Lyme Disease Research: 2002-2006  
     
Epidemiol Infect. 2006 Aug 8;:1-8 [Epub ahead of print]
The Lyme vaccine: a cautionary tale.
Nigrovic LE, Thompson KM.
Division of Emergency Medicine, Children's Hospital Boston, Boston, MA, USA.

People living in endemic areas acquire Lyme disease from the bite of an infected tick. This infection, when diagnosed and treated early in its course, usually responds well to antibiotic therapy. A minority of patients develops more serious disease, particularly after a delay in diagnosis or therapy, and sometimes chronic neurological, cardiac, or rheumatological manifestations. In 1998, the FDA approved a new recombinant Lyme vaccine, LYMErixtrade mark, which reduced new infections in vaccinated adults by nearly 80%. Just 3 years later, the manufacturer voluntarily withdrew its product from the market amidst media coverage, fears of vaccine side-effects, and declining sales. This paper reviews these events in detail and focuses on the public communication of risks and benefits of the Lyme vaccine and important lessons learned.

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Am J Health Promot. 2006 Jul-Aug;20(6):379-82.
An evaluation of a Lyme disease prevention program in a working population.
Nolan K, Mauer MP.
New York State Department of Health, Bureau of Environmental and Occupational Epidemiology, Center for Environmental Health, Troy, New York 12180, USA. kxf07@health.state.ny.us

PURPOSE: Lyme disease vaccine was offered to New York State Department of Health employees considered at risk for Lyme disease because of their job duties. This evaluation was conducted to assess (1) attitudes that affected employees' decisions to accept or decline the vaccine, (2) preventive behaviors among employees who received the vaccine, and (3) effectiveness of the educational modalities offered in improving knowledge of Lyme disease and Lyme disease vaccine. METHODS: A total of 190 eligible employees were identified and were offered two educational modalities before deciding whether to receive the vaccine. The subsequent evaluation involved three telephone interviews, one pre-education and two posteducation-vaccination, to assess factors affecting the decision about vaccination and attitudes, behaviors, and knowledge among vaccine recipients (N=30) and nonrecipients (N=160). RESULTS: This evaluation indicated that the majority of vaccine recipients decided to receive the vaccine because of an anticipated risk of tick exposure. For employees who declined vaccination, many were concerned about the safety (64%), novelty (56%), or efficacy (48%) of the vaccine. Posteducation knowledge of Lyme disease vaccine significantly improved among those who attended an education session compared with those who did not and was retained 1 year later. DISCUSSION: The results suggest that when a vaccine-related disease-prevention program is undertaken, (1) attitudes about disease risks and vaccine risks influence decisions to accept vaccination, and (2) in-person education should be a mandatory element of the program.

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MMW Fortschr Med. 2006 Jun 22;148(25):39-41.
[Stage-oriented treatment of Lyme borreliosis]
[Article in German]
Fingerle V, Wilske B.
Nationales Referenzzentrum fur Borrelien, Max v. Pettenkofer Institut, LMU Munchen. nrz-borrelien@mvp.uni-muenchen.de

Every manifestation of Lyme borreliosis needs to be treated with antibiotics. The type of antibiotic applied and duration of treatment will depend on the stage and severity of the disease. Erythema migrans, Borrelia lymphocytoma, Lyme arthritis and acrodermatitis chronica atrophicans are primarily treated orally. If neurological symptoms, severe Lyme carditis or eye manifestations are present, intravenous treatment is initially recommended. For oral therapy, doxycycline, amoxicillin, cefuroxime and, if intolerance is shown, azithromycin, are available. For intravenous treatment ceftriaxone, cefotaxime or penicillin G is employed. The overall prognosis for treated Lyme borreliosis is good. However, in particular when manifestations with substantial organic injury have persisted, incomplete healing must be expected. With the exception of erythema migrans, every manifestation should be subjected to a careful diagnostic work-up prior to the start of treatment, because premature antibiotic administration is not only associated with an elevated risk for the patient, but can also mask important diagnostic signs.

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MMW Fortschr Med. 2006 Jun 22;148(25):32, 34, 36.
[Early diagnosis of Lyme borreliosis]
[Article in German]
Hofmann H.
Klinik und Poliklinik fur Dermatologie und Allergologie der TU Munchen. h.hofmann@lrz.tum.de

The local inflammatory reaction following a tick bite varies considerably, so that in particular the frequently atypical variations result in a wrong diagnosis and thus to inappropriate treatment. If a tick bite is followed within three weeks by flue-like or neurological symptoms, or joint swelling in the vicinity of the bite, a serological investigation work-up should be carried out. In the early stage, however, Borrelia-specific antibodies can be detected in only 30-80% of the patients. However, during the further course of the illness, the specific IgM and IgG antibody titers almost always increase.

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Neurocrit Care. 2006;4(3):260-6.
Is neuroborreliosis a medical emergency?
Halperin JJ.
NYU School of Medicine, Great Neck, NY, USA. Halperin@LINeuro.com

Although Lyme disease affects the nervous system in many ways (collectively known as neuroborreliosis), only rarely does it present as a medical emergency. In extreme cases, it may cause (1) encephalitis, (2) a rapidly progressive peripheral neuropathy, or (3) a painful truncal radiculopathy that may be confused with a severe visceral process. Knowing when to consider this spirochetosis in the differential diagnosis requires an understanding of its true clinical spectrum, and of an appropriate diagnostic and therapeutic approach.

