Lyme borreliosis

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Seminar

Lyme borreliosis Robert B Nadelman, Gary P Wormser Lyme borreliosis (Lyme disease) is often said to be associated with “protean” manifestations, a reference to the ancient god Proteus, who could assume many forms and thus elude his pursuers. This legendary quality has clouded our understanding of Lyme borreliosis by giving Borrelia burgdorferi infection a mythical aura of its own. This review shows that this illness, while incompletely understood, is far more palpable than Proteus and is (in most cases) much more readily subdued. The clinical presentations of Lyme borreliosis do differ in North America and Eurasia, possibly due to the differing pathogenicity of distinct genospecies of Borrelia burgdorferi. The most common manifestation, however, in both continents is erythema migrans. Diagnosis should rest on a careful history and objective clinical findings, supported by appropriately chosen laboratory tests. Reports of coinfection with other tickborne diseases should prompt a fresh look at Lyme borreliosis. Assertions about “protean manifestations” of B burgdorferi infection should be reappraised. Advances in laboratory techniques are welcome but culture remains the gold standard for the diagnosis—and no laboratory test result should substitute for careful clinical observation and critical analysis. “And he [Proteus] will try you by taking the form of all creatures that come forth and move on the earth, he will be water and magical fire.” “First he turned into a great bearded lion, and then to a serpent, then to a leopard, then to a great bore, and he turned into fluid water...” The Odyssey of Homer (Transl R Lattimore New York: Harper & Row, 1975: iv, 417–18, 456–58)

Epidemiology Lyme borreliosis is an infection caused by the spirochaete Borrelia burgdorferi sensu lato (B burgdorferi) which is transmitted by the usually asymptomatic bite of certain ticks of the genus Ixodes (figure 1). Ticks acquire infection in a complex tick-vertebrate cycle. The whitefooted mouse is the most important reservoir for B burgdorferi (ie, source of infection for the tick) in North America, but in Europe a variety of small mammals (including the dormouse and vole) and some birds are important, possibly reflecting the more varied and complex ecology of the Ixodes ticks in Eurasia. In the western USA low B burgdorferi tick infection rates have been attributed to the fact that Ixodes ticks in that location commonly feed on lizards, which are not thought to be competent reservoirs for B burgdorferi. White-tailed deer, an important host for adult Ixodes ticks, also do not serve as reservoirs for B burgdorferi.1 Lyme borreliosis occurs in northeastern, mid-Atlantic, north-central, and far western regions of the United States, with limited foci in Canada (primarily one section of eastern Ontario), and in much of Europe and northern Asia (panel 1). Migrating birds may have a role in the spread of ticks and B burgdorferi to new locations. Despite reports of Lyme borreliosis-like illnesses in Australia, Africa, South America, and the southern USA, Lancet 1998; 352: 557–65 Department of Medicine, Division of Infectious Diseases, New York Medical College, and the Lyme Disease Diagnostic Center, Westchester Medical Center, Valhalla, NY, USA (R B Nadelman MD, G P Wormser MD) Correspondence to: Dr Robert B Nadelman, Westchester Medical Center, Division of Infectious Diseases, Macy Pavilion 209SE, Valhalla, NY 10595, USA

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Figure 1: I scapularis, the major North American tick vector for Lyme borreliosis Other important vectors in Eurasia ( I ricinus, I persulcatus) and North America ( I pacificus) have a very similar appearance. Upper L to R=nymphal I scapularis, poppy seed, adult female I scapularis, sesame seed; millimetre scale also shown. Hand lens may help in identification. Lower: unfed and fed (for 48 h) nymphal I scapularis.

B burgdorferi has not been isolated from patients there and these regions should not be considered endemic for this infection. Lyme borreliosis occurs with similar frequencies in males and females in the USA, and affects people of all ages. A bimodal age of distribution of US cases has been described with highest rates in children aged 5–9 years old and in adults over 30.

Clinical manifestations Although a wide variety of disease manifestations has been ascribed to Lyme borreliosis, many have been based 557

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Panel 1: Vectors for Lyme borreliosis Tick species*

Geographical location

Tick stage important for transmission of infection

I scapularis (black-legged tick)†

Northeastern, mid-Atlantic, and north-central USA‡

Nymph

I ricinus (sheep tick)§

Western, central, eastern, and southern Europe

Nymph

I persulcatus||

Eastern Europe, Russia, China, Japan, Korea

Adult

I pacificus†

Far western USA and Canada Nymph

*Infection rates for each species and stage may vary considerably from place to place. †I scapularis in the southern USA and I pacificus in the western USA have low B burgdorferi infection rates (<3%); infection rates in I scapularis in locations endemic for Lyme borreliosis range up to 65% for the adult and 30% for the nymphal stage.2 ‡Established I scapularis populations have been well documented in at least one location (Long Point) in Ontario, Canada; isolated reports of I scapularis ticks have come from other Canadian provinces (D Fish, personal communication). §Infection rates for nymphal I ricinus stage, median 12% (range 0–66%);3 infection rates for adult I ricinus stage, median 16% (range 4–52%).3 ||Estimates for infection rates for adult stage I persulcatus range up to 60%.3

on case-reports, uncontrolled series of patients, or indirect (serological) evidence rather than on infection confirmed microbiologically (ie, isolation of B burgdorferi in culture). Early descriptions failed to consider the possibility of coinfection with other tick-borne pathogens, some of which were not recognised when the reports were written. Although manifestations of Lyme borreliosis have been staged,4 the implications of this classification for pathogenesis, prognosis, or treatment, remain unclear. The surveillance definition of Lyme borreliosis developed by the US Centers for Disease Control and Prevention for epidemiological purposes,5 though not intended to

serve as a strict practice guideline, does seem to be useful clinically; and a European guideline is clinically helpful too.6 Well-recognised Lyme borreliosis features are summarised in panel 2. The wider variety of genospecies of B burgdorferi in Eurasia may account for the different manifestations of Lyme borreliosis in Eurasia and North America (panels 3 and 4).

