Lyme borreliosis

Lyme borreliosis

BACTERIAL INFECTIONS Lyme borreliosis What’s new? Sue O’Connell C Abstract C Lyme borreliosis is a tick-transmitted spirochaetal infection cause...

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BACTERIAL INFECTIONS

Lyme borreliosis

What’s new?

Sue O’Connell C

Abstract

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Lyme borreliosis is a tick-transmitted spirochaetal infection caused by pathogenic genospecies of Borrelia burgdorferi sensu lato. It occurs in wooded and heathland areas of temperate regions of the northern hemisphere. The most common clinical presentation is an erythematous rash slowly spreading from the site of a tick bite. Spirochaetes can spread hamatogenously and affect other organs and tissues, particularly the nervous system and joints. Manifestations of disseminated infection include facial palsy, viral-like meningitis, radiculopathy, meningoencephalitis and arthritis. The infection responds to antibiotic treatment at all stages, but early recognition and treatment is strongly recommended to avoid possible development of complications. Patients with long-standing infection and significant tissue damage can have slow or incomplete recovery. A small minority of appropriately treated patients can have persistent non-specific symptoms, similar to those seen following some other infections. Controlled trials in patients with post-Lyme symptoms have shown no evidence of persistent infection and no sustained benefit from prolonged antibiotic treatment. Prevention measures focus on tick and disease awareness, avoidance of tick-infested areas where possible, use of insect repellents, frequent skin inspections for attached ticks, particularly at the end of the day, as early removal minimizes the risk of infection transmission. No vaccine is available.

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An excellent neuroborreliosis treatment trial published in 2008 showed oral doxycycline (200 mg daily for 14 days) to be noninferior to intravenous ceftriaxone (2 g daily for 14 days) Further improvements in diagnostic tests include recombinant and peptide antigen-based antibody tests with greater specificity, and a greater variety of DNA detection methods Additional trial data supported findings from earlier studies, showing that patients with post-Lyme syndrome do not gain sustained benefit from prolonged antibiotic treatments, which can cause potentially dangerous adverse events Over-diagnosis and mistreatment continue to be major concerns, driven by misinformation, especially on the Internet

likely in individuals whose residence, or occupational or recreational activities place them at high risk of tick bites. Ixodid ticks (deer ticks; sheep ticks) (Figure 1) are the vectors of B. burgdorferi.2 They are common in woodland, heath and moorland but can also live in semi-rural areas bordering large population centres. They take a single blood meal in each of the three stages of their 2e3-year life-cycle (Figure 2), attaching themselves to their hosts by barbed mouth-parts. An infected tick can transmit borreliae towards the end of its feed, regurgitating infected saliva into the animal’s skin. Reservoir hosts for the spirochaetes include small and medium-sized mammals (e.g. field mice, hares) and birds, including blackbirds and pheasants.2 Human beings are incidental hosts for ticks, and infections occur mainly in late spring, early summer and autumn e the peak periods for tick feeds.1e3 The annual incidence of Lyme borreliosis can vary, depending on climatic and other factors affecting tick population density and activity and on human activities in tick habitats. Nymphal ticks, the main sources for human infection, are very small and can be overlooked. Tick bites are often not recognized because they do not usually cause significant pain, irritation or itch. People exposed to ticks can minimize their risk of infection by wearing protective clothing (light-coloured longsleeved shirts and long trousers) and using DEET-containing insect repellents. They should check regularly for attached ticks, especially at the end of the day, and remove them gently, preferably using tweezers or a tick hook as close as possible to the skin.1e3 It is particularly important to check the head and neck areas (including scalps) of young children (Figure 3). Borrelial infection is unlikely to occur when ticks are attached for less than 24 h, so prompt removal is a valuable preventive measure. Ixodid ticks can also carry other organisms, including ehrlichiae, babesiae, and, in parts of Europe, tick-borne encephalitis virus.2 Co-infections can occur and can cause atypical presentations.

