of cases, and by itself is not diagnostic of Lyme disease. The patient may have concomitant flu-like symptoms, including myalgias, headache, fatigue, and possibly fever. Classic erythema migrans is not difficult to spot, however, atypical lesions may be more difficult to recognize, leading to misdiagnosis. Vesicular, necrotic, and urticarial lesions have been reported. Additionally, drug reactions, urticaria, and staphylococcal and streptococcal cellulitis have been mistaken for erythema migrans. While it is possible for patients to be asymptomatic, this is uncommon in the United States. (1,5)

Early Disseminated Infection (Stage 2):
Dissemination of the spirochetes occurs days to months after the appearance of the erythema migrans lesion, primarily in those left untreated. In some patients, early disseminated infection may be the initial manifestation of Lyme disease. Commonly during this stage, patients develop secondary erythema migrans lesions, which are not at the site of the tick bite. These lesions are similar to the primary ‘bulls eye’ lesion, but are usually smaller. These lesions are often accompanied by the same systemic symptoms as with primary erythema migrans, including fever, headache and generalized achiness. In patients who have yet to be treated with ntibiotics, other systemic manifestations may occur. Musculoskeletal involvement commonly manifests as monoarticular or oligoarticular arthritis, predominantly affecting the large joints (e.g. knees), seen in 60% to 70%. Focal neurologic involvement most commonly presents as Bell's palsy (CN VII), which is usually bilateral. The most common CNS manifestation is aseptic meningitis with headache and nuchal rigidity. Cardiac manifestations (4% to 10%) include myocarditis or pericarditis, atrial or ventricular arrhythmias, or AV nodal heart block. Other complications include lymphadenopathy, conjunctivitis and radiculoneuropathy. Radiculoneuropathy is more common in European adults, though is also seen in children in the United States. (1,2,4,5,6)

Late Disseminated Disease (Stage 3):
Late disseminated disease occurs months to years following initial spirochete infection. The spirochetes are able to evade the immune system and persist in localized areas. This stage tends to develop in patients who are left untreated, or inadequately treated. The classic manifestation is arthritis (50%); chronic monoarticular arthritis or migratory polyarthritis (1). Arthritis mainly affects the large joints, with the knee being involved in more than 90% of cases (7). Chronic arthritis occurs primarily in patients with DR-2, DR-3, or DR-4 HLA types (8). The affected joint is tender, erythematous, and swollen, though not to the severity of bacterial arthritis. Tertiary neuroborreliosis, arthralgias (20%), encephalopathy and peripheral neuropathy may also occur (5,7).

Diagnosis

Recall the common clinical features of the three stages of Lyme disease:
Stage 1: Erythema migrans, flu-like symptoms
Stage 2: Arthritis, Bell’s palsy, AV block, carditis, in addition to flu-like features, and skin findings.
Stage 3: Chronic monoarthritis, migratory polyarthritis, arthralgias, peripheral neuropathy, and potentially neuroborreliosis and encepalopathy

The diagnosis of Lyme disease primarily relies on eliciting a history of exposure to B. burgdorferi's vectors, and recognizing the characteristic clinical features of the disease (1,5). Most commonly, the diagnosis of Lyme disease is made based on a possible exposure and the presence of erythema migrans. Therefore, if a patient has a history of possible exposure to B. burgdorferi, and if they have erythema migrans, this is sufficient to make a diagnosis of Lyme disease and then begin treatment. Most patients in the early localized stage (stage 1) have a negative serology, since IgM antibody appears 2 to 4 weeks after erythema migrans onset, peaking at 6 to 8 weeks, and then declining after 4 to 6 months. Furthermore, IgG production may take 6 to 8 weeks to appear, peaking at 4 to 6 months. Therefore, the diagnosis of early localized disease does not require laboratory confirmation, nor should it be relied upon (1,2,4,5). However, patients with disseminated disease, either early or late, often have a positive serology and this should be confirmed. Therefore ELISA, and if possible, Western blot, should be performed to confirm the clinical diagnosis. ELISA testing has a high sensitivity, but low specificity, and therefore, false positives are more likely. Western blot, which has a higher specificity, is used to confirm a positive ELISA test. If the ELISA finding is negative, a follow-up with Western blot is not necessary (1,2,4,5).