Erythema migrans Erythema migrans (EM) is the clinical hallmark of Lyme borreliosis9–12 and it is recognised in about 90% of patients with objective evidence of B burgdorferi infection.22,24 The erythema typically begins as a red macule or papule at the site of a tick bite 7–10 days earlier. The rash expands over days to weeks, presumably as the spirochaetes spread centrifugally through the skin (figure 2). Central clearing, often thought of as a sine qua non of EM, may or may not be present and is largely a function of long duration of the rash before treatment.10–12 Secondary cutaneous lesions, with no tick bite site (punctum) may develop after haematogenous spread of spirochaetes. Local symptoms of pruritus, tenderness, and paraesthesia are hardly noticeable in primary lesions11,12 and are absent in secondary lesions. EM must be distinguished from local tick bite reactions, tinea, insect and spider bites, bacterial cellulitis, and plant dermatitis. Systemic complaints in patients with EM are more common in the USA than in Europe (panel 3), perhaps as a result of illness caused by a more virulent genospecies (B burgdorferi sensu stricto rather than B afzelii)12 or more frequent coinfection.24,25 The most frequent associated symptoms in one US report of 79 culture-confirmed patients included fatigue (54%), myalgia (44%), arthralgia (44%), headache (42%), fever

Panel 2: Lyme borreliosis manifestations*† Cutaneous Erythema migrans9–12‡ ● Expanding (over days or weeks) erythematous patch (肁5 cm in diameter). Systemic complaints (including fever) and secondary EM lesions may occur. ● Does not include lesions ocurring within hours of a tick bite (hypersensitivity reactions) or lesions which resolve without antibiotics within 48 h.§ Borrelial lymphocytoma6,13‡ ● Painless bluish-red nodule or plaque usually on ear lobe, nipple, or scrotum. B-lymphocytic infiltrate present on biopsy. Acrodermatitis chronica atrophicans6‡ ● Long-standing red or bluish-red discolouration, usually on extensor surface of extremities, sometimes with dough-like swelling, ultimately becoming atrophic (and sometimes associated with peripheral neuropathy, adjacent periarticular nodules, and/or joint subluxation beneath lesions). Extracutaneous (when no alternative explanation is found): Carditis14 ● Acute onset of high grade (2° or 3°) atrioventricular conduction defects that resolve in days to weeks and may be associated with myopericarditis. ● Does not include palpitations, bradycardia, bundle-branch block, or myocarditis alone without other objective manifestations of Lyme borreliosis. Nervous system15–17 ● Lymphocytic meningitis,‡ cranial neuritis (particularly peripheral facial nerve palsy), radiculoneuropathy, and rarely encephalomyelitis (the last must be confirmed by demonstration of specific intrathecal antibody poduction to B burgdorferi) || ● Does not include headache, fatigue, paraesthesia, or stiff neck without other objective manifestations of Lyme borreliosis. Musculoskeletal system9,19–21 ● Recurrent brief attacks (weeks or months) of objective joint swelling in one or a few joints sometimes followed by chronic arthritis, typically in one or both knees. ● Does not include chronic progressive arthritis not preceded by brief attacks, chronic symmetrical polyarthritis, or arthralgia, myalgia, or fibromyalgia without other objective manifestations of Lyme borreliosis. *Modified from CDC 5 and EUCALB 6 recommendations. †Laboratory evidence required for all manifestations except for erythema migrans (EM) in an area endemic for B burgdorferi infection. Laboratory evidence should be isolation of B burgdorferi from a clinical specimen, specific genetic sequences by PCR in synovial fluid or CSF, or antibodies to B burgdorferi in serum on a twostep test.7,8 (An endemic area is defined as wooded, brushy, or grassy locations in a county [or equivalent district] in which at least two confirmed human cases of Lyme borreliosis have been previously acquired, or in which established populations of a known tick vector are infected with B burgdorferi.) ‡Multiple patients with culture-confirmation of B burgdorferi infection. §Untreated EM resolved spontaneously in 3–4 weeks (mean) in US patients,4 and in 10 weeks (median) in Swedish patients.10 ||Requires simultaneous serum and CSF to determine whether the level of specific antibody to B burgdorferi in CSF is greater than that in serum.8,15,–18

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Panel 3: Lyme borreliosis in North America and Eurasia Feature

North America

Eurasia

Vector

I scapularis or I pacificus

I ricinus or I persulcatus

Agent

B burgdorferi ss*

B burgdorferi ss* (in Europe), B afzelii, or B garinii

Erythema migrans Recollection of tick bite Duration of rash at presentation Central clearing Systemic symptoms Multiple lesions † Seronegativity at presentation

Infrequent (<30%) 2,11,12,22 Short (median 4 days) 11,12 Uncommon (<35%) 11,12 Common (up to 80%) 11,12,22 (≈13%) 11,12 Common (50%) 8,11,12

Common (64%) 12 Long (median 14 days12 to 5–6 weeks10 Common6,10 (>65%) 12 Uncommon (often <35%) 10,12 (≈7%) 10,12 Very common (up to 80%) 10,12

Rheumatological Arthritis in untreated patients with EM Borrelial lymphocytoma Acrodermatitis chronica atrophicans

Common (51%) 21 Rare Rare

Uncommon Well documented Well documented

*ss=sensu stricto †Although it has been thought that multiple EM lesions are more common in North America, a recent comparison study found a similar incidence of multiple EM lesions in culture-confirmed patients in Ljubljana, Slovenia and Westchester County, NY12

and/or chills (39%), and stiff neck (35%).11 Prominent respiratory and/or gastrointestinal complaints are so rare that their presence should suggest an alternative diagnosis or coinfection. The most common objective physical findings are regional lymphadenopathy (23%) and fever (16%).11 Occasional cases of febrile virus-like illness without EM have been attributed to Lyme borreliosis. Some of these patients may have presented before the erythema developed or after the spontaneous resolution of an asymptomatic unrecognised EM, or had a different illness associated with a false-positive Lyme borreliosis serology (eg, granulocytic ehrlichiosis).25 Certainty of Lyme borreliosis in such individuals is lower. Although the EM rash is characteristic of early Lyme borreliosis, it should not be considered pathognomonic. For example, extensive investigation of rashes that resembled EM in the southern USA (associated with Amblyomma americanum rather than I scapularis tick bites) found neither microbiological nor serological evidence of B burgdorferi infection.26 A new presumptive species, B lonestarii sp nov, has been recognised in A americanum ticks but an association with this Lyme borreliosis-like illness has not been established.

