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Lyme borreliosis
BACTERIAL INFECTIONS
Lyme borreliosis
What’s new?
Susan O’Connell C
Abstract C
Lyme borreliosis is a tick-transmitted spirochaetal disease caused by Borrelia burgdorferi sensu lato. It is acquired in forested and heathland areas of the temperate northern hemisphere. The most common presentation is an erythematous rash spreading slowly from the site of a tick bite. Clinical manifestations of disseminated infection include facial palsy, viral-like meningitis, radiculopathy, meningoencephalitis and arthritis. Lyme borreliosis responds to antibiotic treatment at all stages, with excellent results for patients with early disease. Patients with long-standing infection causing significant tissue damage can have slow or incomplete recovery. A small minority of 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, insect repellent use and frequent skin inspections for attached ticks, as early removal minimizes infection risk. No vaccine is currently available.
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cause significant pain, irritation or itch. Ticks are common in woodland, heath and moorland but can also live in semi-rural areas bordering large population centres. Infections occur mainly in late spring, early summer and autumn, the peak tick feeding periods.1 The annual incidence varies, depending on climatic and other factors affecting ticks and human activities in tick habitats.1 Ixodid ticks can also carry other organisms, including ehrlichiae, babesiae and B. miyamotoi, a member of the relapsing fever group of borreliae.1 Tick-borne encephalitis (TBE) virus, for which a vaccine is available, is prevalent in some parts of Europe, and deer tick virus (DTV), another flavivirus, was recently shown to cause encephalitis in the USA.1,4 Tick-transmitted 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 (EM), an early skin lesion, is the most common clinical presentation. The organism can spread, causing various manifestations, including facial palsy, viral-like meningitis, radiculitis and arthritis, usually affecting the knee.
Pathogenesis At least five B. burgdorferi genospecies are pathogenic. Borrelial heterogeneity is significant in organotropism and disease presentation and has implications for vaccine development strategies.5 Only one genospecies (B. burgdorferi sensu stricto) causes human infection in North America and can cause neurological and arthritic complications.1,2 It is found focally in Europe, but two other genospecies are the main causes of European disease: Borrelia garinii, which is particularly associated with neuroborreliosis, and Borrelia afzelii, associated with skin manifestations and occasionally with neurological complications.1,6
Epidemiology and environmental factors Lyme borreliosis is the most common tick-borne infection in the temperate northern hemisphere.1 Over 24,000 confirmed cases were reported in the USA in 2012, mainly from north-east and mid-Atlantic seaboard states, and north-central and Pacific coast states.2 There may be over 200,000 European cases annually, with high incidences in parts of southern Scandinavia, central and eastern Europe.1 About 1200 cases are serologically confirmed annually in the UK.3 Infection can occur at any age in individuals whose residence, occupation or recreational activities place them at risk of bites from Ixodes spp. ticks (deer ticks; sheep ticks), the vectors of B. burgdorferi.1 Bites are frequently unrecognized because they do not usually
Clinical features Infection can be asymptomatic. Disease has been customarily divided into three stages, but the process is a continuing pathological evolution rather than having distinct phases. Progression to later-stage disease is not inevitable, even in untreated patients, and late manifestations are now uncommon because of greater recognition and treatment of earlier-stage infection.1
Susan O’Connell LRCP&SI DipClinMicro was Consultant Medical Microbiologist and Head of the Lyme Borreliosis Unit at the Health Protection Agency Microbiology Laboratory, Southampton, UK until her retirement in 2012. Competing interests: Expert witness in a General Medical Council Fitness to Practice proceeding in 2011.
MEDICINE 42:1
Recent treatment trials of European patients with early Lyme borreliosis, incorporating non-infected controls, have shown excellent long-term outcomes with no excess of symptoms in cases over controls at 6 months and longer Long-term follow-up of patients with neuroborreliosis in a 14day treatment trial shows oral doxycycline (200 mg daily) to be non-inferior to intravenous ceftriaxone (2 g daily). Poorer outcomes occurred in patients with longstanding pre-existing disease Antibody tests with improved specificity are now widely available, but indiscriminate testing of patients with a very low pretest probability of Lyme borreliosis continues to contribute to false-positive results and misdiagnosis Over-diagnosis and mistreatment remain major concerns, driven by misinformation, especially from the Internet
Localized infection: EM, a localized red or pink rash appearing after 2e30 days (usually 5e15 days) at the site of a bite is the most common manifestation (Figures 1 and 2).1,2,7 The rash can be faint, with a more pronounced margin that gradually migrates
14
Ó 2014 Elsevier Ltd. All rights reserved.