Keywords acrodermatitis chronica atrophicans; Borrelia burgdorferi; erythema migrans; facial palsy; Lyme arthritis; Lyme borreliosis; meningitis; neuroborreliosis; radiculopathy

Lyme borreliosis (Lyme disease) is caused by the tick-borne spirochaete Borrelia burgdorferi. Erythema migrans, an early skin lesion, is the most common clinical presentation. The organism can spread, causing various later manifestations, including facial palsy, viral-like meningitis, radiculitis and arthritis, usually affecting the knee.

Epidemiology and environmental factors Lyme borreliosis is the most common tick-borne infection in the temperate northern hemisphere. More than 27,000 cases were reported in the USA in 2007, predominantly from northeast and mid-Atlantic seaboard states, north-central and Pacific coast states.1 There may be over 200,000 European cases annually. The infection is particularly prevalent in parts of southern Scandinavia, Germany, Austria and other Central European countries.2 In the UK, about 1,000 cases are serologically confirmed annually.3 Infection can occur at any age, and is most

Pathogenesis At least four genospecies of B. burgdorferi are pathogenic, and borrelial heterogeneity is significant in organotropism and disease presentation. Only one genospecies (B. burgdorferi sensu stricto) appears to cause human infection in North America, and

Sue O’Connell LRCP&SI DipClinMicro is a consultant medical microbiologist and head of the Lyme Borreliosis Unit at the Health Protection Agency Microbiology Laboratory, Southampton University Hospitals Trust, Southampton, UK. Competing interests: none declared.

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Figure 1 Ixodid tick.

can cause neurological and arthritic complications.1 At least two other pathogenic genospecies occur more commonly in Europe e Borrelia garinii, which is particularly associated with neurological complications, and Borrelia afzelii, associated with later skin manifestations and occasionally with neuroborreliosis.2 Borrelia spielmanii occasionally causes erythema migrans. Antigenic heterogeneity also has implications for vaccine development strategies.

Figure 3 Erythema migrans on face of 2-year-old child who had received a tick bite on her scalp 10 days previously.

B. burgdorferi can spread directly and via the bloodstream and lymphatics to many tissues, and can migrate through the bloode brain barrier. Changes in outer surface protein (Osp) expression, from OspC in the early stage to others (including OspA and OspB) in established infection, can help the organism evade the host immune response. Spirochaetal invasion and cytokine mediation have been implicated in the pathogenesis of neuroborreliosis. Experimental evidence suggests that borrelial lipoproteins adhere to cells and promote vigorous inflammatory reactions. Antibodies produced in response to spirochaetal antigens may also cross-react with axonal tissue components.4 Lyme arthritis may be caused partly by cytokine activity, Certain individuals (particularly those with HLA DR4 alleles) can be genetically predisposed to antibioticrefractory Lyme arthritis, which persists for some time following successful antibiotic treatment of the infection, and can require anti-inflammatory treatments.5

Life-cycle of the deer tick (Ixodes ricinus) Larva feeds on host No. 1 Larvae seek new host

Fully fed larva drops to ground

Eggs hatch to larva Host No. 1 Eggs laid by female

Larva moults to nymph

Fully fed female drops from host to ground Host Host No. 3 No. 2 Female attaches and feeds on host No. 3

Nymph attaches and feeds on host No. 2

Clinical features Infection can be asymptomatic. Clinically significant disease has been customarily divided into three stages, but the process should be regarded as a continuing pathological evolution rather than having distinct phases. Progression to later-stage disease is not inevitable, even in untreated patients.6 European experts estimated that late neuroborreliosis occurs in less than one in 1,000 previously untreated patients.

Nymph moults to adult The relative size of the animals (including Man) approximates their significance as hosts for the different tick life-cycle stages in a typical woodland habitat. Larvae rarely carry Borrelia and their bites are not a significant risk. The life-cycle usually takes 2–3 years. Although the peak feeding time is late spring/early summer, with a lesser peak in autumn, tick activity (and the risk of tick bites) can extend beyond these periods in favourable weather conditions.