Carditis Cardiac disease due to B burgdorferi typically develops weeks to months after infection and is usually manifested

by a fluctuating degree of atrioventricular block which may cause the patient to complain of dizziness, palpitations, dyspnoea, chest pain, or syncope.4,14 Pericarditis with effusion is less common. Carditis was reported in 8% of US patients before the widespread use of antibiotics for EM.4 In more recent series the incidence (as measured by ECG confirmed heart block) has been lower, in both the USA (<1%)22,27 and in Europe (<4%)14 Heart block is typically at or above the atrioventricular node4,14 but can affect the entire cardiac conduction system. Myocardial biopsy is not often done in patients with acute carditis but in anecdotal cases spirochaete-like forms have been associated with a local inflammatory response.14 B burgdorferi has been recovered in culture from the myocardium of several European patients with congestive heart failure, including two with acute myocarditis and one with chronic cardiomyopathy.28 European but not US investigators have found evidence for an association between Lyme borreliosis and dilated cardiomyopathy based upon serological data with anecdotal responses to antibiotics.29 Panel 4: Genospecies of B burgdorferi sl causing Lyme borreliosis* Genospecies

Location

B burgdorferi ss

North America, Only genospecies known to Europe cause clinical disease in North America Eurasia Associated with a milder systemic illness accompanying EM compared with B burgdorferi ss;12 principal cause of acrodermatitis chronica atrophicans23 and a cause of borrelial lymphocytoma.13 Eurasia Closely associated with neurological disease;23 also a cause of EM 23 and borrelial lymphocytoma.13 Slovenia Isolated from borrelial lymphocytoma (one report);13 has been isolated from North American ticks but not patients.

B afzelii

B garinii

DN127

Figure 2: Erythema migrans lesion without central clearing B burgdorferi was recovered on biopsy culture

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Comments

sI=sensu lato; ss=sensu srticto; *Certain other genospecies as well as B japonica, B andersonii, and B miyamotoi sp nov have been isolated from tick vectors but not man. An association between B lonestari sp nov (identified in A americanum ticks) and a Lyme disease-like illness in certain areas of the southern USA has not been proven.

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Panel 5: Neurological manifestations of Lyme borreliosis Clinical features

Diagnostic features

Cranial neuropathy (stage II/weeks*)

Peripheral 7th nerve palsy (may be bilateral) most common neurological manifestations in N Am; EM may be present too; 7th nerve palsy may develop during the first week of treatment for EM, which does not constitute treatment failure.

Antibody usually detectable in serum; CSF may show lymphocytic pleocytosis

Meningitis (stage II/weeks)

Meningismus not prominent; headache may be intermittent; may be associated with cranial neuritis and with radiculopathy (Garin-Boujadoux-Bannwarth syndrome); EM may be present too.

CSF culture positive in 聿10% and PCR positive in <50%; antibody detectable in serum; intrathecal antibody production† and lymphocytic pleocytosis both present in >80%.

Radiculoneuritis (stage II/weeks)

Acute onset of severe localised radicular pain and/or motor weakness with or without sensory loss; sensory complaints and neurological deficits may be multifocal and asymmetrical; may occur as Garin-BoujadouxBannwarth syndrome (see above); more common in Europe than N Am.

Antibody detectable in serum; electrophysiological studies consistent with axonal degeneration in distal nerves as well as nerve roots; CSF pleocytosis in almost all patients,16 and intrathecal antibody production† in >80%

Peripheral neuropathy (chronic axonal neuropathy) (stage III/ months to years)

Paraesthesias and, less commonly, radicular pain; sensory deficits unusual on clinical examination and motor strength and deep tendon reflexes preserved; usually not accompanied by meningitis or cranial neuritis.

Antibody in serum; electrophysiological studies consistent with mild axonal neuropathy;16 CSF usually normal;16 intrathecal antibody production† usually absent; sural nerve biopsy shows distal axonal loss and perivascular infiltrate but without immune complexes or complement deposition. B burgdorferi not demonstrated in nerve tissue.‡

Encephalopathy (stage III/months to years)

Typically subacute or chronic; subtle memory and cognitive dysfunction; physical examination usually normal; may be associated with peripheral neuropathy; may be secondary to indirect effects of neuromodulators rather than direct infection of central nervous system.17

Antibody detectable in serum; may be associated with raised CSF protein or intrathecal antibody production,† and, in a minority of cases, CSF pleocytosis;16 role for formal neurocognitive testing needs confirmation.

Encephalomyelitis (stage III/months to years)

Unifocal or multifocal inflammatory disease which is slowly progressive and involves white-matter more than grey-matter;17 rare.17

Detectable serum and intrathecal antibody production;† may be associated with CSF pleocytosis, increased protein, or positive PCR. MRI, though non-specific, may suggest white-matter disease.

*Time from EM to onset of neurological symptoms. †Requires simultaneous serum and CSF samples to determine whether level of specific antibody to B burgdorferi in CSF is greater than that in serum.8,15–18 ‡Both acute (radiculoneuritis) and chronic forms of Lyme neuropathy probably represent forms of mononeuritis multiplex.17

Neurological disease Early reports indicated that 15–20% of untreated US patients with Lyme borreliosis develop neurological disease (neuroborreliosis) (panel 5). However, 1990–95 data from the State of Connecticut have consistently indicated that neurological Lyme borreliosis accounts for no more than 10% of cases.22,27 In Europe, the frequency may be higher but selection bias could be partly responsible for the difference. Another factor may be the greater neurotropism of B garinii, which has not been isolated in North America.12,13,23 Antibiotics appear to hasten the resolution of meningitis but most studies are uncontrolled. The rate of resolution of motor dysfunction, which is fully reversible in the vast majority of cases, is not enhanced by antimicrobial therapy.30 Symptoms of encephalopathy and peripheral neuropathy improve or do not progress after treatment with intravenous antibiotics.16 B burgdorferi infection is not the cause of multiple sclerosis, amyotrophic lateral sclerosis or Alzheimer’s disease. Case-reports of psychiatric illness in patients who are B burgdorferi seropositive do not provide compelling evidence of causation, and a prospective serosurvey on patients admitted to a psychiatric hospital in Westchester County, NY, found no evidence of Lyme borreliosis in 517 patients over 16 months.31 Rheumatological disease Lyme arthritis is often regarded as primarily a North American manifestation,4,12 but selection bias may explain 560

