Pediatric Lyme Disease

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Background

Lyme disease is the most common tick-borne illness in the United States. Although erythema migrans (EM), the characteristic rash associated with Lyme disease, was initially described in 1921, Lyme disease was first formally described in the medical literature in 1976 following an outbreak of arthritis in Lyme, Connecticut. Since then, the number of reported cases has increased dramatically, likely as a result of increased awareness of clinicians and patients in endemic areas.

Go to Lyme Disease for complete information on this topic.

Pathophysiology

The spirochete Borrelia burgdorferi is introduced into the skin and spreads locally. The local spread leads to EM, a rash that is found in approximately two thirds of cases.

Over days to months, the spirochete may invade the blood stream, leading to disseminated disease. Dissemination to the skin can manifest as multiple EM. B burgdorferi can spread to any tissue but commonly affects the skin, eye, muscle, heart, and central nervous system. Arthritis is a characteristic manifestation of late disease and is caused by the persistence of organisms in the synovium. Some patients, particularly adults, appear to have persistent symptoms after adequate antimicrobial treatment, suggesting an autoimmune component to chronic symptoms.

Etiology

Lyme disease is caused by B burgdorferi[1] which is transmitted by ixodid tick species--primarily Ixodes scapularis, the common deer tick (see the images below).


View Image

The Ixodes scapularis tick is considerably smaller than the Dermacentor tick. The former is the vector for Lyme disease, granulocytic ehrlichiosis, an....


View Image

In general, Ixodes scapularis must be attached for at least 24 hours to transmit the spirochete to the host mammal. Prophylactic antibiotics are more ....

The life cycle of ixodid ticks occurs over 2 years. The adult lays eggs in the spring, and the larvae emerge in the summer. The larvae feed on a wide variety of small animals (eg, the white-footed mouse) that serve as important reservoirs for B burgdorferi. The following spring, the larvae emerge as nymphs that likewise mainly feed on small animals. The nymphs molt into adults the following fall and spend the winter feeding on larger animals, most notably the white-tailed deer. Ticks can acquire B burgdorferi during any of the 3 life-cycle stages.

Lyme disease is passed to humans mostly by nymphs because (1) nymphs are more abundant than adult ticks during the months of greatest human outdoor activity and (2) nymphs are more difficult to detect because of their smaller size. The risk of transmission of B burgdorferi from an infected tick to a human depends on the length of exposure. It takes hours for the tick to attach fully, and experimental studies have indicated that nymphs must feed 36-48 hours and adults 48-72 hours to transmit B burgdorferi.

Epidemiology

The number of reported cases has increased 101% from 9908 cases in 1992 to 19,931 cases in 2006. Incidence is highest in children aged 5-14 years. The 3 distinct regions in the United States are (1) the Northeast (from Massachusetts to Maryland), (2) the upper Midwest (especially Minnesota and Wisconsin), and (3) the West Coast (especially northern California).

Based on the life cycle of the tick in the United States, onset of illness is between May and October, with most cases presenting in June and July.

Lyme disease occurs throughout the world. B burgdorferi infection has been reported in Asian countries, including China, Korea, Japan, Indonesia, Nepal, and eastern Turkey.

In Europe, most Lyme disease is reported by Scandinavian countries, Germany, Austria, and Slovenia. In Europe, Lyme disease is primarily caused by Borrelia afzelii and Borrelia garinii, whose clinical manifestations differ somewhat from those of B burgdorferi. B garinii tends to disseminate less widely than B burgdorferi but is especially neurotropic and may cause encephalomyelitis. B afzelii often infects the skin only but may persist in that site, causing various cutaneous manifestations including acrodermatitis chronica atrophicans.

Prognosis

The prognosis for all stages of Lyme disease is generally excellent when patients are treated early with appropriate antibiotic regimens. For patients with chronic symptoms post infection, randomized controlled trials of extended antibiotic regimens have not shown any efficacy.

Symptoms of arthritis may persist for a few weeks beyond adequate therapy; therefore, retreatment usually is not necessary unless symptoms worsen or persist beyond 2 months. Some individuals with arthritis do have persistent symptoms after clearance of the infection. This phenomenon is most likely related to autoimmunity and is more prevalent among individuals with HLA-DR2, HLA-DR3, or HLA-DR4 allotypes.