BACTERIAL INFECTIONS
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.1,7 Cardiac conduction abnormalities are uncommon, usually occurring within a few weeks of infection. Ocular, hepatic and other manifestations have also been reported.1,7 Lyme encephalopathy is an uncommon manifestation that can occur with other presentations of disseminated or late infection. Patients 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 gradually resolves following treatment of the infection.9 Late encephalomyelitis is rare, estimated to occur in less than one in 1000 previously untreated patients.9 It is characterized by spastic paraparesis, cognitive impairment, cranial neuropathy, bladder dysfunction and dysarthria.1,8 There is cerebrospinal fluid (CSF) pleiocytosis and intrathecal antibody production.8 Appropriate antibiotics will eradicate infection but the degree of recovery depends on the severity of tissue damage prior to treatment.1,8,10
Figure 1 Erythema migrans on the face of a 2-year-old child who had received a tick bite on her scalp 10 days previously.
Lyme arthritis varies in incidence depending on where the infection has been acquired; it is more common in the USA than in Europe. The degree of joint swelling is usually disproportionate to the pain. In some genetically-predisposed patients, inflammation continues for some time after antibiotic treatment (‘antibiotic-refractory’ arthritis). A strong antibody response to B. burgdorferi is detectable in serum.1,7
outwards. A central area of clearing can become evident as previously affected skin returns to normal, but many EM rashes are homogeneous in appearance.1,7 Local lymphadenopathy can occur. About 80% of patients presenting with later-stage disease recall preceding EM. Borrelial lymphocytoma is a rare localized presentation, usually on the earlobe, nipple or scrotum.1,7 Early disseminated infection: the organism can affect many tissues in the following weeks, principally the nervous, musculoskeletal and cardiovascular systems and the skin. Patients can have a flu-like illness with myalgia and arthralgia but without significant respiratory symptoms.1 Multiple areas of EM 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.1,7,8
Acrodermatitis chronica atrophicans is an uncommon late skin manifestation, strongly associated with B. afzelii. Lesions usually occur on the limbs and are initially violaceous. If untreated, they last for years, eventually becoming atrophic (Figure 3) and can be accompanied by peripheral neuropathy.1,7
Figure 2 Erythema migrans following a tick bite on the waist several weeks previously (courtesy of Dr B Bovill).
Figure 3 Acrodermatitis chronica atrophicans (courtesy of the late Dr JE White).
MEDICINE 42:1
Investigations Diagnosis is primarily clinical, particularly in early disease. Disease awareness can be low in non-endemic areas and the
15
Ó 2014 Elsevier Ltd. All rights reserved.
BACTERIAL INFECTIONS
recommend ceftriaxone 2 g daily for 2 weeks for these uncommon presentations and for 3 weeks for patients with late neuroborreliosis.8
possibility overlooked, especially when the patient has experienced only transient or unrecognized exposure to ticks (e.g. on a holiday or day trip). Laboratory evidence, principally antibody tests, should be sought to support the clinical diagnosis of disseminated and late infection, as none of the features is unique to Lyme borreliosis.1,7,8 Antibody tests are likely to be negative in the first 2e4 weeks of infection. Treatment of EM should be initiated on clinical grounds, as an analytically correct negative result does not exclude infection and could be clinically misleading.1,7 Antibody tests are highly sensitive in late-stage disease.1,7 Early-generation screening tests had a poor reputation, principally because of false-positive reactions in the presence of conditions such as other spirochaetal infections, infectious mononucleosis and autoimmune diseases, leading to incorrect diagnoses and presumed treatment failures. Markedly improved tests, based on synthetic peptides or recombinant antigens derived from different genospecies, are now widely available. Some specificity problems remain, exacerbated by inappropriate screening of patients with a very low pre-test likelihood of infection, so reactive and equivocal specimens should also be tested by immunoblot (western blot), to assess antibody specificity.1,7,8 The results must be interpreted in light of the clinical presentation. Positive tests may reflect past exposure rather than currently active infection. This can be significant in the investigation of patients from high-endemic regions such as eastern Europe, where background seroprevalences can range from 5 to 20%.1 Tests can be negative in EM but are seldom negative in late disease; a diagnosis of seronegative late Lyme borreliosis should be made only after thorough serological investigation and careful consideration of alternative diagnoses.1,7
