Diagnosis and Treatment of Lyme borreliosis
Clinical signs of Lyme borreliosis (LB)
The earliest, most common, and in some cases the only manifestation of LB is erythema migrans (a pink or red rash spreading from the site of a tick bite), which appears about 3-30 days after a tick bite. Some patients may also have rather nonspecific 'flu-like symptoms with tiredness, headaches, arthralgia (joint pains) and myalgia (muscle aches). They do not usually have significant respiratory symptoms. Neuroborreliosis (infection of the nervous system) is the commonest complication of LB in the UK. Neuroborreliosis can cause facial palsy (weakness or paralysis of the muscles on one or both sides of the face), viral-like meningitis, pain, weakness or altered sensation of limbs or trunk, or other symptoms. Lyme arthritis, which usually affects the knee, is rare in patients with UK-acquired infection, but is more common when the disease is acquired in North America or some parts of Europe. Other complications affecting the heart, eye and other organs and tissues are rare. [1-4] A small proportion of patients who have had LB may go on to develop a post-infection syndrome resembling chronic fatigue syndrome or fibromyalgia, which has been termed 'post-Lyme syndrome'. [1,4] Similar symptoms can be triggered by a number of other infectious and non-infectious conditions.
Laboratory investigations
Before diagnostic tests are requested, a patient's risk of exposure to ticks should be properly assessed and the clinical history evaluated for features compatible with LB [4-6]. Tests should not be requested if there is no significant risk of a patient having Lyme borreliosis. It is important that relevant clinical information is provided when samples are submitted for testing.
The most commonly used tests look for antibodies to Borrelia burgdorferi (Bb), the organism that causes LB. An infected person’s immune system produces antibodies in response to Bb infection, just one of the mechanisms used by the body to fight infection.The antibody response takes several weeks to reach a detectable level, so antibody tests in the first few weeks of infection may be negative. It is rare for patients to have negative antibody tests in longstanding infections. Laboratory diagnosis in this country follows an internationally recommended two-step approach, using commonly available antibody screening tests as a first stage, followed by immuno-blotting (western blotting) of samples that give reactive or equivocal results in the screening tests. [4-10] Sensitive screening tests are used because they can detect low levels of antibodies; but they have the disadvantage of producing occasional false positive results in samples from some patients with other conditions. These include glandular fever, syphilis, other infections, rheumatoid arthritis, other autoimmune conditions and some neurological conditions. [5-10] Samples giving reactive or indeterminate screening test reactions are then tested in a more detailed system, called immunoblot or western blot, to confirm the presence of Bb-specific antibodies. These second-stage tests allow laboratory workers to give a more accurate assessment of the presence of Bb antibodies.
Interpretation
As with many other infections, antibodies may not be detectable in the first few weeks after infection, because an antibody response takes several weeks to develop, so a negative test at this stage of infection does not exclude a diagnosis of Lyme borreliosis. A second sample taken 2-4 weeks later may be required to show sero-conversion (development of an antibody response). The chances of a positive test in early infection range from about 30% in the first two weeks to about 80% by six weeks, and the positivity rate increases further with duration of active infection. Patients with late-stage LB are very rarely seronegative; there is greater than 99% chance that they will have a positive antibody response. [5,10] If late-stage LB is still suspected in a patient who has negative antibody test results, additional investigations can be performed following consultation between the clinician and laboratory staff. It is important to recognise this gradual development of antibody response in order to appreciate the significance of antibody test results at the different stages of infection. The tests look for the presence or absence of antibodies to Bb, which may or may not relate to presence of active disease. The significance of any result, negative or positive, should be interpreted carefully by clinicians in the overall context of the patient’s clinical findings and tick exposure risk history. People may have antibodies to Bb without having a current infection. Those whose work (e.g. forestry), or place of residence (adjoining woodland, heathland or scrub), or recreational interests expose them to the risk of frequent tick bites may have antibodies due to a previous infection that may have been unrecognised or even asymptomatic. In some cases the patient's current clinical problem may be unrelated to the previous Bb infection.[1,4,5,7,9,10] The antibody test systems used in the HPA’s Lyme Borreliosis Unit (LBU) follow the two-stage system currently recommended by European and American authorities, as described above. All the antibody test kits routinely used in the LBU have been fully validated and CE marked. Those available for use in the USA as well as the EU are also US FDA-approved. All kits are used according to manufacturers’ instructions and quality control procedures observed.
