Cover article

Late Lyme disease: Clearing up confusion

By Michael A. Gerber, MD, and Eugene D. Shapiro, MD

Long-term effects of Lyme disease, such as arthritis and neurologic abnormalities, present diagnostic difficulties. To complicate the issue, a host of nonspecific symptoms often are mistakenly attributed to persistent infection. The good news? Contrary to many parents' and pediatricians' fears, Lyme disease only rarely causes long-term problems in children.

We have learned a great deal about the pathophysiology, diagnosis, and treatment of Lyme disease since it was recognized two decades ago. (See "Lyme disease in review" on below.) Yet much confusion exists about the late-stage manifestations of this illness, in particular arthritis and neurologic problems (see Table 1). How useful is culture or serologic testing in confirming that a patient has Lyme disease? What is appropriate antimicrobial therapy? When is any of a range of nonspecific symptoms, such as headache and fatigue, a manifestation of Lyme disease? We address these and other issues related to late Lyme disease.

LEARNING OBJECTIVES

After reviewing this article the physician should be able to:

TABLE 1
Clinical manifestations of Lyme disease

Overview of Lyme arthritis

Lyme disease has become a relatively common cause of arthritis among children in areas of the United States in which the disease is endemic.¹ In the original description of Lyme arthritis, more than 75% of patients were children, and some evidence suggests that children with Lyme disease are more likely than adults to have arthritis.² Because most reviews of Lyme arthritis in children consist of selected patients and are not population based, neither the frequency of arthritis among children with Lyme disease nor the incidence of Lyme arthritis among children in the general population can be determined. However, in a recently reported, prospective study of 201 consecutive children with newly diagnosed Lyme disease, 13 (6%) of the children presented with arthritis.¹

Lyme arthritis develops through an infectious process; the arthritis responds to antimicrobial therapy, except in a very small percentage of children who develop an autoimmune form of arthritis.

Infectious arthritis. Although Borrelia burgdorferi, the spirochetes that cause Lyme disease, are only rarely cultured from the joints of patients with Lyme arthritis, it appears that Lyme arthritis is caused by an infection of the involved joints. By using extremely sensitive techniques, such as the polymerase chain reaction (PCR) test, B burgdorferi DNA can be detected in the synovial fluid and synovial tissue of more than 80% of untreated patients with Lyme arthritis. After successful antimicrobial therapy, the results of the PCR test rapidly become negative. Patients with Lyme arthritis typically also have a clinical response to antimicrobial therapy.

The paucity of spirochetes in the affected joint contrasts with the prominent clinical and biologic evidence of local inflammation. Moreover, animal models of Lyme arthritis show no correlation between the number of spirochetes present and the severity of arthritis. Apparently, B burgdorferi activates monocytes, resulting in induction of large amounts of pro-inflammatory cytokines such as IL-1ß and TNF-

. Although the exact mechanism of this activation has not been elucidated, the process explains how a relatively small number of organisms can produce prominent clinical findings.

Treatment-resistant (autoimmune) arthritis. About 10% of adults and <5% of children with Lyme arthritis who are treated with appropriate antimicrobial therapy develop arthritis that does not respond to such therapy. It appears that these people may have a genetic predisposition to developing treatment-resistant Lyme arthritis; they are more likely than other patients to be positive for human leukocyte antigen DR4 (HLA-DR4). Unlike what is seen in patients with acute Lyme arthritis, PCR testing reveals B burgdorferi DNA in the synovial fluid or tissues of only a small percentage of patients with treatment-resistant Lyme arthritis.³ Furthermore, the maximum severity and duration of the arthritis in these patients are associated with T-cell responses to specific epitopes of the outer surface protein A (OspA) of B burgdorferi.

In addition, T cells from the synovial fluid of most patients with treatment-resistant Lyme arthritis respond to the human leukocyte function-associated antigen-1 (HLFA-1), while synovial T cells from patients with other forms of chronic inflammatory arthritis do not. HLFA-1 is a widely distributed protein involved in cell-cell interactions that plays a crucial role in the development and preservation of inflammation. Recently, a peptide of HLFA-1 was identified that is homologous to an immunodominant epitope of the B burgdorferi OspA. Crossreactivity to OspA epitopes and self epitopes, such as HLFA-1, may therefore induce autoreactivity through molecular mimicry. This process could provide an explanation for persistent joint inflammation in genetically susceptible individuals after antimicrobial therapy apparently has eradicated B burgdorferi from the joint.

