Lyme borreliosis (LB) is a tick-transmitted spirochetal infection caused by certain genospecies of Borrelia burgdorferi sensu lato. Many wooded and heathland regions of the temperate northern hemisphere provide suitable conditions for Ixodes species ticks and borrelial reservoir hosts (mainly small animals and birds).1 The only genospecies causing LB in the United States is Borrelia burgdorferi sensu stricto (Bb). Several other genospecies, principally Borrelia afzelii (Ba) and Borrelia garinii (Bg), also cause disease in Europe and Asia.1,2
Genospecies heterogeneity is linked to variations in clinical presentations. All pathogenic genospecies can cause erythema migrans (EM), the early rash. Both Bb and Bg are neurotropic, Bb is strongly associated with arthritic complications and Ba is mainly associated with skin manifestations.1 Borreliae are dependent on their host for nutritional requirements and can evade host innate and adaptive humoral and cellular immune responses for prolonged periods through variation of their outer surface proteins. They do not appear to produce toxins; tissue damage seems to be caused principally by host inflammatory response.1
Over 24,000 confirmed cases were notified in the United States in 2011, most commonly in children aged 5–15 years with a secondary peak in the 40–55 age group (http://www.cdc.gov/lyme/). European epidemiological data are not standardized, but estimates suggest over 100,000 cases annually with highest incidences in Scandinavia, central Europe and eastern Europe.2 There is strong seasonality, with most cases of EM and early disseminated disease presenting between May and September, reflecting peak tick-feeding periods.1 Seasonal distribution of late manifestations is less pronounced. Most tick bites in young children occur around the head, neck and upper trunk, whereas adolescents and adults sustain bites more frequently on the trunk and lower limbs, especially in skin folds.
CLINICAL FEATURES OF LB
EM, a rash spreading slowly from the site of a tick bite that may have been inapparent, is the most common single manifestation in both continents and is seen in about 90% of patients in population-based prospective studies..1,3 Although EM has been described as “bulls-eye” or target like, many rashes are homogeneous, with central clearing developing only over time. Some rashes, particularly those caused by Ba, can become extensive if untreated. Systemic symptoms, including myalgia and arthralgia, can accompany EM, especially in Bb and Bg infections. Multiple EM can occur through hematogenous spread to other areas of skin, often accompanied by other features of dissemination, for example, meningitis. Borrelial lymphocytoma is an uncommon early localized, bluish-red skin nodule occurring on the earlobe (particularly in children), nipple or scrotum and is caused mainly by Ba.2
The major presentations of disseminated disease on both continents are neurological and musculoskeletal. In children, the most common manifestations of neuroborreliosis are facial palsy (FP), uncommonly bilateral and meningitis..4 Other cranial nerve palsies and meningoencephalitis occur less frequently and polyradiculoneuritis (commonly seen in adult neuroborreliosis) is unusual. Some children may present with nonspecific complaints such as malaise, headache, fatigue and neck pain without clear neurological signs at physical examination..5 Raised intracranial pressure causing a pseudotumor cerebri-like syndrome, which can be sight threatening if untreated, is an uncommon but important complication of Lyme meningitis in children. Several prediction models to help distinguish Lyme meningitis from aseptic meningitis (principally enteroviral, which has similar seasonality) have been developed in European and American Lyme-endemic regions..3 They suggest that short duration of symptoms, absence of FP and <70% mononuclear cells in CSF are predictive of aseptic rather than Lyme meningitis.
Arthralgia and myalgia can be features of early disseminated disease. Frank arthritis, usually associated with Bb infection, is uncommon, presenting as recurrent attacks of inflammation of 1 or more large joints, usually the knee. It can progress to persistent synovitis with marked effusion..1,6 Most patients respond well to antibiotic treatment, but a subgroup have inflammation persisting for some time without evidence of continuing infection, termed antibiotic-refractory arthritis. This is thought to be immune-mediated and is usually treated with nonsteroidal antiinflammatory agents.1,6
Carditis occurs in <1% of pediatric cases, and affected children almost always have other clinical features of LB. It usually manifests as partial heart block, although complete block occasionally occurs; patients may require temporary pacing..1 Heart block usually resolves within a week. Other rare disease manifestations include uveitis, iridocyclitis and keratitis.1–3
LABORATORY TESTS FOR LB
Direct DNA detection methods have very limited value in routine diagnosis because of lack of target DNA in clinical samples such as blood and CSF..1,2,4 In an American study, only 5% of children with acute neuroborreliosis had positive polymerase chain reaction tests on CSF.1 They can be helpful as adjunctive investigations in Lyme arthritis and atypical skin lesions1–3 and have been useful in testing CSF from rare cases of immunocompromised seronegative patients in whom there was strong clinical suspicion of neuroborreliosis.