Differential Diagnosis

The constitutional symptoms that commonly present in Lyme disease—headache, arthralgia, fatigue, fever—are also frequent clinical manifestations in other illnesses, including influenza. The southern tick-associated rash illness (STARI) is transmitted via the Lone Star tick, and has a similar clinical presentation to Lyme disease. STARI has been reported in the southeastern region of the United States, and presents with mild flu-like symptoms and a rash similar to erythema migrans. The differential for erythema migrans includes erythema annulare, erythema marginatum, pityriasis rosea, subacute cutaneous lupus, syphilis, juvenile idiopathic arthritis, erysipelas, and tinea corporis (a common misdiagnosis). The differential for the arthritis that presents in Lyme disease includes pauciarticular juvenile idiopathic arthritis, acute rheumatic fever, and reactive arthritis. Lastly, other causes of Bell ’s palsy (CN VII) include herpes simplex virus 1, human immunodeficiency virus, and varicella zoster virus infections, reactivation of herpes simplex virus or varicella zoster virus, and recent intranasal influenza vaccination. (5)

Treatment

Early and uncomplicated infections in children and adolescents usually respond well to orally administered antibiotics (5). Parenteral antibiotics are generally recommended for treating meningitis, later-stage neurologic Lyme disease, carditis, and complicated Lyme disease arthritis. Late, complicated Lyme disease may respond slowly or incompletely, and more than one antibiotic treatment course may be required to eliminate active infection (1).

Tick bite:
Children 8 years and older may be prescribed doxycycline following a tick bite if they meet the following criteria: The tick is engorged with blood; the tick has been attached to host for less than 36 hours. In this case, prophylaxis may be started within 3 days. It is important that the child be 8 years or older, since for children under the age of 8, doxycycline may cause permanent discoloration of the teeth. (5)

Erythema migrans, Lyme arthritis (if no neurologic symptoms present):
For children with erythema migrans or Lyme arthritis, without neurologic symptoms, it is recommended that they receive doxycycline (for those greater than 8 years old), amoxicillin or cefuroxime (for younger children) for 14 days. If the child has known drug sensitivities to the aforementioned drugs, macrolides, such as erythromycin, may be prescribed, though these have been shown to be less effective. Additionally, amoxicillin-clavulanate should be prescribed if the lesion cannot be differentiated between bacterial cellulitis and erythema migrans. (2,5)

Isolated Bell’s Palsy (without evidence of Lyme meningitis):
Children presenting with isolated Bell’s palsy (CN VII), without clinical manifestations of Lyme meningitis, should be prescribed a 14-day oral regimen as mentioned above for erythema migrans and Lyme arthritis. Supportive measures for CN VII palsy may include lubricant eye drops (5). Lyme-related Bell's palsy should not be treated with corticosteroids (7).

Lyme meningitis:
Children presenting with Lyme meningitis should be treated with intravenous ceftriaxone for 14 to 28 days (5), or alternatively cefotaxime.

Prognosis

Lyme disease in children and adolescents has an excellent prognosis, and responds well when treated appropriately. Instances of treatment failure are uncommon, and those requiring re-treatment or prolonged treatment are often due to misdiagnosis or misinterpretation of serologies (2).

Gerber et al., (9) reported a prospective, longitudinal, community-based cohort study of children of 201 children with Lyme disease in southeastern Connecticut over a period of 20 months, with a mean age of 7 years and a range of 1 to 21 years. All but 3 of the 201 patients were treated for 2 to 4 weeks with conventional antibiotic therapy, which was administered orally in 96% of cases. All had prompt clinical responses. After 4 weeks, 94% were completely asymptomatic. At follow-up, a mean 25.4 months later, none of the patients had evidence of either chronic or recurrent Lyme disease. Six patients subsequently had a new episode of erythema migrans. No patient progressed from early to late disease.

Prevention

Prevention is best achieved by avoidance of tick habitats. Whenever possible, persons should avoid areas that are likely to be infested with ticks, particularly in spring and summer when nymphal ticks feed. Ticks favor a moist, shaded environment, especially one, provided by leaf litter and low-lying vegetation in wooded, brushy or overgrown grassy habitats (1).

Persons who are exposed 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. Applying insect repellents containing DEET (n,n-diethyl-m-toluamide) to clothes and exposed skin, and applying permethrin, which kills ticks on contact, to clothes, should also help reduce the risk of tick attachment. Examining a child’s entire body for ticks and their prompt removal will help prevent infection (5).

The number of ticks in endemic residential areas can be reduced by removing leaf litter, brush, and woodpiles around houses, at the edges of yards, and by trees and brush to admit more sunlight, thus reducing deer, rodent, and tick habitats. Tick populations have also been reduced by applying pesticides to residential properties.

Persons who are bitten by a deer tick should remove the tick and seek medical attention if any of the signs and symptoms of Lyme disease develop (1,10). Recall that the best way to remove a tick is by using tweezers to firmly and slowly pull the tick near the mouth (not the body) until it releases its hold.