Vaccine-induced arthritis? The only licensed Lyme disease vaccine, LYMErix, is a lipidated recombinant outer surface protein A (rOspA). Because of the possible role of OspA in the molecular mimicry that is believed to result in treatment-resistant Lyme arthritis, some observers are concerned that the vaccine could produce either initial episodes or exacerbations of Lyme arthritis. To date, however, no evidence exists that the rOspA vaccine produces either.⁴

Clinical findings in Lyme arthritis

We were investigators in the largest series of children with Lyme arthritis reported to date in this country.⁵ These children had clinical features similar to ones reported previously from much smaller series of patients in Europe, where arthritis is less often associated with Lyme disease than it is in the United States. In addition, only 19 (21%) of the 90 children with Lyme arthritis in this large series had a history of erythema migrans (the characteristic lesion of Lyme disease), compared with about 90% of the children with Lyme disease in prospective studies performed in this country as well as in Europe.^1,6 The low frequency of erythema migrans may reflect underreporting, but it is more likely that most children with erythema migrans are treated with antimicrobials and do not go on to develop late manifestations of Lyme disease. In fact, as erythema migrans is more widely recognized and treated, the percentage of children with Lyme arthritis who have a history of erythema migrans probably will diminish even further.

In addition to the 19 children whose arthritis was preceded by erythema migrans, four children had a facial nerve palsy. Therefore, the initial episode of Lyme arthritis was preceded by signs or symptoms of early Lyme disease in 23 (26%) of the children. Only eight (35%) of these 23 children had been treated with appropriate antimicrobial therapy at that early stage, however. In those with clinical evidence of early Lyme disease, Lyme arthritis developed at a mean of 4.3 months (a range of two days to 20 months) later.

Lyme arthritis is usually an asymmetric oligo- or mono-arthritis of the large joints, usually the knee, often with very large effusions but minimal pain. In our series, 90% of the children had arthritis of at least one knee, while small joint involvement was rare.⁵ Migratory polyarthritis may occur even in the first days of the infection, but small joint arthritis is unusual and should suggest an alternative diagnosis. Synovitis may last for days to months, although flares typically dissipate after months to years. The arthritis may become chronic in rare instances, however. Although one European report suggests that children with Lyme arthritis typically experience little discomfort, most have mild pain associated with the joint swelling.^1,7 In contrast with adult patients, the children in our series rarely had temporomandibular or sternoclavicular joint involvement.

For the 31 children in our series who underwent arthrocentesis, the mean WBC count in synovial fluid was 38,000 cells/µL (range, 7,000-99,000 cells/µL) with neutrophils predominating. Among the 79 children in whom the erythrocyte sedimentation rate was determined, the highest level for 18 (23%) was <20 mm/hr, for 25 (31%) it was between 20 and 49 mm/hr, and for 36 (46%) it was > 50 mm/hr.

Diagnosis is largely clinical

In most bacterial infections, culture is used to identify the etiologic agent. As noted above, however, B burgdorferi has been recovered from few patients with Lyme arthritis. PCR detects B burgdorferi DNA primarily in untreated patients with clinically active disease, and results almost always become negative within a few weeks after appropriate antimicrobial therapy. However, PCR for synovial fluid is not yet available as a routine tool and has not been evaluated in large groups of children.

The diagnosis of Lyme arthritis is usually based on a characteristic clinical picture, exposure in an endemic area for the disease, and serologic evidence of an infection with B burgdorferi. Detection of specific immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to B burgdorferi is usually accomplished by enzyme-linked immunosorbent assay (ELISA). However, the ELISA method sometimes produces false-positive results because of cross-reactive antibodies in patients with another spirochetal infection (such as syphilis, leptospirosis, and relapsing fever), with a viral infection (such as varicella), or with certain autoimmune diseases (such as systemic lupus erythematosus). In addition, antibodies directed against spirochetes that are part of the normal oral flora may cross-react with antigens of B burgdorferi. For these reasons, all positive ELISA results should be confirmed by Western blot, using the criteria of the Centers for Disease Control and Prevention.

Both the accuracy and reproducibility of available serologic tests (especially widely used, commercially produced kits) are poor.⁸ Use of these commercial diagnostic test kits for Lyme disease will result in a high rate of misdiagnosis. Moreover, as with any diagnostic test, the predictive value of the test depends primarily on the probability that the patient has Lyme disease based on the clinical and epidemiologic history and the physical examination (the "pretest probability" of Lyme disease). Even when more accurate tests performed by reference laboratories are available, clinicians should order serologic tests for Lyme disease selectively, reserving them for patients from populations with a relatively high prevalence of Lyme disease who have specific clinical findings that suggest Lyme disease. The predictive value of a positive test in such patients is high.⁹

Seropositivity may persist for years even after successful antimicrobial therapy. Ongoing seropositivity, even persistence of IgM, is not necessarily a marker of ongoing infection. Seropositivity therefore cannot be used to assess the adequacy of antimicrobial therapy.

Treating Lyme arthritis

The optimal duration and dosage of therapy for Lyme arthritis has not been established. Several observational studies and case reports suggest, however, that most children with Lyme arthritis can be treated effectively with a single, four-week course of orally administered doxycycline or amoxicillin (see Table 2).¹⁰ When considering oral antimicrobial therapy for Lyme arthritis, the physician must be alert to the presence of subtle neurologic symptoms, such as peripheral dysesthesia, that may require intravenous rather than oral therapy. Because symptoms resolve slowly—often taking weeks to months—adequacy of treatment should not be assessed clinically for two to three months after treatment. Nonprogressive, self-limiting symptoms such as myalgia, headache, and fatigue may persist for months after appropriate antibiotic treatment. These nonspecific symptoms are occasionally misinterpreted as active ongoing infection.