this. The clinical features of Lyme arthritis are fundamentally similar in Europe and North America.4 In a study of 55 untreated patients with erythema migrans diagnosed in Connecticut between 1977 and 1979, followed up for a mean duration of 6 years, objective arthritis developed in more than half of the patients. The arthritis occurred within 1 year for 90% (mean time 6 months, range 4 days to 2 years, from the onset of EM).21 In the absence of antibiotic treatment, intermittent attacks of migratory monoarthritis or asymmetric oligoarthritis occur, lasting a mean of 3 months (range 3 days to 11·5 months).21 The knee is affected at some point in almost all patients, but other large and (less often) small joints may be affected. Temporomandibular joint involvement occurred in 11 (39%) of 28 patients with arthritis in one series. Although large effusions may occur, joint pain and erythema are often minimal. Baker’s cysts may develop. Synovial fluid analysis typically reveals a modestly elevated protein and white cell count (median 24 250 white cells/␮L; range 2100–72 250) with a polymorphonuclear predominance9 and a normal glucose level. Synovitis lasting 1 year or more may ensue for a minority of US patients, sometimes associated with joint destruction.4,9,19–21 Although B burgdorferi DNA can be detected by PCR in the synovial fluid of up to 85% of untreated patients with Lyme arthritis, B burgdorferi has rarely been successfully cultured from joint fluid.20 In patients who receive antibiotics, the presence of B burgdorferi can no longer be detected by PCR in repeat synovial fluid examinations.20

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Panel 6: Clinical features of Lyme borreliosis in children at time of diagnosis* Manifestation

Frequency

EM (solitary/multiple lesions) Arthritis Facial nerve palsy Meningitis Carditis

89% (66%/23%) 6% 3% 2% 0·5%

*Prospective study of 201 consecutive children (median age 7 years; range 1–21) with Lyme borreliosis seen in Connecticut. At follow-up a mean of 2 years after antibiotic treatment, no child had persistent disease. Adapted from ref 22.

Acrodermatitis chronica atrophicans Acrodermatitis chronica atrophicans develops insidiously on a distal extremity, characterised by a swollen bluish-red appearing skin lesion which ultimately atrophies.4,6 One third of patients have an associated (usually sensory) polyneuropathy. B burgdorferi has been recovered from skin biopsy specimens of acrodermatitis chronica atrophicans lesions of more than 10 years’ duration.4 Since the usual causative agent, B afzelli, does not occur in the US, acrodermatitis chronica is essentially a European disease. Miscellaneous Borrelial lymphocytoma, principally caused by B afzelli and B garinii,13 is a tumour-like nodule which typically appears (in European patients) on the pinna of the earlobe or on the nipple or areola of the breast.6 Lesions resolve spontaneously but disappear within a few weeks after antibiotics. Direct involvement of the eye (eg, uveitis, keratitis, vitritis, and optic neuritis) has been attributed to B burgdorferi infection.4 However, since ophthalmological disorders have hardly ever been associated with the isolation of B burgdorferi in culture, the pathogenesis in these cases is uncertain. Conjunctivitis, originally described in 11% of patients with EM, was rare (<5%) in recent studies of culture-positive patients.11,12 Children account for a disproportionate number of Lyme borreliosis cases, presumably because of increased exposure and decreased attention to prevention. Manifestations are similar to those in adults (panel 6).22 Case reports have suggested that adverse outcomes may be associated with pregnancies complicated by maternal Lyme borreliosis.4 However, a recent prospective report from Slovenia described unremarkable outcomes in 51/58 (88%) consecutive pregnant women who had EM and were treated with oral or intravenous penicillin or intravenous ceftriaxone. Adverse events in six pregnancies (five preterm births [one with atrial and ventricular septal defects], one missed abortion, and one with ureteral stenosis at age 7 months) could not clearly be attributed to B burgdorferi infection.32 The risk of transplacental transmission of B burgdorferi is probably minimal when appropriate antibiotics (panel 7) are given to pregnant women with Lyme borreliosis. There are no published data to support a congenital Lyme borreliosis syndrome.

Laboratory detection For the diagnosis of an infectious disease, the “gold standard” is isolation of the causative agent in culture. Unfortunately, this standard has not been met in most case-series of Lyme borreliosis, despite the fact that B burgdorferi (unlike Treponema pallidum) can be readily cultured in vitro.8,10–13,26,28,36–38

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The reliability of methods other than culture to detect spirochaetes in tissue specimens is open to question. For example, although forms resembling B burgdorferi can be identified by silver impregnation histochemical staining, spirochaetes can be difficult to distinguish from elastic tissue fibres or procollagen fibres and other artifacts. Monoclonal antibody staining and polymerase chain reaction (PCR) techniques to detect DNA sequences specific for B burgdorferi in clinical specimens, even if positive, cannot distinguish between live and dead organisms, and results may persist as positive after clinical cure.25 A PCR may yield false-positive results if appropriately specific primers are not used or if precautions are not taken against contamination.25 Assays to detect B burgdorferi antigens in urine or in CSF have been insufficiently studied.8 In routine patient management, the diagnosis of EM in locations endemic for Lyme borreliosis is purely clinical. Laboratory testing is neither necessary nor recommended; when it is done in patients presenting with EM, culture is virtually 100% specific and appears to be more sensitive (57–86%)8,26 than serology (about 50% in the USA and <50% in Europe).10,12 In suspected extracutaneous Lyme borreliosis, laboratory support for the diagnosis is essential.5–7,14 Culture of B burgdorferi has been a highly insensitive diagnostic technique for these patients, presumably the tissues that contain the organism are so inaccessible. Although potentially useful and constantly improving, B burgdorferi antibody tests lack sensitivity (primarily in early disease) and specificity, and the assays have not been standardised.8,39 This has led to erroneous diagnoses and may have contributed to fundamental misunderstandings of Lyme borreliosis. A two-step serological approach has been proposed by US authorities7 (and is being studied in Europe6), to increase specificity. A positive or equivocal first test (usually an enzyme-linked immunosorbent assay [ELISA] or indirect immunofluorescence assay [IFA]) is followed on the same serum sample by an immunoblot test which can detect IgM and IgG antibodies to individual B burgdorferi antigens that have been separated by electrophoresis. If the immunoblot is negative the reactive ELISA or IFA will very probably have been a false-positive. A positive IgG blot is necessary to support a diagnosis of Lyme borreliosis in a patient who has been ill for more than a month.7 However, even sequential testing is not indicated if there is little or no clinical evidence of Lyme borreliosis because of the low positive predictive value.8,17 Neither ELISA (as usually reported) nor immunoblot permits detection of four-fold rises in antibody titre (seroconversion). Since IgM and IgG antibodies to B burgdorferi may persist in serum for years after clinical recovery,39 serology has no role in measuring response to treatment. Patients with extracutaneous Lyme borreliosis almost always have diagnostic serum antibodies to B burgdorferi4,6 except for some patients with early seventh nerve palsy or occasional patients who have antibodies in CSF only.8 The specificity and sensitivity of T-lymphocyte recognition of B burgdorferi antigens are controversial.4,8,17 Reports claiming the utility of measuring specific B burgdorferi-associated immune complexes in the diagnosis of seronegative Lyme borreliosis require confirmation. 561