Co-infection

Babesiosis is a tick-borne disease that is caused by the protozoan Babesia microti. Like Lyme disease, B. microti is also transmitted by the black-legged or deer tick (I. scapularis). Because both diseases share the same vector, they may present concurrently. Babesiosis commonly manifests with fever, myalgia, chills, headache, and hemolytic anemia. Blood smear reveals the characteristic "Maltese cross" pattern. Serologic testing and polymerase chain reaction are also used for the diagnosis (1,5).

Human granulocytic ehrlichiosis (HGE) is caused by Anaplasma phagocytophilum. As with Lyme disease and Babesiosis, the I. scapularis species are the principal vectors in HGE. About seven days following the inciting tick bite, flu-like symptoms of fever, chills, cough, fatigue, headache and myalgia appear, as does a maculopapular, macular or petechial rash affecting the trunk and upper extremities; often difficult to distinguish from Rocky Mountain Spotted Fever (6).

Vaccine

In 1998, the vaccine LYMErix was released, but voluntarily withdrawn from the market in 2002 due to anti-vaccine factions and lawsuits, a complicated vaccine administration schedule, declining physician support, low public demand, and possible autoimmune responses. A second vaccine, ImuLyme, was developed; however the manufacturer did not pursue a license for release. Currently, there is no available vaccine for Lyme disease (11).


Questions

1. True/False: Children with Bell's palsy should be treated with corticosteroids.

2. True/False: Multiple erythema migrans lesions are a sign of late disseminated Lyme disease.

3. True/False: If a child has an erythema migrans lesion and a history of possible exposure to B. burgdorferi, a diagnosis of Lyme disease does not require serologic testing.

4. True/False: Most patients with Lyme disease do not recall having had a tick bite.

5. True/False: Children under the age of 8 years may be treated with doxycycline.

6. True/False: The best way to remove a tick is with tweezers, pulling slowly and firmly near its mouth.

7. True/False: Lyme disease occurs most commonly in the summer, when nymphal ticks feed.

8. True/False: False positives are uncommon in ELISA serology testing.

9. True/False: A 10 year old child presenting with Lyme meningitis should be treated with doxycycline.


References

1.Stanek G, Wormser GP, Gray J, Strle F. Lyme borreliosis. Lancet 2012;379:461.

2. Philip SS. Current Medical Diagnosis and Treatment [Internet]. 2013. New York: McGraw-Hill. Spirochetal Infections; [cited 2013 Mar 23]. Available from: http://www.accessmedicine.com.eres.library.manoa.hawaii.edu/content.aspx?aID=18802&searchStr=lyme+disease

3. Centers for Disease Control and Prevention [Internet]. Reported Cases of Lyme Disease by Year, United States, 2002-2011; 2012 Sept 12 [cited 2013 Mar 24]. Available from: http://www.cdc.gov/lyme/stats/chartstables/casesbyyear.html

4. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089.

5. Arnold DH, Spiro DM. Visual Diagnosis: A 5-year-old Child Who Has Facial Palsy and Rash. Pediatrics in Review 2007;28(12):465-469.

6. Bratton RL, Corey R. Tick-borne disease. American Family Physician 2005;71(12):2323-2330.

7. Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007;69:91.

8. Jones KL, Glickstein LJ, Damle N, et al. Borrelia burgdorferi genetic markers and disseminated disease in patients with early Lyme disease. J Clin Microbiol 2006;44:4407.

9. Gerber MA, Shapiro ED, Burke GS, et al. Lyme disease in children in southeastern Connecticut. Pediatric Lyme Disease Study Group. N Engl J Med 1996;335:1270.

10. Bacon RM, Kugeler KJ, Mead PS, Centers for Disease Control and Prevention (CDC). Surveillance for Lyme disease--United States, 1992-2006. MMWR Surveill Summ 2008;57:1.

11. Poland GA. Vaccines against Lyme Disease: What Happened and What Lessons Can We Learn?. Clinical Infectious Disease 2011;52(3):253-258.


1. False. Bell's palsy due to Lyme disease should NOT be treated with corticosteroids. It should be treated for Lyme with a 14 day oral regimen of antibiotics and may include supportive care, such as lubricant eye drops.

2. False. Multiple erythema migrans lesions is a sign of early disseminated disease.

3. True.

4. True.

5. False. Children under 8 should not be treated with doxycycline as there is a risk of permanent discoloration of teeth since doxycycline binds calcium.

6. True.

7. True.

8. False. ELISA has high sensitivity, low specificity, and therefore false positives are common, especially in low risk patients. This is why a positive ELISA is followed up with a Western blot test.

9. False. The recommended treatment for Lyme meningitis is ceftriaxone IV.


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