TABLE 2
Recommended treatment for Lyme arthritis

Arthritis is considered refractory to antimicrobial therapy when one of the following conditions is present:

• the arthritis in the joint being treated does not resolve or resolves but the joint becomes inflamed again

• a second joint becomes inflamed after treatment of the first joint has been completed

• evidence of new extra-articular infection appears after treatment for arthritis is completed.

If the arthritis is refractory, a single course of parenterally administered antimicrobial may be given for 14 to 28 days. Some experts would prescribe a second course of an oral antimicrobial before using a parenteral agent.

In patients who have persistent arthritis despite appropriate antimicrobial therapy, PCR testing of synovial fluid, if performed in a reliable laboratory, may help to guide decisions about retreatment. If results of PCR testing are negative, the patient should be treated with an anti-inflammatory agent, not an antimocrobial. If persistent joint swelling is painful or if it limits limb function (which is rare in childhood), arthroscopic synovectomy may be indicated.¹¹ Lyme disease, like other infections, may trigger a fibromyalgia syndrome that does not respond to additional courses of an antimicrobial but may improve with symptomatic therapy.

Outcomes in Lyme arthritis

Limited information is available about the long-term outcome in adults and children with Lyme arthritis who have not received appropriate antimicrobial therapy. It appears, however, that, even without appropriate antimicrobial therapy, the number of recurrences of arthritis decreases with time. Within 10 years of their initial episode of arthritis, virtually all patients in one long-term study in children had no more recurrences.¹²

The results of studies of long-term outcomes among adults with Lyme arthritis who were treated with various antimicrobial regimens have differed. In a recent investigation of patients older than 12 years, researchers found that disease resolved in about 90% of patients—regardless of whether they were treated with four weeks of orally administered doxycycline or four weeks of orally administered amoxicillin plus probenecid.¹³

We also have little information about long-term outcome in children who have been treated with appropriate antimicrobial therapy. In three uncontrolled studies of a small number of children treated with either orally administered penicillin V, tetracycline, amoxicillin, or doxycycline, about 95% were asymptomatic at follow-up evaluation.^14-16 In our recent investigation, cited above, the prognosis for children with Lyme arthritis who were treated with appropriate antimicrobial therapy was excellent.⁵ At the follow-up evaluation, performed two to 12 years (median, seven years) after onset of Lyme arthritis, none of the 90 children had evidence of active arthritis.

Neurologic manifestations of Lyme disease

Headache, palsy of the facial nerve or of other cranial nerves, meningitis, radiculitis, and encephalitis are examples of neurologic manifestations that occur at various stages of Lyme disease.¹⁷ Iritis, optic neuritis, pseudotumor cerebri, focal meningoencephalitis, a Guillain-Barré-like syndrome, and ataxia also have been associated with Lyme disease.

A major problem in determining the frequency with which Lyme disease causes many of these problems (particularly the unusual manifestations) is that the diagnosis often depends on serologic tests, the specificities of which frequently are poor.⁹ The literature contains many anecdotal reports of unusual neurologic problems that are attributed to Lyme disease solely because of a positive serologic test result. In addition to having poor specificity, a positive test has poor predictive value if the pretest probability that a particular symptom is due to Lyme disease is low, as is often the case with unusual or nonspecific symptoms.⁹ Furthermore, a positive test simply is a marker of prior infection (which may have occurred years earlier) and does not necessarily indicate a causal relationship between Lyme disease and symptoms or signs of illness at the moment.

Late neurologic manifestations of Lyme disease, sometimes termed tertiary neuroborreliosis, have been described almost exclusively among adults and are rare even in that population. Chronic demyelinating encephalitis, polyneuritis, and impairment of memory have all been attributed to Lyme disease, although the frequency with which such late manifestations occur, especially among patients who have received appropriate antimicrobial treatment, is controversial. Signs and symptoms of inflammation of the peripheral nerves may also develop in adults; specific symptoms vary widely and are generally manifestations of so-called mononeuropathy multiplex: a multifocal, inflammatory disorder affecting multiple individual nerves.¹⁸ Adults may also develop a radicular syndrome, another manifestation of mononeuropathy multiplex caused by Lyme disease.

An acute or chronic leukoencephalitis is another rare form of late nervous system Lyme disease seen almost exclusively in adults. Results of MRI scans in these patients may resemble those seen in patients with multiple sclerosis, with areas of increased signal in the white matter of either the brain or spinal cord. These patients typically have signs of disease of the white matter, such as ataxia, pain or tingling, and spasticity; in virtually all, evidence of synthesis of specific antibodies to B burgdorferi is found in their cerebrospinal fluid (CSF). This process can often be arrested, and sometimes reversed, with appropriate antimicrobial treatment.