Antibody tests are valuable, provided their inherent limitations are appreciated. An antibody response takes several weeks to develop and immune response tends to be slower in Ba infections than Bb-associated disease, which usually presents more acutely and with more systemic symptoms. A negative antibody result does not exclude EM; this diagnosis should be made on clinical appearance and assessment of tick exposure risk..1–3 Early treatment is highly desirable to prevent possible progression to later complications. An antibody response may be transient or undetectable following successful treatment of very early infection.2
Serology can help to support the diagnosis of later LB.1–3 Most patients with neuroborreliosis are seropositive at presentation; some children with isolated FP are initially seronegative but usually seroconvert within 2–3 weeks. Antibodies may be detectable in CSF earlier than in serum in some cases.3 Patients with presentations of longstanding disease such as Lyme arthritis or acrodermatitis chronica atrophicans (ACA), a late skin manifestation rarely reported in children, are strongly seropositive.1 Seronegativity in late-stage disease very rarely occurs in immunocompetent patients. Only 2 reported cases of apparently seronegative ACA, 1 of seronegative Lyme arthritis and no reliable reports of seronegative late-stage neuroborreliosis were identified when European clinical case definitions for LB were updated in 2011..2
The significance of seropositivity should be interpreted carefully in light of clinical findings. Background seroprevalence, reflecting previous exposure (symptomatic or asymptomatic), ranges from 4% to 20% in adults in highly endemic regions and was 4.8% in a recent German pediatric study..1,3 Also, although new generation antibody tests are markedly more specific compared with their predecessors false-positive reactions can still occur, especially in IgM tests in the presence of conditions such as infectious mononucleosis or autoimmune diseases. To minimize the risk of false positivity, tests should be requested only when there is well-founded clinical suspicion of LB and not in situations of low pretest probability.1–3 Serology is not indicated in routine follow up because borrelial antibodies can persist for prolonged periods after successful treatment of disseminated disease..1,2
TREATMENT AND OUTCOMES OF LB
Numerous European and American specialist societies and expert groups have developed diagnostic and treatment guidelines (see http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1287144781602).1,2,4Table 1 summarizes common recommendations, but readers should consult appropriate local guidelines where available. Most presentations can be treated with oral antibiotics (doxycycline, amoxicillin, phenoxymethylpenicillin or cefuroxime axetil). Ceftriaxone is the most commonly preferred parenteral agent, with once-daily dosing facilitating outpatient treatment. Recent prospective studies have shown that oral doxycycline is noninferior to ceftriaxone in neuroborreliosis, and it is now recommended in Europe for the treatment of acute FP, meningitis and radiculoneuritis.4 Ceftriaxone currently remains the preferred choice for children with other presentations of neuroborreliosis and for those with contraindications to doxycycline.
Several recent EM treatment studies have incorporated noninfected control groups.1,7 Excellent responses were seen, with resolution of rash within 7–14 days. Nonspecific symptoms including headache, myalgia, arthralgia, fatigue and parasthesias were no more common in cases than controls at 6-month follow up.
A Swedish long-term (median 5 years) follow-up study of 84 children treated for neuroborreliosis also incorporated a noninfected control group..8 Of 53 patients with FP at presentation, 11 had moderate facial nerve dysfunction at follow up; other motor or sensory deficits were found in 5 patients. Patients treated with oral doxycycline did not have a higher rate of sequelae than those receiving ceftriaxone. Daily activities and school performance seemed similar in case and control groups and nonspecific symptoms (headache, fatigue, memory or concentration problems) were no more common among cases than controls.
Excellent outcomes were seen in an American study of 99 children with Lyme arthritis.6 Arthritis resolved completely following antibiotic treatment in 76 patients. Those with antibiotic-refractory arthritis responded well to NSAIDs or other treatments and no patients developed chronic arthritis or joint deformities.