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Coinfection I scapularis ticks carry several other infections that may be transmitted, separately or simultaneously with B burgdorferi. Examples are Babesia microti, a parasite that causes a malaria-like infection,24 and the rickettsial agent that causes human granulocytic ehrlichiosis.25 In Europe, species of Babesia and Ehrlichia are present in I ricinus, which is also a vector for a flavivirus causing tick-borne encephalitis. It is unclear whether a Powassan/tick-borne-encephalitis-like virus, which has been identified in I scapularis from New England (USA),40 is associated with human illness. Coinfection may alter the clinical presentation and response to treatment of Lyme borreliosis.24,25 Certain clinical features (eg, thrombocytopenia or leukopenia) which are not characteristic of Lyme borreliosis, should suggest coinfection with human granulocytic ehrlichiosis or babesiosis.24,25 Re-evaluation of the true incidence of fever, other constitutional symptoms and abnormal liverfunction tests in Lyme borreliosis is warranted in areas in which human granulocytic ehrlichiosis is present, because coinfection could have confounded older studies. The possibility of coinfection with the tick-borne encephalitis virus in European patients is worth exploring too.

Treatment Although most manifestations of Lyme borreliosis resolve spontaneously without treatment, antibiotics may hasten resolution and prevent disease progression. An approach to treatment is summarised in panel 7. Quinolones, sulpha drugs, first-generation cephalosporins, rifampicin, and aminoglycosides have no appreciable activity against B burgdorferi; nor is there evidence to support combination antimicrobial therapy, prolonged (>1 month) or repeated antibiotic courses, or pulse or intermittent antibiotic therapy or the use of antibiotics to “release” borrelia antigens to enhance diagnosis. Within 24 h of the start of antibiotics, 15% of patients may transiently have intensified signs (eg, rash and fever) and symptoms (eg, arthralgias) consistent with Jarisch-Herxheimer reaction. There is no convincing evidence that such reactions occur after, or persist beyond, 24 h. Treatment is symptomatic. Most persons treated for Lyme borreliosis have an excellent prognosis. Although some patients treated for EM in recent series continue to have a variety of mild nonspecific complaints following antibiotic therapy, objective extracutaneous disease after treatment is very rare. One recent study in New England reported that most Lyme borreliosis patients who were unwell 3 months after treatment had laboratory evidence of coinfection with babesiosis.24 Patients with carditis and neurological disease also tend to do well, though some do have residual deficits such as mild seventh nerve palsy after treatment.14–16,18 In patients with arthritis, clinical recovery typically coincides with antibiotic therapy (often combined with a non-steroidal anti-inflammatory drug;19,20 occasional patients with subtle signs of neuroborreliosis who are treated orally (particularly with amoxicillin and probenecid) may develop overt neuroborreliosis.19 The concomitant use of amoxicillin and probenecid may be inadvisable because probenecid can impair penetration of ␤-lactam antibiotics into brain parchenchyma.30 A small number of US patients with Lyme arthritis and the HLA-DR4 haplotype, who 562

continue to have synovial inflammation for months or even years after apparent eradication of B burgdorferi from the joint with antibiotic therapy,4,19–21,39 have improved after synovectomy.19 Although viable B burgdorferi have been recovered from a few European patients after therapy,38 two prospective US studies reported that B burgdorferi could not be grown from skinbiopsy specimens in patients treated for EM whose preantibiotic skin cultures had been positive.36,37 Almost all treatment trials for Lyme borreliosis have lacked healthy controls, and underlying morbidity in “healthy” populations is well documented. For instance, a recent study compared complaints in 212 randomly selected patients with a history of Lyme borreliosis (reported to the Connecticut Health Department) 1–11 years earlier with age and residence matched controls. Preliminary results indicate that the patients with a history of Lyme borreliosis and the “healthy” controls had a similar incidence of an assortment of somatic complaints.41 Lyme borreliosis, like other infections, may trigger a fibromyalgia syndrome which does not appear to respond to repeated courses of antibiotics but may improve with symptomatic therapy.39 Many US patients with a variety of complaints of uncertain aetiology, including pain and fatigue syndromes, have been labelled as having “chronic Lyme disease” and prescribed unconventional treatments. These treatments have included months or even years of high-dose antibiotics (some never previously tested against B burgdorferi) singly or in combination, hyperbaric oxygen, ozone, and even the intentional inoculation of malaria to eradicate “persistent” spirochaetes. These treatments have not been shown to be effective and are potentially dangerous;42 they may also impede diagnostic evaluation.39,42

Prevention Recommendations to prevent Lyme borreliosis include avoiding exposure to nymphal stage Ixodes (or adult stage I persulcatus) ticks by limiting outdoor activities in tickinfested locations, using tick repellents, tucking in clothing, and frequent skin inspections for early detection and removal of ticks. Use of acaricides on property and construction of deer fences have also been proposed. Control of deer populations may diminish the numbers of ticks in isolated (ie, island) populations but is impractical since near-total elimination of deer is required for significant risk reduction.2 Antibiotic prophylaxis given to asymptomatic individuals after recognised I scapularis tick bites has not been shown to be effective in reducing the low (<5%) risk of acquiring Lyme borreliosis.35 Indeed, for every 10 cases of Lyme borreliosis theoretically prevented by prophylactic amoxicillin, one severe life-threatening drug reaction would be expected.35 Although the risk of Lyme borreliosis appears to be increased for those on whom a tick has fed for more than 48 h, there are no data to indicate that antimicrobial prophylaxis is beneficial even for this group. A different approach is vaccination, which has been used in dogs since 1990. A single recombinant outer surface protein A (OspA) vaccine has been highly effective in preventing B burgdorferi infection in animals and appears to be safe and immunogenic in man. The published results of two US field trials of OspA vaccine preparations appear promising, principally in adults