Outcome following appropriate treatments Long-term outcomes following appropriate treatment of early presentations are excellent.1,12,14,15 Patients with severe tissue damage before treatment may recover only slowly or incompletely.1,10,13 A small minority of patients have persistent symptoms following appropriate treatment, predominantly fatigue, without evidence of active infection.16 Similar findings have been described following other infections, and appear to correlate with severity of initial illness.17 Multiple or prolonged courses of antibiotics have been shown not to be beneficial in trials, and can cause significant adverse effects.1,8,11,16
Inappropriate diagnosis and management Much media information on Lyme borreliosis, particularly on the Internet, is inaccurate, leading to misconceptions about the illness.18 Over-diagnosis and over-treatment have become serious problems.18,19 Patients with non-specific symptoms and no significant tick exposure risk, who are seronegative or have false-positive results, have been given a diagnosis of ‘chronic Lyme disease’ and treated inappropriately.19 They are at risk of serious adverse events, and opportunities for managing other underlying conditions can be missed.
Prevention Simple measures to avoid tick bites and prompt removal of attached ticks can greatly reduce risk, as infection is unlikely to occur if ticks are attached for less than 18 hours.1e3,11 Precautions include using N,N-diethyl-m-toluamide (DEET)-containing insect repellents and checking skin (including skin-fold areas) regularly for attached ticks, especially at the end of the day. Ticks should be removed gently, using tweezers or a tick hook as close as possible to the skin.1e3 Antibiotic prophylaxis is not routinely recommended after tick bites in Europe, but could be considered in special circumstances (e.g. in immunocompromised patients bitten in areas of known high endemicity). No vaccines are currently available; a European vaccine trial is underway.5 A
Management Antibiotics Numerous European and American authorities have published diagnostic and treatment guidelines.1,7,8,11 The most commonly used oral antibiotics are doxycycline or amoxicillin. Azithromycin is not licensed for this use but could be considered if the recommended oral agents are contraindicated; patients should be carefully followed up because treatment failures can occur. The recommended parenteral antibiotics are ceftriaxone (preferred because of its once-daily dosing), cefotaxime or benzylpenicillin. Patients with suspected tick-transmitted co-infections can require additional agents. Most clinical manifestations can be treated orally. A 14-day course of oral doxycycline (adult dose 200 mg daily) or amoxicillin (adult dose 500 mg three times daily) is generally recommended for EM, although recent studies have shown good outcomes with a 10-day course of doxycycline.12 Oral 2-week courses are also used for disseminated infections without neurological involvement. Patients with Lyme arthritis or acrodermatitis are usually treated orally for 4 weeks. A Norwegian 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 Guidelines from the European Federation of Neurological Societies recommend either of these agents for adult patients with manifestations of early neuroborreliosis other than encephalitis, myelitis or vasculitis. They
MEDICINE 42:1
REFERENCES 1 Stanek G, Wormser GP, Gray JS, Strle F. Lyme borreliosis. Lancet 2012; 379: 461e73. 2 http://www.cdc.gov/lyme/ (Accessed 28 May 2013). 3 http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/ LymeDisease/EpidemiologicalData/lymLymeepidemiology/ (Accessed 28 May 2013). 4 El Khoury MY, Hull RC, Bryant PW, et al. Diagnosis of acute deer tick encephalitis. Clin Infect Dis 2013; 56: e40e7. 5 Wressnigg N, Pollabauer EM, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomized, dose escalation phase 1/2 trial. Lancet Infect Dis 2013; 13: 680e9.
16
Ó 2014 Elsevier Ltd. All rights reserved.