Some patients have subjective symptoms (eg, headache, myalgia, concentration difficulties) continuing for some time following treatment in the absence of objective clinical or laboratory evidence of persistent infection.2. This postinfection syndrome seems to be more common in adults than children. Several studies have shown that nonspecific symptoms can persist for several months, but recent European research incorporating uninfected controls has shown no excess of nonspecific symptoms in cases over controls when reviewed at 6 months and later..1,7,8 At least 4 studies of patients with postinfection symptoms showed no laboratory evidence for persistent infection and no sustained benefit from prolonged antibiotic treatment, which carried significant risks..1,9
LB IN PREGNANCY
There is no reliable evidence to support a congenital Lyme syndrome; pregnant women who develop LB should be treated similarly to other adults, apart from avoidance of doxycycline use..1,2 There is also no evidence that infection can be transmitted through breast-feeding or sexual contact.
PREVENTION OF LB
No vaccine is currently available, but studies on a polyvalent vaccine are underway in Europe. Current prevention strategies concentrate on increasing awareness of ticks and disease risk, avoiding tick infested areas, use of DEET-containing insect repellents and frequent checks for attached ticks, as early removal minimizes infection risk..1 Postexposure antibiotic prophylaxis is not routinely recommended in Europe; single-dose doxycycline prophylaxis is recommended in the United States under limited circumstances.1,3 Previous infection is unlikely to confer immunity and tick bite prevention measures should be taken to avoid Lyme reinfection as well as other tick-borne infections.
CHRONIC LYME DISEASE
This term is ambiguous and has been used to describe several distinct patient groups.1,2 They include patients with manifestations of untreated late-stage infection (eg, arthritis, ACA or encephalomyelitis), those with permanent or slow-to-heal tissue damage following a resolved infection and patients with postinfection syndrome. Another important group comprises patients who have had LB in the past and subsequently develop another unrelated condition. However, many patients with a diagnosis of chronic Lyme disease reviewed at tertiary referral centers had no credible evidence of current or past LB, but had other well-defined illnesses or conditions such as chronic fatigue syndrome, fibromyalgia or neurocognitive issues.1
There is widespread misinformation on the Internet spuriously linking Lyme to conditions such as autism, ADHD and behavioral problems. Some “Lyme-specialty” clinics promote unvalidated or nonspecific tests (eg, lymphocyte transformation tests, CD-57 counts, live-blood microscopy and unorthodox immunoblot applications) and potentially dangerous treatments to parents of children with a variety of physical, mental or psychological conditions..1,10 These unethical activities occur in many countries, including regions where LB is not endemic and can cause serious difficulties for children, parents and their healthcare providers.
OTHER IXODID TICK-TRANSMITTED DISEASES
Several viral, bacterial, rickettsial and protozoal infections can be tick-transmitted and occasionally cause coinfections with LB, which may modify clinical presentations and may require additional antimicrobial agents for treatment. Important infections include tick-borne encephalitis (for which a vaccine is available), babesiosis and anaplasmosis..1 A relapsing fever-group spirochaete, Borrelia miyamotoi, has recently been identified as pathogenic in Europe and North America, causing viral-like symptoms and meningoencephalitis.
1. Stanek G, Wormser GP, Gray JS, et al. Lyme borreliosis. Lancet. 2012;379:461–473
2. Stanek G, Fingerle V, Hunfeld K-P,, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. CMI. 2010
3. Huppertz H-I, Bartmann P, Heininger U, et al. Rational diagnostic strategies for Lyme borreliosis in children and adolescents: recommendations by the Committee of Infectious Diseases and Vaccinations of the German Academy for Pediatrics and Adolescent Health. Eur J Pediatr. 2012;171:1619–1624
4. Mygland A, Ljostad U, Fingerle V, et al. European Federation of Neurological Society guidelines for the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol. 2010;17:8–16
5. Broekhuijsen-van Henten DM, Braun KP, Wolfs TF. Clinical presentation of childhood neuroborreliosis; neurological examination may be normal. Arch Dis Child. 2010;95:910–914
6. Tory HO, Zurakowski D, Sundel RP. Outcomes of children treated for Lyme arthritis: results of a large pediatric cohort. J Rheumatol.. 2010;37:1049–1055
7. Stupica D, Lusa L, Ruzić-Sabljić E, et al. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis. 2012;55:343–350
8. Skogman BH, Glimåker K, Nordwall M, et al. Long-term clinical outcome after Lyme neuroborreliosis in childhood. Pediatrics. 2012;130:262–269
9. Klempner MS, Baker PJ, Shapiro ED, et al. Treatment trials for post-Lyme disease symptoms revisited. Am J Med. 2013;126:665–669
10. Auwaerter PG, Bakken JS, Dattwyler RJ, et al. Antiscience and ethical concerns associated with advocacy of Lyme disease. Lancet Infect Dis. 2011;11:713–719