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Panel 7: Treatment of Lyme borreliosis*† Antimicrobial

Duration§ (days)

EM

Phenoxymethylpenicillin (penicillin V) Tetracycline† Azithromycin

Amoxicillin, cefuroxime axetil, doxycycline probably equally effective; failure rate <5%; no evidence that intravenous ceftriaxone is advantageous in “disseminated” early disease. 14 Covers human granulocyte ehrlichiosis (HGE); risk of photosensitivity. 14 Not active against HGE. 14 Useful when cellulitis cannot be distinguished from EM (as is co-amoxiclav); alternative for some penicillin allergic patients; most expensive; not active against HGE. 14 Not active against HGE. 14 Covers HGE; risk of photosensitivity. 7–10 2nd line choice, more failures than with amoxicillin;34 not active against HGE.

Borrelial lymphocytoma First-line oral EM regimen†

14

Doxycycline† Amoxicillin Cefuroxime axetil

Acrodermatitis chronica atrophicans

Evaluation for neuropathy prudent; intravenous antibiotics (see below) may be effective, but advantages over oral therapy not established.

First-line oral EM regimen†

21–28

Carditis First-line oral EM regimen† Ceftriaxone

14 14

For 1° heart block. For advanced (2° or 3°) heart block; no proof that intravenous more effective than oral. No clinical trials; treatment does not shorten course;30 perform lumbar puncture if clinical signs of meningitis.

Facial nerve palsy First-line oral EM regimen†

14–28

Meningitis Ceftriaxone Cefotaxime Penicillin G Doxycycline

14 14 14 14–28

Radioculoneuritis Meningitis regimen†

(see above)

Peripheral neuropathy Meningitis regimen†

(see above)

Encephalomyelitis Ceftriaxone Cefotaxime Penicillin G

14–28 14–28 14–28

Chronic encephalopathy Ceftriaxone Cefotaxime Penicillin G

14–28 14–28 14–28

Equivalence to IV penicillin18 requires confirmation. Concomitant menigitis frequent.

Up to 6 weeks of therapy recommended by one expert panel17 but no data available.

Arthritis

Doxycycline† Amoxicillin Ceftriaxone

Comments

Oral therapy as effective as intravenous; some patients treated orally develop neurological disease (see text);19 role of synovial fluid PCR to determine duration of treatment unclear;20 no comparison studies with shorter courses of therapy. 28 28 14

Lyme borreliosis in pregnancy†

No comparison trials; treatment duration should be appropriate for individual manifestation of Lyme borreliosis (see above).

Penicillin G Ceftriaxone Amoxicillin Asymptomatic tick bite None

Efficacy of prophylaxis not proven; risk of adverse effects for 10-day regimens studied comparable to risk of contracting Lyme borreliosis.35 If not pregnant; for pregnant women with tick bites, either a 10 day course of amoxicillin or no treatment are options. No studies have been done in this population.

*Few regimens studied in published trials in children; selection of amoxicillin in preference to penicillin V, or doxycycline to tetracycline is based upon convenience (decreased dosing) and theoretical concerns (higher attainable levels) and not upon comparison studies. †Pregnant or lactating women, and children 聿9 years old should not receive tetracyclines; tetracyclines are the only antimicrobial agents known to be effective against HGE agent. ‡Paediatric dose should not exceed maximum adult dose. §Limited data available on treatment duration; studies comparing treatment duration in EM showed no outcome differences;4 duration of treatment for EM ranging from 10 to 30 days has been recommended.4 In one study of objective late Lyme disease (mostly arthritis) there was no difference in outcome with 14 or 28 days of ceftriaxone.33

under 60 years of age.30,43,44 The efficacy of these vaccines may be partly related to the ability of OspA antibodies (ingested during the blood meal by the vector tick) to kill B burgdorferi in the tick gut, thus preventing transmission of the spirochaete.45 A single antigen OspA vaccine is expected to be less effective in Eurasia

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where species of Borrelia are more heterogeneous and OspA more variable.

Research directions The linear chromosome (910 725 base-pairs) and 11 plasmids of B burgdorferi have been sequenced.46 This 563

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achievement should help to clarify how this organism survives in ticks and in animal reservoirs and how it infects humans and interacts with host defences. Insights into pathogenesis and pointers to novel diagnostic, preventive, and therapeutic methods are likely too. Also exciting is the observation that environmental triggers such as temperature and tick feeding influence gene expression in B burgdorferi,47 which in turn may relate to virulence properties and immunogenicity. Our research has been supported in part by cooperative agreements U50/CCU 210286 (RBN) and U50/CCU 210280 (GPW) from the Centers for Disease Control and Prevention and by grant RO1-AR43135 (GPW) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. We thank Allen Steere, David Dennis, John Halperin, Durland Fish, and John Nowakowski for critical reviews of our paper.