Unfortunately, antibodies induced by the infection are not protective against further exposures to B burgdorferi; therefore, reinfection easily could be confused with a recurrence. Because antibodies may persist for years following an infection, repeat infection is a difficult diagnosis without specific signs of Lyme disease (eg, EM rash). Increasing titers after adequate treatment certainly raises suspicion of an active infection.

Patient Education

Primary care providers should educate parents and children who live in endemic areas about the risk of Lyme disease. Anticipatory guidance should focus on prevention measures and post–tick exposure counseling on watching for symptoms and signs of Lyme disease.

For patient education resources, see the Bites and Stings Center and Muscle Disorders Center, as well as Lyme Disease, Ticks, Chronic Fatigue Syndrome, and Chronic Pain.

History

Most patients with Lyme disease do not recall a tick bite. The clinical presentation depends on the stage at which the disease is recognized: (1) early disease, (2) early disseminated disease, or (3) late disease.

Early disease

Early disease usually develops 7-14 days after a tick bite. Two thirds of patients with Lyme disease present with the typical rash, erythema migrans (EM).[2] The rash may be a confluent patch of erythema or may have central clearing. The rash typically expands over days and is not evanescent. EM is a clinical diagnosis, and serologic testing for children with a single EM lesion is generally not recommended because patients may be seronegative early in the course of illness.

During early disease, with or without the rash, patients may complain of a flulike illness characterized by fever, chills, myalgias, arthralgias, headache, and malaise. In the area of the tick bite, tender adenopathy may be noted.

Early disseminated disease

Early disseminated disease usually develops 3-10 weeks after inoculation. Approximately 25% of individuals infected with B burgdorferi have signs and symptoms of disseminated disease at presentation.

Multiple EM lesions are present. These are relatively small erythematous macules (1-5 cm) and are often oval. Unlike primary single EMs, these lesions can be evanescent and do not show the typical expansion over days.

Patients with early disseminated disease may complain of fever, myalgias, arthralgias, malaise, and headache. Persistent headache alone is a rare presentation of Lyme disease but should be considered in patients in endemic areas during summertime.

Cranioneuropathies, especially peripheral seventh nerve palsy (Bell palsy), are common (3% of Lyme disease). In endemic areas, Lyme disease is the most commonly identified cause of acquired facial palsy, especially in children[3] Headache, absence of previous herpetic lesions, and meningeal symptoms are noted in most pediatric Lyme disease patients with facial palsy.

Aseptic meningitis may develop at this stage. Encephalitis is rare. Carditis may present as complete heart block.

Late disease

Late disease develops weeks to months after inoculation. Its hallmark is arthritis, which tends to involve large joints (the knee is involved in 90% of cases). Arthritis must be differentiated from arthralgia, which is common in early disease.

Most patients presenting with late disease do not have a history of EM, because the rash typically leads to earlier treatment, which prevents the development of late disease.

Physical Examination

Early disease

Physical findings in patients with early disease are as follows:

Early disseminated disease

Physical findings in patients with early disseminated disease are as follows:

Late disease

In patients with late disease, the typical physical finding is arthritis. Arthritis is located mostly in large joints, especially the knee. Warmth, swelling from effusion, and limited range of motion help distinguish arthritis from simple arthralgia.

Complications

The agents responsible for babesiosis and ehrlichiosis share the same tick vector as B burgdorferi, making co-infection possible. Severe and even fatal acute infection caused by these agents is more common in asplenic individuals (babesiosis) or older adults (Ehrlichia); however, unlike B burgdorferi, chronic infection by these agents is not observed. To add to the confusion, ehrlichial infection may cause a false-positive result for Lyme disease on immunoglobulin M (IgM) Western blot analysis.

One nonmedical complication of Lyme disease has been the public and media’s misconceptions about the disease. Unfortunately, many clinicians perform too many tests when the prior probability of disease is low, resulting in many false-positive tests.

The combination of nonspecific symptoms and suboptimal test results has led to overtreatment for suspected (but not proven) Lyme disease and to the concept of refractory Lyme disease.

Go to Ophthalmic Aspects of Lyme Disease for complete information on this topic.

Approach Considerations

The most sensitive and specific test for Lyme disease is identifying the erythema migrans rash. For cases without a rash, workup for pediatric Lyme disease may include blood studies and serology, as well as polymerase chain reaction (PCR) or lumbar puncture if indicated.

Go to Lyme Disease for complete information on this topic.