Other diagnostic tests
Other tests that can be used include detection of Bb DNA using polymerase chain reaction (PCR). This type of molecular test is useful in certain circumstances, especially on joint fluids in suspected Lyme arthritis, and on samples from suspected skin infections. It is less helpful than antibody testing of CSF and is of little value in testing blood samples, as borreliae are rarely present in the bloodstream after the early stage of infection. PCR tests for Bb DNA are performed in the Southampton HPA laboratory’s Molecular Diagnostic Unit (MDU), which has wide experience in providing an extensive range of molecular diagnostics tests for many regional specialist units, including bone marrow transplant and intensive care.
Tests that are not recommended for use in diagnosis of Lyme disease
These include live blood microscopy, urinary antigen tests, lymphocyte transformation tests, immunoblots used as first stage tests or interpreted using non-standard interpretive criteria and NK-CD57 tests. These tests have been shown to be unreliable and have been associated with high rates of misdiagnosis.See here for further information
Treatment
A review of Lyme borreliosis, including clinical presentations, diagnosis and treatment, with emphasis on European-acquired infections was published in The Lancet in 2003.[1] The treatment guideline published by the Infectious Diseases Society of America (IDSA) in 2006 is an authoritative and comprehensive English-language reference, based on an extensive evaluation of published evidence. [4] Its recommendations are similar to those of various European experts and specialist societies as published in The Lancet and elsewhere (see list below). EUCALB has also compiled a summary of recommendations for treatment from European sources.[11] The American Academy of Neurology (AAN) published Practice Parameters for the diagnosis of neuroborreliosis in 1996, and for the treatment of neuroborreliosis in 2007 [12,13]. Both are based on careful reviews of the scientific literature and are recommended as valuable resources in the diagnosis and management of patients with suspected neuroborreliosis, especially those with complicated presentations. The IDSA guidelines, the AAN Practice Parameters, EUCALB recommendations and several other diagnosis and treatment guidelines are available via the HPA website (see listings below). We strongly recommend that these or the other listed guidelines are consulted for treatment details, including recommended doses and durations for patients of all age groups, and for information regarding alternative antibiotic treatments for patients who have contra-indications to usual first line agents. Advice on treatment may also be obtained from Regional Infectious Diseases Units or the LBU.
In general, the oral antibiotics doxycycline, amoxycillin or cefuroxime axetil are recommended for two weeks (range 10-21 days) for erythema migrans and isolated facial palsy, and for four weeks when treating patients with Lyme arthritis. There is increasing evidence that doxycycline is also useful for treating some other forms of neuroborreliosis [14]. The usual adult doses of these antibiotics are: doxycycline 100mg twice daily; amoxicillin 500mg three times daily; cefuroxime axetil 500mg twice daily. Doxycycline use is contraindicated for children aged under twelve years and for pregnant and breastfeeding women. Intravenous treatment, usually with ceftriaxone for two weeks (range 10-28 days), is recommended for some neurological presentations and occasionally for second-line treatment of arthritis and for some other uncommon presentations (see listed guidelines). The usual adult dose of ceftriaxone is 2g daily.
Erythromycin is not recommended for treating any stage of LB, as it has a high failure rate. Newer macrolides such as azithromycin or clarithromycin may be used if first and second-line antibiotics are contraindicated, but patients should be carefully followed up clinically, as treatment failures can occur with these agents.
Longstanding neuroborreliosis may be slow to respond to treatment, as damaged nerve tissue is slow to heal. Re-treatment may be indicated in occasional cases of neuroborreliosis and arthritis but there is no evidence that very prolonged or multiple courses of antibiotics are valuable in these presentations or for patients with persistent post-Lyme symptoms [1,2,4,13] and they can cause serious and even fatal adverse effects [15,16].
Vaccine
There is no vaccine against Lyme borreliosis currently available in Europe or North America. (A vaccine had been available in the USA but was withdrawn in 2002). Research into new vaccines is continuing, but no product is likely to be available in the new future.
Co-infections
Other infections can be transmitted by bites from infected ticks. These include anaplasmosis, babesiosis, and Q fever. All are rare tick-transmitted infections in the UK; Q fever is more frequently acquired through other transmission routes. In some parts of Europe ticks can transmit a virus which causes tick-borne encephalitis, (TBE) for which a vaccine is available. If a tick-transmitted co-infection occurs with LB it may give an atypical clinical presentation. Clinicians should be aware of the possibility of co-infections, which may also influence treatment choice.
References
1. Stanek G, Strle F. Lyme borreliosis. Lancet 2003;362(9396):1639-47. Available at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2803%2914798-8/fulltext
2. Steere A. Lyme disease. New Eng J Med 2001;345(2):115-25
3. Stanek G, O’Connell S, Cimmino M et al. European Union Concerted Action on risk assessment in Lyme borreliosis: clinical case definitions. Wien Klin Wochecnschr 1996;108:741-47.
4. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Wormser G P, Dattwyler R J, Shapiro E D, et al. Clin Infect Dis 2006; 43: 1089-34. Available free at http://www.journals.uchicago.edu/doi/pdf/10.1086/508667
5. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of lyme borreliosis. Clin Microbiol Rev. 2005 Jul;18(3):484-509. Available free at http://cmr.asm.org/cgi/reprint/18/3/484.
6. Recommendations for Test Performance and Interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR 1995; 44(31): 590-1 http://www.cdc.gov/mmwr/preview/mmwrhtml/00038469.htm
7. B. Wilske, L. Zöller, V. Brade, H. Eiffert, U.B. Göbel, G. Stanek, H.-W. Pfister. MiQ12. Quality Standards for the Microbiological Diagnosis of Infectious Diseases: Lyme Borreliosis. Available at:- http://nrz-borrelien.lmu.de/miq-lyme/frame-miq-lyme.html
8. The laboratory diagnosis of Lyme borreliosis: Guidelines from the Canadian Public Health Laboratory Network. Canadian J Infect Dis 2007;18(2):145-148
9. Wilske B, Fingerle V, Schulte-Spechtel U. Microbiological and serological diagnosis of Lyme borreliosis. FEMS Immunol Med Microbiol 2007;49:13-21.
10. Wilske B. Diagnosis of Lyme borreliosis in Europe. Vector-Borne Zoonotic Dis 2003;3:215-27.
11. EUCALB website treatment pages: http://meduni09.edis.at/eucalb/cms/index.php?option=com_content&task=view&id=43&Itemid=75
12. Halperin JJ, Logigian EL, Finkel MF, Pearl RA. Practice parameters for the diagnosis of patients with nervous system Lyme borreliosis (Lyme disease).Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1996 46: 619-27
13. Halperin JJ, Logigian EL, Finkel MF et al. Practice Parameter: Treatment of nervous system Lyme disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007;69:91-102. Available at http://www.neurology.org/cgi/rapidpdf/01.wnl.0000265517.66976.28v1
14. Ljostad U, Skogvoll 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;7:690-95.
15. Patel R, Grogg KL, Edwards WD et al. Death from inappropriate therapy for Lyme disease. Clin Infect Dis 2000;31:1107-9
16. Ettestad PJ, Campbell GL, Welbel SF et al. Biliary complications in the treatment of unsubstantiated Lyme disease. J Infect Dis 1995;171:356-61
Diagnostic and/or treatment recommendations and guidelines available in other languages from some European societies and specialist groups.
1. Denmark : Dessau RB, Bangsborg JM, Ejlertsen T et al. Lyme Borreliose Klinik, diagnostik og behandling. (Forfattergruppen er nedsat af Dansk Selskab for Kilisk Mikrobiologi, Dansk Selskab for Infektions medicin og Dansk Neurologisk Selskan) 2006
2. France : 16e Conference de Consensus en therapeutique anti-infectieuse : Borreliose de Lyme : demarches diagnostiques, therapeutiques et preventives. Societe de Pathologie Infectieuse de Langue Francaise 2006 http://www.infectiologie.com/site/medias/_documents/consensus/2006-lyme-long.pdf
3. Germany : Neuroborreliose: Leitlinien der Deutschen Gesellschaft fur Neurologie 2003 Expert group: Kaiser R, Kolmel HW, Pfister HW, Rauer S, Wilske B. AWMF-Leitlinien-Register Nr. 030/071 http://www.uni-duesseldorf.de/AWMF/ll/index.html
4. Germany: Kutane Manifestationen der Lyme Borreliose. Leitlinien der Deutschen Dermatologischen Gesellschaft. AWMF-Leitlinien-Register Nr. 030/044. http://www.uni-duesseldorf.de/AWMF/ll/index.html
5. Netherlands: Richtlijn Lyme Borreliose 2004. Kwaliteitsinstituut voor de Gezondheitzorg CBO. ISBN 90-76906-89-0
6. Slovenia: Strle F. Wien Klin Wochenschr 1999;111:911-915
7. Switzerland : Evison J, Aebi C, Peter O et al. Borreliose de Lyme; recommandations de la Societe Suisse d’Infectiologie. Rev Med Suisse 2006;2:919-40. (Also available in German in Schweizerische Artzezeitung 2005 ;86 :2332-8 ;2375-84 ;2422-8)
Last reviewed: 15 February 2010