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22 Gerber MA, Shapiro ED, Burke GS, et al. Lyme disease in children in southeastern Connecticut. N Engl J Med 1996; 335: 1270–74. 23 van Dam VP, Kuiper H, Vos K, et al. Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis. Clin Infect Dis 1993; 17: 708–17. 24 Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis: evidence for increased severity and duration of illness. JAMA 1996; 275: 1657–60. 25 Nadelman RB, Horowitz HW, Hsieh T-C, et al. Simultaneous human ehrlichiosis and Lyme borreliosis. N Engl J Med 1997; 337: 27–30. 26 Kirkland KB, Klimko TB, Meriwether RA, et al. Erythema migranslike rash illness at a camp in North Carolina: a new tick-borne disease? Arch Intern Med 1997; 157: 2635–41. 27 State of Connecticut Department of Public Health. Lyme disease update. Conn Epidemiol 1993; 13: 9. 28 Stanek G, Klein J, Bittner R, Dietmar G. Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy. N Engl J Med 1990; 322: 249–52. 29 Sonnesyn SW, Diehl SC, Johnson RC, Kubo SH, Goodman JL. A prospective study of the seroprevalence of Borrelia burgdorferi infection in patients with severe heart failure. Am J Cardiol 1995; 76: 97–100. 30 Wormser GP. Treatment and prevention of Lyme disease, with emphasis on antimicrobial therapy for neuroborreliosis and vaccination. Semin Neurol 1997; 17: 45–52. 31 Nadelman RB, Herman E, Wormser GP. Screening for Lyme disease in hospitalized psychiatric patients: prospective serosurvey in an endemic area. Mt Sinai J Med 1997; 64: 409–12. v 32 Maraspin V, Cimperman J, Lotri c-Furlan, Pleterski-Rigler D, Strle F. Treatment of erythema migrans in pregnancy. Clin Infect Dis 1996; 22: 788–93. 33 Dattwyler RJ, Luft BJ, Maladorno D, et al. Treatment of late Lyme disease—a comparison of 2 weeks vs 4 weeks of ceftriaxone. In: Proceedings of the Seventh International Congress on Lyme Borreliosis (San Francisco, June 16–21, 1996): 662 (abstr). 34 Luft BJ, Dattwyler RJ, Johnson RC, et al. Azithromycin compared with amoxicillin in the treatment of erythema migrans: a doubleblind, randomized, controlled trial. Ann Intern Med 1996; 124: 785–91. 35 Warshafsky S, Nowakowski J, Nadelman RB, Kamer RS, Peterson SJ. Wormser GP. Efficacy of antibiotic prophylaxis for prevention of Lyme disease. J Gen Intern Med 1996; 11: 329–33. 36 Berger BW, Johnson RC, Kodner C, Coleman L. Failure of Borrelia burgdorferi to survive in the skin of patients with antibiotic-treated Lyme disease. J Am Acad Dermatol 1992; 27: 34–37. 37 Nadelman RB, Nowakowski J, Forseter G, et al. Failure to isolate Borrelia burgdorferi after antimicrobial therapy in culture-documented Lyme borreliosis associated with erythema migrans: report of a prospective study. Am J Med 1993; 94: 583–88. 38 Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borrelioss. Infection 1989; 17: 355–59. 39 Steere AC, Taylor E, McHugh GL, Logigian EL. The overdiagnosis of Lyme disease. JAMA 1993; 269: 1812–16. 40 Telford SR III, Armstrong PM, Katovolos P, et al. A new tick-borne encephalitis-like virus infecting New England deer ticks, Ixodes dammini. Emerging Infect Dis 1997; 3: 165–70. 41 Seltzer EG, Shapiro ED, Gerber MA, Cartter ML. Long-term outcomes of persons with Lyme disease. Clin Infect Dis 1997; 25: 361 (abstr 36). 42 Ettestad PJ, Campbell GL, Welbel SF, et al. Biliary complications in the treatment of unsubstantiated Lyme disease. J Infect Dis 1995; 171: 356–61. 43 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: 209–15. 44 Sigal LH, Zahradnik JM, Lavin P, et al. A vaccine consisting of recombinant Borelia burgdorferi outer-surface protein A to prevent lyme disease. N Engl J Med 1998; 339: 216–22. 45 de Silva AM, Fikrig E. Arthropod- and host-specific gene expression by Borrelia burgdorferi. J Clin Invest 1997; 94: 377–79. 46 Fraser CM, Casjens S, Huang WM, et al. Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi. Nature 1997; 390: 580–86. 47 Schwan TG, Piesman J, Golde WT, Dolan MC, Rosa PA. Induction of an outer surface protein on Borrelia burgdorferi during tick feeding. Proc Natl Acad Sci USA 1995; 92: 2909–13.

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Further reading

General Barbour AG, Fish D. The biological and social phenomenon of Lyme disease. Science 1993; 260: 1610–16. Rahn DW, Evans J, eds. Lyme disease. Philadelphia: American College of Physicians, 1998. Sigal LH, ed. A symposium: National Clinical Conference on Lyme Disease. Am J Med 1995; 98 (suppl 4A): 1S–91S. Weber K, Burgdorfer W, Schierz G, eds. Aspects of Lyme borreliosis. Berlin: Springer-Verlag, 1993.

Aetiology Balmelli T, Piffaretti J-C. Association between different clinical manifestations of Lyme disease and different species of Borrelia burgdorferi sensu lato. Res Microbiol 1995; 146: 329–40. Baranton G, Postic D, Saint Girons I, et al. Delineation of Borrelia burgdorferi sensu stricto, Borrelia garinii sp nov, and Group VS461 associated with Lyme borreliosis. Int J Syst Bacteriol 1992; 42: 378–83. Marti Ras N, Postic D, Foretz M, Baranton G. Borrelia burgdorferi sensu stricto, a bacterial species “made in the USA”? Int J Syst Bacteriol 1997; 47: 1112–17. Ohlenbusch A, Matuschka F-R, Richter D. Etiology of the acrodermatitis chronica atrophicans lesion in Lyme disease. J Infect Dis 1996; 174: 421–23.

Epidemiology and transmission Ai C, Hu R, Hyland K, et al. Epidemiological and aetiological evidence for transmission of Lyme disease by adult Ix odes persulcatus in an endemic area in China. Int J Epidemiol 1990; 19: 1061–65. Berglund J, Eitrem R, Ornstein K, et al. An epidemiologic study of Lyme disease in Sweden. N Engl J Med 1995; 333: 1319–24. Dennis DT. Lyme disease. Dermatol Clinics 1995; 13: 537–51. Garcia-Monco JC. European Lyme disease. In: Coyle PK. Lyme disease. St Louis: Mosby-Year Book, 1993: 219–25. Korenberg EI, Kryuchechnikov VN, Kovalevsky YV. Advances in investigations of Lyme borreliosis in the territory of the former USSR. Eur J Epidemiol 1993; 9: 86–91. Matuschka F-R, Fischer P, Heiler M, Blümcke S, Spielman A. Stageassociated risk of transmission of the Lyme disease spirochete by European Ix odes ticks. Parasitol Res 1992; 78: 695–98.