Blood Studies

In patients with Lyme disease, the white blood cell (WBC) count can be normal or elevated. The erythrocyte sedimentation rate (ESR) is usually elevated. The serum aspartate transaminase (AST) may be elevated. C3 and C4 levels are generally normal or slightly elevated. Antinuclear antibody (ANA) and rheumatoid factor test results are negative.

Microscopic hematuria and mild proteinuria have also been described. Joint fluid in patients with arthritis may have 25,000-125,000 WBCs/µL, often with a polymorphonuclear predominance. Cerebrospinal fluid (CSF) in patients with meningitis often reveals a mild pleocytosis (< 1000 cells/µL) with lymphocyte predominance.

Culturing B burgdorferi is impractical; the organism is difficult to culture and requires an invasive procedure, such as biopsy or lumbar puncture, to obtain adequate samples.

Serology

Serology is the standard of diagnosis in later stages of the disease. Reported specificity of Lyme serology is only 90-95%. Therefore, the positive predictive value of the test is highly dependent on the prevalence of disease. Lyme serology should not be performed in children with nonspecific symptoms without history of tick exposure or from nonendemic areas. Antibodies are known to persist for many years despite eradication of the infection. Diagnosis of repeat infection or evidence of cure can be difficult based on serology alone.

Lyme serology should be performed by a reference laboratory and should include a 2-step process. Step 1 is to perform an enzyme-linked immunosorbent assay (ELISA) or immunofluorescent assay (IFA). Step 2, performed if the ELISA or IFA result is positive, is a Western blot analysis against specific antigens. This step is not interpretable in the absence of a positive ELISA or IFA result. Most assays require immunoglobulin (Ig) against at least 3 specific proteins (for IgM) or 5 specific proteins (for IgG) for results to be considered positive.

In response to the need for improved serological tests for the diagnosis and monitoring of Lyme disease, a study recently examined Luciferase Immunoprecipitation Systems (LIPS).[5] Antibody responses to several B burgdorferi antigens were measured, including VlsE, Flagellin (FlaB), BmpA, DbpA, and DbpB.

The best diagnostic performance was achieved with the synthetic protein consisting of a VlsE-OspC-VlsE-OspC peptide sequence, designated VOVO. The study concluded that LIPS screening using VOVO and other B burgdorferi antigens provided an efficient quantitative approach for evaluating antibody responses in Lyme disease.

Polymerase Chain Reaction

With the exception of synovial fluid, PCR testing is not recommended because of unacceptable low sensitivity, especially from the CSF (though it does have high specificity if the result is positive). CSF titers to B burgdorferi should not be used for diagnosis of Lyme meningitis but may have value in patients who have recurrent infection or for following serial markers in patients with persistent symptoms. CSF titers should be performed and interpreted at a reference laboratory.

With regard to Lyme arthritis, one study reported that results from standard and quantitative polymerase chain reaction (PCR) techniques included findings that B burgdorferi were active and viable in the skin lesions of erythema migrans patients, but were moribund or dead in the synovial fluid of Lyme arthritis patients. These results suggest that detection of B burgdorferi DNA in synovial fluid is not a reliable test for active joint infection in Lyme disease.[6]

Lumbar Puncture

Whether all patients with cranioneuropathy require lumbar puncture before treatment is controversial. Occasionally Lyme disease presents as pseudotumor cerebri; an opening pressure is essential for diagnosis.

Currently, in most patients with isolated Bell palsy and no associated signs of aseptic meningitis, most physicians do not perform a lumbar puncture. For most other patients with cranioneuropathies and suspected Lyme disease, a lumbar puncture should be performed, particularly in patients who live in an endemic area and present during peak Lyme disease season or with headache; CSF pleocytosis leads to treatment as indicated for CNS Lyme disease.

Computed tomography (CT) scan or magnetic resonance imaging (MRI) should be performed before the lumbar puncture if increased intracranial pressure or mass lesion is suspected. Occasionally, Lyme disease presents as pseudotumor with frank papilledema; imaging should be done prior to lumbar puncture in these cases.

Joint Aspiration

Joint aspiration for diagnostic reasons is unnecessary if only Lyme disease is suspected (and not septic arthritis or another etiology of effusion).

Approach Considerations

Treatment for all stages of Lyme disease requires antibiotics (see Medication). Efforts directed toward prevention are important.