Long ago, it was recognized that some adults with longstanding, objective evidence of Lyme arthritis sometimes reported difficulty with memory, fatigue, and impairment of cognition. Neuropsychologic testing often provided objective quantification of such problems, which resolved after patients were treated appropriately with antimicrobials. Those patients were thought to have a form of late neurologic Lyme disease known as "Lyme encephalopathy." In a small percentage of these patients with objective evidence of Lyme arthritis, analysis shows abnormalities in CSF, and intrathecal production of specific antibodies against B burgdorferi can be demonstrated. Their symptoms are probably due to a mild form of leukoencephalitis. Most of these patients have normal CSF findings, however, and their symptoms are probably caused by the very common "toxic metabolic" encephalopathy that may be seen in any chronic inflammatory disease. In other patients, with only vague, nonspecific symptoms and no objective evidence of either arthritis or of active CNS inflammation, such nonspecific symptoms should not be attributed to active Lyme disease.

Lyme's "unrelated" manifestations

"Unrelated manifestations" of Lyme disease may seem an oxymoron but is entirely appropriate for a discussion of Lyme disease because so many different symptoms—from fatigue, poor performance in school, or just "not being oneself," to arthralgia and virtually any other symptom one can imagine—have been attributed to Lyme disease and particularly to "chronic Lyme disease." A panel of experts that developed clinical guidelines for the Infectious Diseases Society of America for managing patients with Lyme disease concluded that "chronic Lyme disease" is not a diagnostic entity.¹⁰ Nevertheless, some patients and physicians continue to insist that a host of mostly nonspecific complaints are manifestations of "chronic Lyme disease."

Why is there so much controversy? The answer to this question lies in several factors:

Nonspecific symptoms associated with Lyme disease may persist after infection has been successfully treated. Patients with Lyme disease frequently have nonspecific symptoms, such as headache and fatigue, when they see a physician; however, objective signs of Lyme disease, such as an erythema migrans rash, seventh nerve palsy, or a swollen joint, also are present. In children with Lyme disease, nonspecific symptoms are virtually never the only manifestation of Lyme disease. Occasionally, the nonspecific symptoms persist for weeks after treatment is completed, although they resolve eventually, usually within two months. There is no evidence that persistence of nonspecific symptoms indicates either inadequately treated or continuing infection.

Prevalence of nonspecific symptoms sometimes attributed to Lyme disease leads to false assumptions about the presence of the disease itself. Nonspecific symptoms sometimes attributed to Lyme disease are highly prevalent in the general population. One survey in Great Britain found that about 15% of the general population experiences chronic severe pain.¹⁹ The nonspecific symptoms also can be caused by common ailments, such as viral illness, or may be a manifestation of anxiety. Nevertheless, the idea that Lyme disease might cause nonspecific symptoms that are not accompanied by objective signs of illness has been publicized by patient-advocate groups and augmented by misinformation in the lay press and on the Web. In some instances, anxious and often misinformed parents are driven by the fear that their child's nonspecific complaints may be a manifestation of Lyme disease that, if not detected and treated, could lead to serious chronic disability.

Many people don't realize that long-term problems are rare, especially in children. A large body of evidence indicates that Lyme disease rarely causes long-term problems in children. And, the long-term problems that have been documented have been almost exclusively in adults with objective evidence of Lyme disease. Most of these patients were never treated with an antimicrobial for Lyme disease, received treatment only many years after disease began, or developed a chronic, autoimmune arthritis because of genetic predisposition.^20,21 Because several years elapsed between the time Lyme disease was first described in a group of children and the time physicians learned its cause and how to treat it, most of these children either were not treated for many years after their original symptoms appeared or were not treated at all.¹² Nevertheless, the long-term outcome in most of these children has been excellent.

Long-term studies of both children and adults who were treated for Lyme disease have found that their outcome also was excellent; in most instances, their condition was not significantly different than that of age-matched controls without Lyme disease. This is true not only for people with early, localized Lyme disease, but also for those with late Lyme disease or with neurologic manifestations of Lyme disease such as facial nerve palsy.^5,22,23 Indeed, studies that included extensive neuropsychological testing of children treated for Lyme disease indicated that they were entirely normal.

Recently reported results of two large, double-blind randomized clinical trials of long-term antimicrobial treatment for "chronic Lyme disease" provide more evidence that patients with chronic symptoms after conventional treatment for Lyme disease do not benefit from additional prolonged treatment with antimicrobials.²⁴ The trials, sponsored by the National Institutes of Health, were overseen by an independent data and safety monitoring board. Subjects were adults who had previously been given a diagnosis of Lyme disease and had persistent symptoms that they attributed to it. One trial enrolled only patients who were seropositive for antibodies to B burgdorferi while the other trial enrolled patients who were seronegative when the study began.

The patients in both trials were divided into two treatment groups: One that received parenteral ceftriaxone for one month followed by oral doxycycline for two months and one that was given placebo in the same manner. About 45% of both those who received antimicrobials and those who received placebo in both trials reported improvement. In November 2000, the monitoring board stopped the study before projected enrollment was complete, concluding that, even if additional subjects were enrolled, the probability of finding a significant difference between the effect of antibiotic treatment and the effect of placebo was nonexistent.