Localized infection: the most common clinical manifestation is erythema migrans, a localized, red or pink rash appearing after 2e30 days (usually 5e15 days) at the site of a bite (Figures 3 and 4).6,7 The rash can be faint, with a more pronounced margin that gradually migrates outwards to produce a sizeable lesion. A

By courtesy of Professor Jeremy Gray and Mr Bernard Kaye

Figure 2

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associated antigen, triggering a continuing T cell response in genetically susceptible individuals. A strong antibody response to B. burgdorferi is detectable in serum5 (Figure 5). Acrodermatitis chronica atrophicans is an uncommon late skin manifestation. The lesions are usually found on the limbs, are initially violaceous and can last for years if untreated, eventually becoming atrophic (Figure 5). They are strongly associated with B. afzelii infection, which has been cultured from lesions years after onset, despite a strong antibody response.6 The condition is often accompanied by peripheral neuropathy. Lyme encephalopathy is an uncommon manifestation that can occur with other presentations of disseminated or late infection. Patients sometimes complain of poor memory and concentration, and have subtle learning difficulties, but do not have clinical, laboratory or imaging evidence of central nervous system infection. The presentation is similar to toxic-metabolic syndromes seen in other systemic inflammatory diseases, and symptoms resolve following treatment of the systemic infection.8

Figure 4 Erythema migrans following tick bite on waist several weeks previously (courtesy of Dr B Bovill).

central area of clearing can become evident as previously affected skin returns to normal, but many EM rashes are homogeneous in appearance.2,6,7 There may be local lymphadenopathy. About 80% of patients presenting with later-stage disease recall preceding erythema migrans. Borrelial lymphocytoma is a rare, localized presentation, usually on the earlobe, nipple or scrotum.6

Investigations Diagnosis is primarily clinical, particularly in early infection. In non-endemic areas awareness of Lyme borreliosis can be low and the possibility overlooked, particularly when the patient has experienced only transient or unrecognized exposure to ticks (e.g. on a holiday or day trip). Laboratory evidence should be sought to support the clinical diagnosis of disseminated and late infection, as none of the features is unique to Lyme borreliosis.6,9e12 Borrelial culture is slow and has a low yield, even in untreated patients. Borrelial DNA detection by polymerase chain reaction analysis is more sensitive and can give rapid results with skin biopsies from suspected erythema migrans and acrodermatitis, and synovial tissue or fluid from suspected Lyme arthritis. It is less useful in neuroborreliosis, because target DNA may be present only in very low copy numbers in CSF. The method does not differentiate between living and non-viable organisms.9 Antibody tests remain the mainstay of laboratory diagnosis. They are likely to be negative in the first 2e4 weeks of infection, as the immune response is slower to develop than in some other infections, but are highly sensitive in late stage disease.6,9 Screening tests have had a poor reputation, principally because

Early disseminated infection: in the following weeks the organism can affect many tissues, principally the nervous, musculoskeletal and cardiovascular systems and the skin. There can be a flu-like illness with myalgia and arthralgia but without significant respiratory symptoms.6 Multiple areas of erythema migrans can occur, but are uncommon in UK-acquired infections. Early neurological presentations include facial palsy, which can be bilateral, other cranial nerve lesions, lymphocytic meningitis and painful radiculoneuritis, which can cause shingles-like pain.2,6,8 Musculoskeletal complications include persistent arthralgia. Recurrent large joint inflammation (usually affecting the knee, and uncommon in UK-acquired infection) can become persistent without antibiotic treatment. The degree of joint swelling is usually disproportionate to the pain.5,6 Cardiac conduction abnormalities are uncommon, usually occurring within a few weeks of infection. Ocular, hepatic and other manifestations have also been reported.6 Late Lyme borreliosis is a continuing pathological process in a minority of previously untreated or inadequately treated patients. It has become uncommon in recent years because of greater recognition and effective treatment of earlier-stage infections. Late encephalomyelitis is a rare condition characterized by spastic paraparesis, cognitive impairment, cranial neuropathy, bladder dysfunction and dysarthria. There is cerebrospinal fluid (CSF) pleiocytosis and intrathecal antibody production. Appropriate antibiotics will eradicate infection but the degree of recovery depends on the severity of tissue damage prior to treatment.6,8 Late Lyme arthritis is more common in USA-acquired than in European infections. In some patients, inflammation continues for some time after antibiotic treatment. This may be related to failure in regulating immune responses, or molecular mimicry between borrelial OspA protein and human lymphocyte function-

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Figure 5 Acrodermatitis chronica atrophicans (courtesy of the late Dr J E White).