Clinical manifestations Erythema migrans Berger BW. Dermatologic manifestations of Lyme disease. Rev Infect Dis 1989; 11: S1475–81. Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical manifestations of Lyme disease. Ann Intern Med 1983; 99: 66–82. Strle F, Nelson JA, Ruzic-Sabljic E, et al. European Lyme borreliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin Infect Dis 1996; 23: 61–65.

Carditis Rubin D, Sorbera D, Nikitin P, McAllister A, Wormser GP, Nadelman RB. Prospective evaluation of heart block complicating early Lyme disease. Pacing Clin Electrophysiol 1992; 15: 252–55. Sangha O, Phillips CB, Fleishmann KE, et al. Lack of cardiac manifestations among patients with previously treated Lyme disease. Ann Intern Med 1998; 128: 346–53. Steere AC, Batsford WP, Weinberg M, et al. Lyme carditis: an important cause of reversible heart block. Ann Intern Med 1980; 110: 339–45.

Neuroborreliosis Clark JR, Carlson RD, Sasaki CT, Pachner AR, Steere AC. Facial paralysis in Lyme disease. Laryngoscope 1985; 95: 1341–45. Garcia-Monco JC, Benach JL. Lyme neuroborreliosis. Ann Neurol 1995; 37: 691–702. Goldblatt D, Joynt RJ, Younger DS, Haperin JJ, eds. Lyme disease. Semin Neurol 1997; 17: 1–75. Halperin JJ, Volkman DJ, Wu P. Central nervous system abnormalities in Lyme neuroborreliosis. Neurology 1991; 41: 1571–82. Halperin JJ, Luft BJ, Volkman DJ, Dattwyler RJ. Lyme neuroborreliosis— peripheral nervous system manifestations. Brain 1990; 113: 1207–21. Hansen K, Lebech A-M. The clinical and epidemiological profile of Lyme neuroborreliosis in Denmark 1985–1990. Brain 1992; 115: 399–423.

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Reik L. Lyme disease and the nervous system. New York: Thieme Medical, 1991.

Rheumatological Gross DM, Forsthuber T, Tary-Lehmann M, et al. Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis. Science 1998; 281: 703–06. Hovmark A, Åsbrink E, Olsson I. Joint and bone involvement in Swedish patients with Ix odes ricinus-borne Borrelia infection. Z bl Bakt Hyg A 1986; 263: 275–84. Steere AC, Dwyer E, Winchester R. Association of chronic Lyme arthritis with HLA-DR4 and HLA-DR2 alleles. N Engl J Med 1990; 323: 219–23.

Miscellaneous Miralles D, Hartman B, Brause B, Fisher L, Murray HW. Not everything that glitters is Lyme disease. Am J Med 1992; 93: 352–53. Plörer A, Sepp N, Schmutzhard E, et al. Effects of adequate versus inadequate treatment of cutaneous manifestations of Lyme borreliosis on the incidence of late complications and late serologic status. J Invest Dermatol 1993; 100: 103–09. Sigal LH. Summary of the first 100 patients seen at a Lyme referral center. Am J Med 1990; 88: 577–81. Silver HM. Lyme disease during pregnancy. Infect Dis Clin N Am 1997; 11: 93–97. Weber R, Pusterla N, Loy M, Lutz H. Leukopenia and thrombocytopenia in a patient with Lyme borreliosis were due to human granulocytic ehrlichiosis. Clin Infect Dis 1998; 26: 253–4.

Laboratory Aguero-Rosenfeld M, Nowakowski J, McKenna DF, et al. Serodiagnosis in early Lyme disease. J Clin Microbiol 1993; 31: 3090–95. Benach JL, Bosler EM, Hanrahan JP, et al. Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med 1983; 308: 740–42. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995; 33: 419–27. Feder HM Jr, Gerber MA, Luger SW, Ryan RW. Persistence of antibodies to B burgdorferi in patients treated for Lyme disease. J Infect Dis 1992; 15: 788–93. Steere AC, Berardi VP, Weeks KE, Logigian EL, Ackermann R. Evaluation of the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for Lyme neuroborreliosis. J Infect Dis 1990; 161: 1203–09. Wilske B, Fingerle V, Herzer P, et al. Recombinant immunoblot in the serodiagnosis of Lyme borreliosis. Comparison with indirect immunofluorescence and enzyme-linked immunosorbent assay. Med Microbiol Immunol 1993; 182: 255–70. Wilske B, Schierz G, Preac-Mursic V, et al. Intrathecal production of specific antibodies against Borrelia burgdorferi in patients with lymphocytic meningoradiculitis. J Infect Dis 1986; 153: 304–14. Wormser GP, Horowitz HW, Dumler JS, Schwartz I, Aguero-Rosenfeld M. False-positive Lyme serology in human granulocytic ehrlichosis. Lancet 1996; 347: 981–82. Wormser GP, Nowakowski J, Nadelman RB, Bittker S, Cooper D, Pavia C. Improving the yield of blood cultures for patients with early Lyme disease. J Clin Microbiol 1998; 36: 296–98.

Treatment and prevention Dattwyler RJ, Luft BJ, Kunkel MJ, et al. Ceftriax one compared with dox ycycline for the treatment of acute disseminated Lyme disease. N Engl J Med 1997; 337: 289–94. Massarotti EM, Luger SW, Rahn DW, et al. Treatment of early Lyme disease. Am J Med 1992; 92: 396–403. Nadelman RB, Luger SW, Frank E, Wisniewski M, Collins JJ, Wormser GP. Comparison of cefurox ime ax etil and dox ycycline in the treatment of early Lyme disease. Ann Intern Med 1992; 117: 273–80. Shapiro ED, Gerber MA, Holabird NB, et al. A controlled treatment trial of antibiotic prophylax is for Lyme disease after deer tick bites. N Engl J Med 1992; 327: 1769–73. Strle F, Maraspin V, Pleterski-Rigler D, et al. Treatment of borrelial lymphocytoma. Infection 1996; 24: 80–84. Weber K, Preac-Mursic V, Wilske B, Thurmayr R, Neubert U, Scherwitz C. A randomized trial of ceftriax one versus oral penicillin for the treatment of early European Lyme borreliosis. Infection 1990; 18: 91–96. Wormser GP. Prospects for a Lyme disease vaccine. Clin Infect Dis 1995; 21: 1267–74.

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