Nevertheless, physicians in referral centers that specialize in Lyme disease continue to be deluged by patients who either are thought to have—or who believe they have—"chronic Lyme disease." Reports from those centers indicate that the great majority of such patients either did not have Lyme disease or that the symptoms that led to the referral were not caused by Lyme disease.^{25, 26} The challenge for clinicians who are faced with such patients, or with their parents, is to be able to address their concerns without dismissing them.

A common misperception—or fear—is that virtually any symptom or behavioral abnormality that follows supposedly adequate treatment for Lyme disease might be the consequence of what was actually inadequate treatment. In many instances, reassurance allays a parent's anxiety; at other times, though, a parent may insist that the child is ill, even though objective signs of organic illness are absent. Helping such patients obtain the type of help they need without alienating child and parents is an art. Sometimes this can be best accomplished by explaining that you want simultaneously to explore both possible organic and behavioral causes of the problem.

Tying it together

No discussion of Lyme disease would be complete without addressing how to reduce the risk of a tick bite, which is described in "Preventing Lyme disease" below. Children who do contract the disease respond well to antibiotic treatment and even those with late Lyme disease have an excellent prognosis if treated appropriately. In patients with arthritis or neurologic abnormalities believed to be caused by Lyme disease, diagnosis should be based on the presence of characteristic objective findings, a history of exposure in an area endemic for the disease, and serologic evidence of infection with B burgdorferi. Keep in mind, however, the limitations of serologic testing.

REFERENCES

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

2. Steere AC, Malawista SE, Snydman DR, et al: Lyme arthritis: An epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum 1977;20:7

3. Carlson D, Hernandez J, Bloom BJ, et al: Lack of Borrelia burgdorferi DNA in synovial samples from patients with antibiotic treatment-resistant Lyme arthritis. Arthritis Rheum 1999;42:2705

4. Sigal LH: Management of Lyme arthritis. Comp Ther 1999;25:228

5. Gerber MA, Zemel LS, Shapiro ED: Lyme arthritis in children: Clinical epidemiology and long-term outcomes. Pediatrics 1998;102:905

6. Huppertz HI, Bohme M, Standaert SM, et al: Incidence of Lyme borreliosis in the Wurzburg region of Germany. Eur J Clin Microbiol Infect Dis 1999;18:697

7. Huppertz HI, Karch H, Suschke HJ, et al: Lyme arthritis in European children and adolescents. Arthritis Rheum 1995;38:361

8. Shapiro ED, Gerber MA: Lyme disease. Clin Infect Dis 2000;31:533

9. Seltzer EG, Shapiro ED: Misdiagnosis of Lyme disease: When not to order serologic tests. Pediatr Infect Dis J 1996;15:762

10. Wormser GP, Nadelman RB, Dattwyler RJ, et al: Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 2000;31 (Suppl 1):S1

11. Steere AC: Diagnosis and treatment of Lyme arthritis. Med Clin North Am 1997;81:179

12. Szer IS, Taylor E, Steere AC: The long-term course of Lyme arthritis in children. N Engl J Med 1991;325:159

13. Steere AC, Levin RE, Molloy PJ, et al: Treatment of Lyme arthritis. Arthritis Rheum 1994;37:878

14. Culp RW, Eichenfield AH, Davidson RS, et al: Lyme arthritis in children: An orthopaedic perspective. J Bone Joint Surg (Am) 1987;69:96

15. Eichenfield AH, Goldsmith DP, Benach JL, et al: Childhood Lyme arthritis: Experience in an endemic area. J Pediatr 1986;109:753

16. Rose CD, Fawcett PT, Eppes SC, et al: Pediatric Lyme arthritis: Clinical spectrum and outcome. J Pediatr Orthop 1994;14:238

17. Belman AL, Iyer M, Coyle PK, et al: Neurologic manifestations in children with North American Lyme disease. Neurology 1993;43:2609

18. Halperin JJ, Luft BJ, Volkman DJ, et al: Lyme neuroborreliosis—peripheral nervous system manifestations. Brain 1990;113:1207

19. Croft P, Rigby AS, Boswell R, et al: The prevalence of chronic widespread pain in the general population. J Rheumatol 1993;20:710

20. Logigian EL, Kaplan RF, Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990;323:1438

21. Steere AC, Dwyer E, Winchester R: Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med 1990;323:219

22. Seltzer EG, Gerber MA, Cartter ML, et al: Long-term outcomes of persons with Lyme disease. JAMA 2000;283:609

23. Vazquez M, Sparrow S, Goudreau D, et al: Long-term outcomes of children with facial nerve palsy due to Lyme disease. Pediatr Res 1999;45 (part 2):177A (abstract #1033)

24. National Institutes of Allergy and Infectious Diseases: Interim analysis of NIAID's chronic Lyme disease treatment studies statement. November 29, 2000, Bethesda, Md.