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of false-positive reactions in the presence of conditions such as infectious mononucleosis, rheumatoid disease, autoimmune diseases and other spirochaetal infections, which can lead to incorrect diagnosis and presumed treatment failure. Recent developments, including tests based on peptide antigens or antigens from different genospecies, have improved performance. Some specificity problems remain, exacerbated by inappropriate screening of patients with a very low pre-test likelihood of Lyme borreliosis, so reactive and equivocal specimens should also be tested by immunoblot (western blot), to assess antibody specificity to a range of borrelial antigens (Figure 6).9,10,12 Results must be interpreted in light of the clinical situation. Positive tests may reflect past exposure rather than currently active infection. Tests can be negative in erythema migrans, which is primarily a clinical diagnosis made on the typical appearance and history of tick exposure. Prompt treatment can partially or completely abrogate the antibody response. Tests are seldom negative in later disease; a diagnosis of seronegative Lyme borreliosis should be made only after thorough serological investigation and careful consideration of alternative diagnoses.9,10,12

Comprehensive diagnostic and treatment guidelines have been published by the Infectious Diseases Society of America, the American Academy of Neurology and several European authorities3,6,10e12 The most commonly used oral antibiotics are doxycycline, amoxicillin and cefuroxime axetil. Erythromycin and phenoxymethylpenicillin are not recommended, because they are unlikely to achieve satisfactory concentrations in tissues such as the central nervous system and synovium. Azithromycin, though not licensed for this use, could be considered if there are contraindications to the recommended oral agents, but patients should be carefully followed up because treatment failures can occur. The recommended parenteral antibiotics are ceftriaxone (preferred because of its convenient once-daily dosing), cefotaxime or benzylpenicillin. Dose, route of administration and duration vary with the clinical situation. Patients with suspected co-infection can require additional agents. A 14-day course of oral doxycycline (adult dose 200 mg daily) or amoxicillin (adult dose 500 mg t.i.d.) is generally recommended in erythema migrans. Disseminated infections without neurological involvement may require a 2e4-week course of oral antibiotics. Patients with Lyme arthritis or ACA are usually treated with 4-week courses of oral treatment. Many current recommendations suggest that neuroborreliosis (other than isolated facial palsy) should be treated with parenteral agents for 14e28 days, but a recent trial double-blind randomized controlled trial of 14-day treatments of neuroborreliosis in adults showed non-inferiority of oral doxycycline (200 mg daily) compared to intravenous ceftriaxone (2 g daily).13 These findings are likely to lead to stronger recommendations for the use of oral doxycycline in the treatment of acute neuroborreliosis in future guidelines.

Management Antibiotics e there are two important factors in antibiotic treatment:  B. burgdorferi is slow to replicate, and a longer course is recommended than for some ‘conventional’ bacterial infections.  B. burgdorferi can disseminate widely to tissues that can be poorly penetrated by certain antibiotics.

Outcome following appropriate treatment In general the long-term outcomes following appropriate treatment are excellent. Patients with severe tissue damage before treatment may recover only slowly or incompletely. A small minority of patients have persistent symptoms following appropriate treatment, predominantly fatigue, without evidence of active infection, termed ‘post-Lyme syndrome’.14 Similar findings have been described following other infections, and appear to correlate with severity of initial illness.15 Multiple or prolonged courses of antibiotics have been shown not to be beneficial in trials, and can cause significant adverse effects.14,16