BACTERIAL INFECTIONS
16 Marques A. Chronic Lyme disease: a review. Infect Dis Clin N Am 2008; 22: 341e60. 17 Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. Br Med J 2006; 333: 575. 18 Halperin JJ, Baker P, Wormser GP. Common misconceptions about Lyme disease. Am J Med 2013; 126: 264.e1e7. 19 Hassett AL, Radvanski DC, Buyske S, Savage SV, Sigal LH. Psychiatric co-morbidity and other psychological factors in patients with “chronic Lyme disease”. Am J Med 2009; 122: 843e50.
6 Rupprecht TA, Koedel U, Fingerle V, Pfister H- W. The pathogenesis of Lyme neuroborreliosis e from infection to inflammation. Mol Med 2008; 14: 205e12. 7 Stanek G, Fngerle V, Hunfeld K-P, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect 2011; 17: 69e79. 8 Mygland A, Ljostad U, Fingerle V, et al. EFNS guidelines for the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol 2010; 17: 8e16. 9 Halperin JJ. Nervous system Lyme disease. Infect Dis Clin N Am 2008; 22: 261e74. 10 Eikeland R, Mygland A, Herlofson K, Ljostad U. Risk factors for a nonfavorable outcome following treated European neuroborreliosis. Acta Neurol Scand 2013; 127: 154e60. 11 Wormser GP, O’Connell S. Treatment of infection caused by Borrelia burgdorferi sensu lato. Expert Rev Anti Infect Ther 2011; 9: 245e60. 12 Stupica D, Lusa L, Rusic-Sjabljic E, Cerar T, Strle F. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis 2012; 55: 343e50. 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 Neurol 2008; 7: 690e5. 14 Cerar D, Cerar T, Rusic-Sjabljic E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med 2010; 123: 79e86. 15 Skogman BH, Croner S, Nordwall M, et al. Lyme neuroborreliosis in children:a prospective study of clinical features, prognosis and outcome. Pediatr Infect Dis J 2008; 27: 1089e94.
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Practice points C
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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 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 within the preceding few months Antibody tests can be negative in early infection; patients with late Lyme disease are rarely seronegative Antibody tests should not be performed when the pre-test likelihood of Lyme disease is low
Ó 2014 Elsevier Ltd. All rights reserved.
Lyme borreliosis
What’s new?
Susan O’Connell C
Abstract C
Lyme borreliosis is a tick-transmitted spirochaetal disease caused by Borrelia burgdorferi sensu lato. It is acquired in forested and heathland areas of the temperate northern hemisphere. The most common presentation is an erythematous rash spreading slowly from the site of a tick bite. Clinical manifestations of disseminated infection include facial palsy, viral-like meningitis, radiculopathy, meningoencephalitis and arthritis. Lyme borreliosis responds to antibiotic treatment at all stages, with excellent results for patients with early disease. Patients with long-standing infection causing significant tissue damage can have slow or incomplete recovery. A small minority of 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, insect repellent use and frequent skin inspections for attached ticks, as early removal minimizes infection risk. No vaccine is currently available.
C
C
cause significant pain, irritation or itch. Ticks are common in woodland, heath and moorland but can also live in semi-rural areas bordering large population centres. Infections occur mainly in late spring, early summer and autumn, the peak tick feeding periods.1 The annual incidence varies, depending on climatic and other factors affecting ticks and human activities in tick habitats.1 Ixodid ticks can also carry other organisms, including ehrlichiae, babesiae and B. miyamotoi, a member of the relapsing fever group of borreliae.1 Tick-borne encephalitis (TBE) virus, for which a vaccine is available, is prevalent in some parts of Europe, and deer tick virus (DTV), another flavivirus, was recently shown to cause encephalitis in the USA.1,4 Tick-transmitted 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 (EM), an early skin lesion, is the most common clinical presentation. The organism can spread, causing various manifestations, including facial palsy, viral-like meningitis, radiculitis and arthritis, usually affecting the knee.