25. Steere AC, Taylor E, McHugh GL, et al: The overdiagnosis of Lyme disease. JAMA 1993;269:1812

26. Reid MC, Schoen RT, Evans J, et al: The consequences of overdiagnosis and overtreatment of Lyme disease: An observational study. Ann Intern Med 1998; 128:354

DR. GERBER is professor of pediatrics, division of infectious disease, Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

DR. SHAPIRO is professor of pediatrics, epidemiology, and investigative medicine, departments of pediatrics and epidemiology and the Children's Clinical Research Center, Yale University School of Medicine, New Haven, Conn. He has received honorariums from Smith Kline Beecham, the manufacturer of LYMErix Lyme vaccine, for speaking at medical meetings.

Lyme disease in review

Lyme arthritis was recognized as a distinct entity in 1975 during an investigation of a cluster of children in Lyme, Conn., who were initially thought to have juvenile rheumatoid arthritis. It soon became apparent that Lyme arthritis was part of a complex multisystem disorder—Lyme disease—that could also affect the skin, nervous system, and heart.

The identification of the skin lesion erythema migrans as a feature of Lyme disease and the epidemiologic investigations of affected patients implicated certain Ixodes ticks as the vector. The presence of erythema migrans also linked Lyme disease to some clinical syndromes in Europe, such as erythema chronicum migrans, meningopolyneuritis, and acrodermatitis chronica atrophicans, which had been thought to be separate entities. The isolation in 1982 of a previously unrecognized spirochete, Borrelia burgdorferi, from Ixodes ticks as well as from patients with Lyme disease, erythema migrans, meningopolyneuritis, and acrodermatitis chronica atrophicans, brought all of these syndromes together and linked them with this microorganism.

Recent phylogenetic studies based on relatedness of DNA have subdivided the microorganism that causes Lyme disease, B burgdorferi sensu lato, into multiple genospecies—B burgdorferi sensu stricto, B garinii, and B afzelii. In North America, virtually all characterized isolates have been B burgdorferi sensu stricto. In contrast, in Europe all three groups have been identified and most isolates have been from the B garinii or B afzelii groups. These differences in predominant strains may explain some of the differences in the clinical epidemiology of Lyme disease in Europe and North America.

Lyme disease has been reported in 49 states and in more than 50 countries. In the United States, most cases occur in southern New England, the eastern parts of the Middle Atlantic states, and the upper Midwest. To a lesser extent, Lyme disease also is endemic along the northern Pacific coast. Reported cases in the United States have increased 70%, from 9,909 in 1992 to 16,802 in 1998. More than 92% were reported by 10 states, and more than 92% occurred in 165 counties. The increase in reported cases is probably a result of both a true increase in incidence within known endemic areas and more complete reporting because of enhanced Lyme disease surveillance in endemic areas. Although the vector ticks have moved into some new areas, most of the increase in reported cases has occurred in places known to be endemic for Lyme disease and probably is due to an increase in the population of ticks.¹

Lyme disease is a zoonosis. It is acquired by transmission of B burgdorferi to humans through the bite of an infected tick of the Ixodes species. In the eastern and midwestern United States, the vector is Ixodes scapularis (formerly known as Ixodes dammini), the black-legged species commonly known as the deer tick. In the western United States, the disease is transmitted by a close relative, Ixodes pacificus— the western black-legged tick.

REFERENCE

1. Centers for Disease Control and Prevention: Surveillance for Lyme disease—United States, 1992-1998. MMWR 2000;49(SS03):1

Important note from the editors

As this issue of Contemporary Pediatrics went to press, the New England Journal of Medicine (NEJM) posted three major articles and an editorial about Lyme disease on its Web site ( www.nejm.org ). NEJM took this action before scheduled publication of those articles in its July 12^th issue because, according to the publication's editors, of their "potential importance in the treatment of Lyme disease."

Two of the three NEJM articles reinforce points that Michael A. Gerber, MD, and Eugene D. Shapiro, MD, make in this article. (For a summary of the National Institutes of Health trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease—the subject of the NEJM-posted article by Klempner and colleagues—see the discussion beginning with the last paragraph on page 54.)

The third article reports on the efficacy of prophylaxis with single-dose doxycycline for prevention of Lyme disease, based on a study of 482 people who removed an attached Ixodes scapularis tick from their body. An erythema migrans lesion developed at the site of the tick bite in far fewer of subjects who received a single 200-mg dose of doxycycline than in those who did not receive the drug. The authors, Nadelman and colleagues, conclude that a prophylactic dose of doxycycline given within 72 hours after a bite from I scapularis can prevent Lyme disease.