Guidelines have been established for the treatment of nervous system Lyme disease,[7] the management of Lyme disease,[8] and the clinical assessment, treatment and prevention of Lyme disease, granulocytic anaplasmosis, and babesiosis.[9]

Go to Lyme Disease for complete information on this topic.

Antibiotic Therapy

Administer antibiotic therapy to patients who develop a flulike illness within 3 weeks postexposure to a deer tick (in an area endemic for Lyme disease). Beyond 3 weeks, serological testing is appropriate.

Facial nerve palsies improve without treatment; however, antibiotic therapy should prevent late disease. Similarly, arthritis improves without treatment but tends to recur in the same joint or other new joints.

Prevention of Pediatric Lyme Disease

The best prevention for Lyme disease is education and awareness.

Long pants and socks should be worn when in areas of likely tick exposure. Parents of children in endemic areas must be vigilant to check for ticks (especially the nymphs because of their smaller size) from the spring to the fall. Checking inside skin folds, behind ears, the umbilicus, groin, axilla, hairline, and scalp must be routine. Through education, parents can recognize early symptoms and signs.

Insecticides, sprayed on clothing or directly on the skin, can deter ticks, but use of these agents must be weighed against toxicity from overzealous application.

A Lyme disease vaccine was licensed by the US Food and Drug Administration (FDA) in 1998 but was subsequently withdrawn from the market in 2002 due to concerns regarding efficacy and side effects. The vaccine was made of recombinant outer surface protein A (OspA). Newer vaccines are in development.

Prophylactic antibiotics after any tick exposure are not recommended. Even in endemic areas, the risk of transmission from a tick is estimated to be only 1-2%. In hyperendemic areas, a single dose of doxycycline (adults) has been shown to decrease development of disease if given within 72 hours of tick bite.

Preventing exposure and removing ticks promptly is a much better strategy. However, in an endemic area, prolonged attachment, a concerned parent, or pregnancy may prompt consideration of prophylaxis or empiric treatment.

Postexposure prophylaxis has, however, shown some efficacy in an adult study. A single 200-mg dose of doxycycline within 72 hours of the tick bite decreased the development of Lyme disease. The efficacy of oral amoxicillin in children for postexposure prophylaxis has not been adequately studied.

A 2010 meta-analysis examined trials in which patients with no clinical evidence of Lyme disease were randomly allocated to treatment or placebo groups within 72 hours after an Ixodes tick bite.[10] Of the four studies that met the criteria, 1082 randomized subjects were included. The risk of Lyme disease in the control group was 2.2% compared with 0.2% in the antibiotic-treated group. Antibiotic prophylaxis significantly reduced the odds of developing Lyme disease compared with placebo. However, these data are not specific to the pediatric population.

For a known tick exposure, a thorough search for other ticks is necessary. Following discovery of an attached tick, education about symptoms and signs of Lyme disease is the most appropriate treatment.

Consultations

The following consultations may be indicated:

Medication Summary

The antibiotic regimen for Lyme disease depends on the stage and manifestations of the disease.

Amoxicillin (Amoxil, Trimox, Biomox)

Clinical Context:  Amoxicillin is a penicillin antibiotic and is the drug of choice for early localized and early disseminated disease without evidence of central nervous system (CNS) involvement. It can be used for arthritis that is not persistent or recurrent.

Doxycycline (Bio-Tab, Doxy, Vibramycin)

Clinical Context:  Doxycycline is a tetracycline antibiotic that is the drug of choice for early localized and early disseminated disease without evidence of CNS involvement. It can be used for arthritis that is not persistent or recurrent. It has also been promoted for single-dose postexposure prophylaxis.

Cefuroxime (Ceftin, Kefurox)

Clinical Context:  Cefuroxime is a second-generation cephalosporin that can be used for early localized and early disseminated disease without evidence of CNS involvement. It can be used for arthritis that is not persistent or recurrent.

Ceftriaxone (Rocephin)

Clinical Context:  Ceftriaxone is a third-generation cephalosporin that is the drug of choice for CNS infections (eg, meningitis, multiple cranioneuropathies), arthritis that is persistent (ie, minimal improvement within 7 d of initiating oral therapy with other agents) or recurrent, or for carditis.

Penicillin (Pfizerpen)

Clinical Context:  Penicillin has the same uses as ceftriaxone. Administer it for CNS infection, persistent or recurrent arthritis, and carditis.