Pathogenesis At least five B. burgdorferi genospecies are pathogenic. Borrelial heterogeneity is significant in organotropism and disease presentation and has implications for vaccine development strategies.5 Only one genospecies (B. burgdorferi sensu stricto) causes human infection in North America and can cause neurological and arthritic complications.1,2 It is found focally in Europe, but two other genospecies are the main causes of European disease: Borrelia garinii, which is particularly associated with neuroborreliosis, and Borrelia afzelii, associated with skin manifestations and occasionally with neurological complications.1,6
Epidemiology and environmental factors Lyme borreliosis is the most common tick-borne infection in the temperate northern hemisphere.1 Over 24,000 confirmed cases were reported in the USA in 2012, mainly from north-east and mid-Atlantic seaboard states, and north-central and Pacific coast states.2 There may be over 200,000 European cases annually, with high incidences in parts of southern Scandinavia, central and eastern Europe.1 About 1200 cases are serologically confirmed annually in the UK.3 Infection can occur at any age in individuals whose residence, occupation or recreational activities place them at risk of bites from Ixodes spp. ticks (deer ticks; sheep ticks), the vectors of B. burgdorferi.1 Bites are frequently unrecognized because they do not usually
Clinical features Infection can be asymptomatic. Disease has been customarily divided into three stages, but the process is a continuing pathological evolution rather than having distinct phases. Progression to later-stage disease is not inevitable, even in untreated patients, and late manifestations are now uncommon because of greater recognition and treatment of earlier-stage infection.1
Susan O’Connell LRCP&SI DipClinMicro was Consultant Medical Microbiologist and Head of the Lyme Borreliosis Unit at the Health Protection Agency Microbiology Laboratory, Southampton, UK until her retirement in 2012. Competing interests: Expert witness in a General Medical Council Fitness to Practice proceeding in 2011.
MEDICINE 42:1
Recent treatment trials of European patients with early Lyme borreliosis, incorporating non-infected controls, have shown excellent long-term outcomes with no excess of symptoms in cases over controls at 6 months and longer Long-term follow-up of patients with neuroborreliosis in a 14day treatment trial shows oral doxycycline (200 mg daily) to be non-inferior to intravenous ceftriaxone (2 g daily). Poorer outcomes occurred in patients with longstanding pre-existing disease Antibody tests with improved specificity are now widely available, but indiscriminate testing of patients with a very low pretest probability of Lyme borreliosis continues to contribute to false-positive results and misdiagnosis Over-diagnosis and mistreatment remain major concerns, driven by misinformation, especially from the Internet
Localized infection: EM, a localized red or pink rash appearing after 2e30 days (usually 5e15 days) at the site of a bite is the most common manifestation (Figures 1 and 2).1,2,7 The rash can be faint, with a more pronounced margin that gradually migrates
14
Ó 2014 Elsevier Ltd. All rights reserved.
BACTERIAL INFECTIONS
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.1,7 Cardiac conduction abnormalities are uncommon, usually occurring within a few weeks of infection. Ocular, hepatic and other manifestations have also been reported.1,7 Lyme encephalopathy is an uncommon manifestation that can occur with other presentations of disseminated or late infection. Patients 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 gradually resolves following treatment of the infection.9 Late encephalomyelitis is rare, estimated to occur in less than one in 1000 previously untreated patients.9 It is characterized by spastic paraparesis, cognitive impairment, cranial neuropathy, bladder dysfunction and dysarthria.1,8 There is cerebrospinal fluid (CSF) pleiocytosis and intrathecal antibody production.8 Appropriate antibiotics will eradicate infection but the degree of recovery depends on the severity of tissue damage prior to treatment.1,8,10
Figure 1 Erythema migrans on the face of a 2-year-old child who had received a tick bite on her scalp 10 days previously.
Lyme arthritis varies in incidence depending on where the infection has been acquired; it is more common in the USA than in Europe. The degree of joint swelling is usually disproportionate to the pain. In some genetically-predisposed patients, inflammation continues for some time after antibiotic treatment (‘antibiotic-refractory’ arthritis). A strong antibody response to B. burgdorferi is detectable in serum.1,7
outwards. A central area of clearing can become evident as previously affected skin returns to normal, but many EM rashes are homogeneous in appearance.1,7 Local lymphadenopathy can occur. About 80% of patients presenting with later-stage disease recall preceding EM. Borrelial lymphocytoma is a rare localized presentation, usually on the earlobe, nipple or scrotum.1,7 Early disseminated infection: the organism can affect many tissues in the following weeks, principally the nervous, musculoskeletal and cardiovascular systems and the skin. Patients can have a flu-like illness with myalgia and arthralgia but without significant respiratory symptoms.1 Multiple areas of EM 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.1,7,8
Acrodermatitis chronica atrophicans is an uncommon late skin manifestation, strongly associated with B. afzelii. Lesions usually occur on the limbs and are initially violaceous. If untreated, they last for years, eventually becoming atrophic (Figure 3) and can be accompanied by peripheral neuropathy.1,7
Figure 2 Erythema migrans following a tick bite on the waist several weeks previously (courtesy of Dr B Bovill).