In an accompanying NEJM editorial, Dr. Shapiro cautions that these findings do not mean that everyone bitten by a deer tick should routinely receive antimicrobial chemoprophylaxis. He notes the following reasons: The risk of Lyme disease after a tick bite is low; doxycycline often causes nausea and vomiting; most practitioners have trouble identifying an at least partially engorged nymphal deer tick (the only kind that appears capable of transmitting Borrelia burgdorferi); and increased use of doxycycline might have a considerable effect on the prevalence of resistant strains of bacteria. Dr. Shapiro also points out that data are insufficient to endorse a single dose of doxycycline in children younger than 8 years. His conclusion? "It may be reasonable to administer doxycycline to persons bitten by ticks in areas where the incidence of Lyme disease is high and when the tick is a nymphal deer tick that is at least partially engorged with blood."

Preventing Lyme disease

Reducing the risk of a tick bite is one obvious strategy to prevent Lyme disease. The potential for prevention offered by vaccination currently is limited because the only licensed vaccine for Lyme disease is not approved for use in children younger than 15 years.

Avoiding tick bites. In endemic areas, clearing brush and trees, removing leaf litter and woodpiles, and keeping grass mowed may reduce exposure to ticks. Application of pesticides to residential properties is effective in suppressing populations of ticks but may be harmful both to other wildlife and to people. Erecting fences to exclude deer from residential yards and maintaining tick-free pets also may reduce exposure to ticks.

Children should avoid habitats that are heavily infested with ticks, such as wooded areas, if possible. People who are in such areas may reduce their exposure by using wide trails and being careful not to stray off them and not to sit on the ground. Light-colored clothing (to make recognition and removal of ticks easier), long sleeves that are tight at the wrists, and long pants that are tucked into light-colored socks are the clothes of choice. A hat should be worn in densely wooded areas.

Tick and insect repellents that contain DEET (n,n-diethylmetatoluamide) applied to the skin provide additional protection, but must be reapplied every one or two hours for maximum effectiveness. Serious neurologic complications in children from either frequent or excessive application of DEET-containing repellents have been reported, but they are rare and the risk is low when these products are used according to instructions. Use of products with concentrations of DEET greater than 30% does increase the risk of adverse effects and is unnecessary. DEET should be applied only on exposed skin and should be used sparingly; it should not be used on a child's face or hands or on skin that is either irritated or abraded. After the child returns indoors, skin that was treated should be washed with soap and water.

Permethrin (a synthetic pyrethroid) is available in a spray for application to clothing. It is particularly effective because it kills ticks on contact. Permethrin should not be applied directly to the skin.

Studies indicate that Borrelia burgdorferi generally is transmitted from infected ticks only after the tick has been attached for longer than 48 hours. An attached tick should therefore be removed promptly. Instruct parents to inspect their own and their children's bodies and clothing after possible exposure to Ixodes ticks. Any tick that is found should be grasped with medium-tipped tweezers as close to the skin as possible and removed by gently pulling the tick straight out. If some of the mouth parts remain embedded in the skin, they should be left alone because they usually are extruded eventually; additional attempts to remove them often result in unnecessary damage to tissue and may increase the risk of local bacterial infection. Analysis of ticks to determine if they are infected with B burgdorferi is not indicated because the predictive value of such tests for development of human disease is unknown.

The risk of infection after a recognized deer tick bite in an endemic area is estimated to be less than 2%.¹ Serologic testing for Lyme disease at the time of a recognized tick bite is not recommended. The presence of antibodies to B burgdorferi when the tick is removed is probably attributable to either a false-positive test result or to an earlier infection with B burgdorferi rather than to a new infection from the recent bite. Although some physicians like to reassure patients by testing sera for antibodies at the time of a tick bite and six to eight weeks later, this practice usually is unnecessary, especially if it is likely that the tick was attached for fewer than 48 hours. In addition, interpretation of serologic tests is complicated by the poor predictive value of a positive test in this setting.

Routine use of an antimicrobial agent to prevent Lyme disease in a person who is bitten by a deer tick, even in a highly endemic area, is not recommended because the value of such treatment is unproved and is associated with potential risks and with costs.¹

Protecting older children with vaccination. Two manufacturers have produced vaccines for Lyme disease that use rOspA as the antigen. The vaccines were tested for both safety and efficacy in humans. LYMErix, the only licensed vaccine, is not approved for use in children younger than 15 years. LYMErix contains 30 mg of purified rOspA lipidated protein combined with 0.5 mg of aluminum adjuvant. An investigation showed that the efficacy of LYMErix in preventing clinical Lyme disease was 49% in the first year, after two injections.² In the second year, after the third injection, the vaccine's efficacy in preventing symptomatic Lyme disease was 76%. Serologic tests were performed on subjects at entry and again 12 and 20 months later to detect asymptomatic infection with B burgdorferi. The efficacy of this vaccine in preventing asymptomatic infection was 83% in the first year and 100% in the second year.

Three doses of the vaccine are required for optimal protection in adults (although the vaccine is more immunogenic in children); the second dose is given one month after the first dose and a third dose is given 12 months after the first dose. Preliminary data suggest that other immunization schedules (such as 0, 1, 6 months or 0, 1, 2 months) are safe and induce antibody responses similar to the 0, 1, 12 month schedule. At this time, however, only the 0, 1, 12 month schedule is approved by the Food and Drug Administration (FDA). The duration of immunity has not been clearly established, and the need for, or timing of, booster doses after a patient has completed the primary immunization series has yet to be determined.