Inappropriate diagnosis and management Much of the information on Lyme borreliosis available in the media, particularly on the Internet, is inaccurate, leading to misconceptions about the illness. Over-diagnosis and overtreatment have become serious problems.14,16 Prolonged, inappropriate treatment can be given to patients with non-specific symptoms and no significant tick exposure risk, who have falsepositive results in screening tests or positive results in unvalidated tests, or are seronegative. This carries risks of serious adverse events, and opportunities for managing other underlying conditions are missed. Figure 6 Borrelia burgdorferi IgG and IgM immunoblots. Lanes 16 and 17: sample from patient with erythema migrans. Lanes 18 and 19: sample from patient with Lyme arthritis. Lanes 20 and 21: sample from patients with erythema migrans for several weeks. Lanes 22 and 23: sample from patient with early erythema migrans.

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Prevention  Public education programmes are helpful in lowering the incidence of infection in endemic areas. Simple,

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12 Socie´te´ de Pathologie Infectieuse de Langue Franc¸aise. Borreliose de Lyme: de´marches diagnostiques, the´rapeutiques et pre´ventives. Med Mal 2007; 37 (Suppl 3): S153e74. Also available at: http://www. infectiologie.com/site/medias/_documents/consensus/2006-lymelong.pdf. Accessed 20/10/09. 13 Ljostad U, Skogvall E, Eikeland R, et al. Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre non-inferiority, double-blind randomised trial. Lancet Neurology 2008; 7: 690e5. 14 Marques A. Chronic Lyme disease: a review. Infect Dis Clin N Am 2008; 22: 341e60. 15 Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 2006; 333: 575. 16 Feder Jr HM, Johnson BJ, O’Connell S, et al. A critical appraisal of ‘‘chronic Lyme disease’’. N Engl J Med 2007; 357: 1422e30.

commonsense measures to avoid tick bites and prompt removal of attached ticks can greatly reduce the risk.1e3,10,12  Antibiotic prophylaxis is not routinely recommended after tick bites, but may be considered in special circumstances (e.g. in immunocompromised patients bitten in areas of known high endemicity).  No vaccines are currently available.

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REFERENCES 1 http://www.cdc.gov/ncidod/dvbid/lyme/index.htm. Accessed 05/10/09. 2 http://meduni09.edis.at/eucalb/cms/index.php?lang¼en. Accessed 05/10/09. 3 http://www.hpa.org.uk/servlet/Satellite?c¼Page&childpagename¼ HPAweb%2FPage%2FHPAwebAutoListName&cid¼1191942149546 &p¼1191942149546&pagename¼HPAwebWrapper. Accessed 05/10/09. 4 Rupprecht TA, Koedel U, Fingerle V, Pfister H-W. The pathogenesis of Lyme neuroborreliosis e from infection to inflammation. Mol Med 2008; 14: 205e12. 5 Steere AC, Angelis SM. Therapy for Lyme arthritis. Arthr Rheum 2006; 54: 3079e86. 6 Stanek G, Strle F. Lyme borreliosis. Lancet 2003; 362: 1639e47. 7 Dandache P, Nadelman RB. Erythema migrans. Infect Dis Clin N Am 2008; 22: 235e60. 8 Halperin JJ. Nervous system Lyme disease. Infect Dis Clin N Am 2008; 22: 261e74. 9 Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005; 18: 484e509. 10 Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43: 1089e134. 11 Halperin JJ, Shapiro ED, Logigian E. Practice parameter: treatment of nervous system Lyme disease e an evidence-based review. Neurology 2007; 69: 91e102.

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Ticks are tiny and may not be noticed; ask about possible tick exposure rather than a definite history of tick bites Absence of a history of erythema migrans does not exclude later-stage Lyme disease e it may have been overlooked, or infection could have occurred without a rash Consider the possibility of neuroborreliosis in patients with shingles-like pain without shingles-type rash who have had tick exposure risk within the preceding few months Antibody tests can be negative in early infection, but patients with late Lyme disease are rarely seronegative Antibody tests should not be performed when the pre-test likelihood of Lyme disease is low Samples giving positive screening test results should be assessed further for specificity using immunoblots

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