Figure 3 Acrodermatitis chronica atrophicans (courtesy of the late Dr JE White).
MEDICINE 42:1
Investigations Diagnosis is primarily clinical, particularly in early disease. Disease awareness can be low in non-endemic areas and the
15
Ó 2014 Elsevier Ltd. All rights reserved.
BACTERIAL INFECTIONS
recommend ceftriaxone 2 g daily for 2 weeks for these uncommon presentations and for 3 weeks for patients with late neuroborreliosis.8
possibility overlooked, especially when the patient has experienced only transient or unrecognized exposure to ticks (e.g. on a holiday or day trip). Laboratory evidence, principally antibody tests, should be sought to support the clinical diagnosis of disseminated and late infection, as none of the features is unique to Lyme borreliosis.1,7,8 Antibody tests are likely to be negative in the first 2e4 weeks of infection. Treatment of EM should be initiated on clinical grounds, as an analytically correct negative result does not exclude infection and could be clinically misleading.1,7 Antibody tests are highly sensitive in late-stage disease.1,7 Early-generation screening tests had a poor reputation, principally because of false-positive reactions in the presence of conditions such as other spirochaetal infections, infectious mononucleosis and autoimmune diseases, leading to incorrect diagnoses and presumed treatment failures. Markedly improved tests, based on synthetic peptides or recombinant antigens derived from different genospecies, are now widely available. Some specificity problems remain, exacerbated by inappropriate screening of patients with a very low pre-test likelihood of infection, so reactive and equivocal specimens should also be tested by immunoblot (western blot), to assess antibody specificity.1,7,8 The results must be interpreted in light of the clinical presentation. Positive tests may reflect past exposure rather than currently active infection. This can be significant in the investigation of patients from high-endemic regions such as eastern Europe, where background seroprevalences can range from 5 to 20%.1 Tests can be negative in EM but are seldom negative in late disease; a diagnosis of seronegative late Lyme borreliosis should be made only after thorough serological investigation and careful consideration of alternative diagnoses.1,7
Outcome following appropriate treatments Long-term outcomes following appropriate treatment of early presentations are excellent.1,12,14,15 Patients with severe tissue damage before treatment may recover only slowly or incompletely.1,10,13 A small minority of patients have persistent symptoms following appropriate treatment, predominantly fatigue, without evidence of active infection.16 Similar findings have been described following other infections, and appear to correlate with severity of initial illness.17 Multiple or prolonged courses of antibiotics have been shown not to be beneficial in trials, and can cause significant adverse effects.1,8,11,16
Inappropriate diagnosis and management Much media information on Lyme borreliosis, particularly on the Internet, is inaccurate, leading to misconceptions about the illness.18 Over-diagnosis and over-treatment have become serious problems.18,19 Patients with non-specific symptoms and no significant tick exposure risk, who are seronegative or have false-positive results, have been given a diagnosis of ‘chronic Lyme disease’ and treated inappropriately.19 They are at risk of serious adverse events, and opportunities for managing other underlying conditions can be missed.