The mode of action of this rOspA vaccine is unique. OspA is expressed by B burgdorferi that reside in the midguts of dormant ticks, but expression is later down-regulated in response to a blood meal. Because ticks must become engorged with blood before they can transmit the organism, patients with natural infection from B burgdorferi have little exposure and little antibody response to OspA (at least in the early stages of infection. When a tick infected with B burgdorferi bites an immunized host, the tick ingests the host's protective OspA antibodies. These antibodies then destroy the B burgdorferi in the gut of the tick, preventing transmission to the host.

In the vaccine efficacy trial, the most frequently reported adverse side effects were pain, redness, and swelling at the site of the injection. These effects were usually mild and self-limited. No hypersensitivity reactions were reported, and, 30 days or more after the injections, neither the type nor the frequency of symptoms varied when recipients of vaccine and of placebo were compared. In addition, the groups did not differ significantly in the frequency of either severe or unexpected adverse effects. There was also no evidence that the vaccine exacerbated prior Lyme arthritis, caused neurologic disease, or caused arthritis in subjects— including those with a history of Lyme disease.

The FDA is considering an application to approve use of the vaccine in children younger than 15 years. The decision to recommend Lyme vaccine should be based on determination of the person's risk of developing Lyme disease, which depends on the likelihood of being bitten by ticks infected with B burgdorferi. Overall risk is relatively low for most people, even those who live in an endemic area. Consider the potential benefits of the vaccine compared with other protective measures, including early diagnosis and treatment of Lyme disease, as well as the costs and adverse side effects of the vaccine.³ The rOspA vaccine does not protect all recipients from infection with B burgdorferi and is not effective against other tick-borne diseases, such as human granulocytic ehrlichiosis and babesiosis. Those who are vaccinated should therefore continue to practice personal protective measures against tick bites.

REFERENCES

1. Warshafsky S, Nowakowski J, Nadelman RB, et al: Efficacy of antibiotic prophylaxis for prevention of Lyme disease. J Gen Intern Med 1996;11:329

2. Steere AC, Sikand VK, Meurice F, et al: Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl J Med 1998;339:209

3. Committee on Infectious Diseases, American Academy of Pediatrics: Prevention of Lyme disease. Pediatrics 2000;105:142

ACCREDITATION

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Jefferson Medical College and Medical Economics, Inc.

Jefferson Medical College of Thomas Jefferson University, as a member of the Consortium for Academic Continuing Medical Education, is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. All faculty/authors participating in continuing medical education activities sponsored by Jefferson Medical College are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their article(s). Full disclosure of these relationships, if any, appears with the author affiliations at the beginning of the article.

CONTINUING MEDICAL EDUCATION CREDIT

This CME activity is designed for practicing pediatricians and other health-care professionals as a review of the latest information in the field. Its goal is to increase participants' ability to prevent, diagnose, and treat important pediatric problems.

Jefferson Medical College designates this continuing medical educational activity for a maximum of one hour of Category 1 credit towards the Physician's Recognition Award (PRA) of the American Medical Association. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.

This credit is available for the period of July 15, 2001, to July 15, 2002. Forms received after July 15, 2002, cannot be processed.

Although forms will be processed when received, certificates for CME credits will be issued every four months, in March, July, and November. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education at 215-955-6992.

HOW TO APPLY FOR CME CREDIT

1. Each CME article is prefaced by learning objectives for participants to use to determine if the article relates to their individual learning needs.

2. Read the article carefully, paying particular attention to the tables and other illustrative materials.

3. Complete the CME Registration and Evaluation Form below. Type or print your full name and address in the space provided, and provide an evaluation of the activity as requested. In order for the form to be processed, all information must be complete and legible.

4. Send the completed form, with $20 payment if required (see Payment, below), to:

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5. Be sure to mail the Registration and Evaluation Form on or before July 15, 2002. After that date, this article will no longer be designated for credit and forms cannot be processed.

FACULTY DISCLOSURES

Jefferson Medical College, in accordance with accreditation requirements, asks the authors of CME articles to disclose any affiliations or financial interests they may have in any organization that may have an interest in any part of their article. The following information was received from the author of "Late Lyme disease: Clearing up confusion."

Michael A. Gerber, MD, has nothing to disclose.

Eugene D. Shapiro, MD, has received honorariums from Smith Kline Beecham, the manufacturer of Lyme vaccine, for speaking at medical meetings.

CME REGISTRATION AND EVALUATION FORM

Date of publication: July 2001
Title: "Late Lyme disease: Clearing up confusion"
Author: Michael A. Gerber, MD and Eugene D. Shapiro, MD
MP Code: CP0701

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Michael Gerber, Eugene Shapiro. Late lyme disease: Clearing up confusion. Contemporary Pediatrics 2001;7:46.