Class Summary

The goal of pharmacotherapy with antibiotics is to reduce morbidity and prevent complications. Antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Author

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Sarah L Wingerter, MD, Attending Physician, Department of Emergency Medicine, St Christopher's Hospital for Children; Clinical Assistant Professor of Pediatrics (Adjunct), Temple University School of Medicine

Disclosure: Nothing to disclose.

Stephen C Aronoff, MD, Waldo E Nelson Chair and Professor, Department of Pediatrics, Temple University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Gary J Noel, MD, Professor, Department of Pediatrics, Weill Cornell Medical College; Attending Pediatrician, New York-Presbyterian Hospital

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Larry I Lutwick, MD, Professor of Medicine, State University of New York Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus

Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Richard G Bachur, MD, and Marvin Harper, MD, to the development and writing of the source article.

References

  1. Feder HM Jr. Lyme disease in children. Infect Dis Clin North Am. Jun 2008;22(2):315-26, vii. [View Abstract]
  2. Halperin JJ. Nervous system lyme disease: diagnosis and treatment. Rev Neurol Dis. Winter 2009;6(1):4-12. [View Abstract]
  3. Nigrovic LE, Thompson AD, Fine AM, Kimia A. Clinical predictors of Lyme disease among children with a peripheral facial palsy at an emergency department in a Lyme disease-endemic area. Pediatrics. Nov 2008;122(5):e1080-5. [View Abstract]
  4. Cohn KA, Thompson AD, Shah SS, Hines EM, Lyons TW, Welsh EJ, et al. Validation of a clinical prediction rule to distinguish lyme meningitis from aseptic meningitis. Pediatrics. Jan 2012;129(1):e46-53. [View Abstract]
  5. Burbelo PD, Issa AT, Ching KH, Cohen JI, Iadarola MJ, Marques A. Rapid, simple, quantitative, and highly sensitive antibody detection for lyme disease. Clin Vaccine Immunol. Jun 2010;17(6):904-9. [View Abstract]
  6. Li X, McHugh GA, Damle N, Sikand VK, Glickstein L, Steere AC. Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or lyme arthritis. Arthritis Rheum. Aug 2011;63(8):2238-47. [View Abstract]
  7. [Guideline] Halperin JJ, Shapiro ED, Logigian E, Belman AL, Dotevall L, Wormser GP, 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. Jul 3 2007;69(1):91-102. [View Abstract]
  8. [Guideline] The ILADS Working Group. Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther. 2004;2(1 Suppl):S1-13.
  9. [Guideline] Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, 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. Nov 1 2006;43(9):1089-134. [View Abstract]
  10. Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP. Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis. J Antimicrob Chemother. Jun 2010;65(6):1137-44. [View Abstract]

The Ixodes scapularis tick is considerably smaller than the Dermacentor tick. The former is the vector for Lyme disease, granulocytic ehrlichiosis, and babesiosis. The latter is the vector for Rocky Mountain spotted fever. This photo displays an adult I scapularis tick (on the right) next to an adult Dermacentor variabilis; both are next to a common match displayed for scale. Photo by Darlyne Murawski; reproduced with permission.

In general, Ixodes scapularis must be attached for at least 24 hours to transmit the spirochete to the host mammal. Prophylactic antibiotics are more likely to be helpful if feeding is longer. This photo shows 2 I scapularis nymphs. The one on the right is unfed; the other has been feeding for 48 hours. Note its larger size and the fact that the midgut diverticula (delicate brown linear areas on the body) are blurred. Photo by Darlyne Murawski; reproduced with permission.

The Ixodes scapularis tick is considerably smaller than the Dermacentor tick. The former is the vector for Lyme disease, granulocytic ehrlichiosis, and babesiosis. The latter is the vector for Rocky Mountain spotted fever. This photo displays an adult I scapularis tick (on the right) next to an adult Dermacentor variabilis; both are next to a common match displayed for scale. Photo by Darlyne Murawski; reproduced with permission.

In general, Ixodes scapularis must be attached for at least 24 hours to transmit the spirochete to the host mammal. Prophylactic antibiotics are more likely to be helpful if feeding is longer. This photo shows 2 I scapularis nymphs. The one on the right is unfed; the other has been feeding for 48 hours. Note its larger size and the fact that the midgut diverticula (delicate brown linear areas on the body) are blurred. Photo by Darlyne Murawski; reproduced with permission.