Prevention Simple measures to avoid tick bites and prompt removal of attached ticks can greatly reduce risk, as infection is unlikely to occur if ticks are attached for less than 18 hours.1e3,11 Precautions include using N,N-diethyl-m-toluamide (DEET)-containing insect repellents and checking skin (including skin-fold areas) regularly for attached ticks, especially at the end of the day. Ticks should be removed gently, using tweezers or a tick hook as close as possible to the skin.1e3 Antibiotic prophylaxis is not routinely recommended after tick bites in Europe, but could be considered in special circumstances (e.g. in immunocompromised patients bitten in areas of known high endemicity). No vaccines are currently available; a European vaccine trial is underway.5 A
Management Antibiotics Numerous European and American authorities have published diagnostic and treatment guidelines.1,7,8,11 The most commonly used oral antibiotics are doxycycline or amoxicillin. Azithromycin is not licensed for this use but could be considered if the recommended oral agents are contraindicated; patients should be carefully followed up because treatment failures can occur. The recommended parenteral antibiotics are ceftriaxone (preferred because of its once-daily dosing), cefotaxime or benzylpenicillin. Patients with suspected tick-transmitted co-infections can require additional agents. Most clinical manifestations can be treated orally. A 14-day course of oral doxycycline (adult dose 200 mg daily) or amoxicillin (adult dose 500 mg three times daily) is generally recommended for EM, although recent studies have shown good outcomes with a 10-day course of doxycycline.12 Oral 2-week courses are also used for disseminated infections without neurological involvement. Patients with Lyme arthritis or acrodermatitis are usually treated orally for 4 weeks. A Norwegian 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 Guidelines from the European Federation of Neurological Societies recommend either of these agents for adult patients with manifestations of early neuroborreliosis other than encephalitis, myelitis or vasculitis. They
MEDICINE 42:1
REFERENCES 1 Stanek G, Wormser GP, Gray JS, Strle F. Lyme borreliosis. Lancet 2012; 379: 461e73. 2 http://www.cdc.gov/lyme/ (Accessed 28 May 2013). 3 http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/ LymeDisease/EpidemiologicalData/lymLymeepidemiology/ (Accessed 28 May 2013). 4 El Khoury MY, Hull RC, Bryant PW, et al. Diagnosis of acute deer tick encephalitis. Clin Infect Dis 2013; 56: e40e7. 5 Wressnigg N, Pollabauer EM, Aichinger G, et al. Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomized, dose escalation phase 1/2 trial. Lancet Infect Dis 2013; 13: 680e9.
16
Ó 2014 Elsevier Ltd. All rights reserved.
BACTERIAL INFECTIONS
16 Marques A. Chronic Lyme disease: a review. Infect Dis Clin N Am 2008; 22: 341e60. 17 Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. Br Med J 2006; 333: 575. 18 Halperin JJ, Baker P, Wormser GP. Common misconceptions about Lyme disease. Am J Med 2013; 126: 264.e1e7. 19 Hassett AL, Radvanski DC, Buyske S, Savage SV, Sigal LH. Psychiatric co-morbidity and other psychological factors in patients with “chronic Lyme disease”. Am J Med 2009; 122: 843e50.
6 Rupprecht TA, Koedel U, Fingerle V, Pfister H- W. The pathogenesis of Lyme neuroborreliosis e from infection to inflammation. Mol Med 2008; 14: 205e12. 7 Stanek G, Fngerle V, Hunfeld K-P, et al. Lyme borreliosis: clinical case definitions for diagnosis and management in Europe. Clin Microbiol Infect 2011; 17: 69e79. 8 Mygland A, Ljostad U, Fingerle V, et al. EFNS guidelines for the diagnosis and management of European Lyme neuroborreliosis. Eur J Neurol 2010; 17: 8e16. 9 Halperin JJ. Nervous system Lyme disease. Infect Dis Clin N Am 2008; 22: 261e74. 10 Eikeland R, Mygland A, Herlofson K, Ljostad U. Risk factors for a nonfavorable outcome following treated European neuroborreliosis. Acta Neurol Scand 2013; 127: 154e60. 11 Wormser GP, O’Connell S. Treatment of infection caused by Borrelia burgdorferi sensu lato. Expert Rev Anti Infect Ther 2011; 9: 245e60. 12 Stupica D, Lusa L, Rusic-Sjabljic E, Cerar T, Strle F. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis 2012; 55: 343e50. 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 Neurol 2008; 7: 690e5. 14 Cerar D, Cerar T, Rusic-Sjabljic E, Wormser GP, Strle F. Subjective symptoms after treatment of early Lyme disease. Am J Med 2010; 123: 79e86. 15 Skogman BH, Croner S, Nordwall M, et al. Lyme neuroborreliosis in children:a prospective study of clinical features, prognosis and outcome. Pediatr Infect Dis J 2008; 27: 1089e94.
MEDICINE 42:1
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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 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 within the preceding few months Antibody tests can be negative in early infection; patients with late Lyme disease are rarely seronegative Antibody tests should not be performed when the pre-test likelihood of Lyme disease is low
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