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Rev Neurol. 2006 Apr 10;42 Suppl 3:S91-6.
[Neuroborreliosis and the pediatric population: a review.]
[Article in Spanish]
Lopez-Alberola RF.
University of Miami School of Medicine, Miami, EE.UU.

AIMS. To review the medical literature on neuroborreliosis, in particular its clinical features in both adults and children, and highlight the differences between the two groups, with an emphasis on the pediatric population. DEVELOPMENT. The neurologic manifestations of the disease variably affect different areas of the neuroaxis, central or peripheral, and can present with early or late symptomatology, depending on the age group. Although the literature includes a wide range of neurologic abnormalities, the most frequent symptom reported in the pediatric population is headache, and the most common sign being facial palsy. An immunologic process with cross-reacting antibodies and antibodies directed against neuronal proteins may exist as the causative factor. Because of characteristic cerebrospinal fluid (CSF) findings, CSF examination and serologic testing for Borrelia burgdorferi, the causative agent, should be performed in patients, particularly if a child, having been in an endemic area, presenting with an acute neurologic disorder of unexplained etiology. Treatment with antibiotics, if initiated early-on, is curative, especially in children. CONCLUSIONS. The pediatric population carries the highest risk for Lyme disease relative to other age groups. Younger patients tend to be more acutely affected, with involvement primarily of the central nervous system, exhibiting an inflammatory response in the CSF and signs/symptoms of aseptic meningitis and facial nerve palsy, whereas older patients present with features of peripheral nervous system pathology, tipically with a radiculopathy. Despite having a greater incidence of neuroborreliosis, the clinical course in most children is milder and shorter than that reported for adults.

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Adv Ther. 2006 Jan-Feb;23(1):1-11.
Atovaquone plus cholestyramine in patients coinfected with Babesia microti and Borrelia burgdorferi refractory to other treatment.
Shoemaker RC, Hudnell HK, House DE, Van Kempen A, Pakes GE; COL40155 Study Team.
Center for Research on Biotoxin-Associated Illnesses Pocomoke City, Maryland 21851, USA.

Ten percent of US patients with Lyme disease are coinfected with Babesia microti. A double-blind, placebo-controlled, crossover trial enrolled 25 patients with confirmed Borrelia burgdorferi/B microti coinfection, abnormal visual contrast sensitivity (VCS), and persistent symptoms despite prior treatment with atovaquone and azithromycin. Patients were randomly assigned to atovaquone suspension or placebo plus cholestyramine for 3 weeks, were crossed over for 3 weeks, and then received open-label atovaquone and cholestyramine for 6 weeks. Symptoms and VCS scores were recorded at baseline and after weeks 3, 6, 9, and 12. Improvements in symptoms and VCS deficits were observed only after at least 9 weeks of treatment. At week 12, 5 patients were asymptomatic, and 16 had a notable reduction in the number of symptoms. The entire cohort demonstrated significant increases in VCS scores. Adverse effects were rare. Patients coinfected with B burgdorferi and B microti derive measurable clinical benefit from prolonged treatment with atovaquone and cholestyramine. Longer-term combination therapy may be indicated.

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Int J Med Microbiol. 2006 Mar 8; [Epub ahead of print]
Risk of culture-confirmed borrelial persistence in patients treated for erythema migrans and possible mechanisms of resistance.
Hunfeld KP, Ruzic-Sabljic E, Norris DE, Kraiczy P, Strle F.
Institute of Medical Microbiology, University Hospital of Frankfurt, Paul-Ehrlich Str. 40, D-60596 Frankfurt/Main, Germany; The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.

Erythema migrans (EM) develops at the site of the tick bite in 77-90% of Lyme borreliosis (LB) patients and is therefore a common manifestation of early disease. Clinical treatment failures have been reported in early LB cases for almost every suitable antimicrobial agent. The exact risk of resistance to antibiotic treatment in patients with EM, however, is not known and there are few published cases of culture-proven treatment failure. Moreover, currently available diagnostic techniques cannot reliably discriminate between possible reinfection, true endogenous relapse and co-infection with other tick-borne pathogens. These drawbacks together with the phenomenon of resistance to therapy in individual patients undoubtedly contribute to the inconsistencies surrounding the optimal treatment regimens for LB and are often misinterpreted and misused to support prolonged antibiotic treatment regimens. The question for the underlying mechanisms of possible antimicrobial resistance in Borrelia burgdorferi sensu lato remains unresolved but a better understanding of such genetic or phenotypic mechanisms would be helpful for the treatment of LB and other spirochetal diseases. Investigations on this issue, at best, should start with borrelial isolates cultured from patients before the start of antibiotic therapy and again after the conclusion of treatment. This task, however, remains challenging insofar, as culture is rarely successful under routine laboratory conditions after antimicrobial therapy. Here, we review recent clinical and experimental data on treatment resistance in EM patients suggesting that, although rare, borrelial persistence does occur at the site of the infectious lesion after antibiotic treatment. Borrelial persistence, however, is unlikely to result from acquired resistance against antimicrobial agents that were used for initial specific chemotherapy.

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Int J Med Microbiol. 2006 Mar 6; [Epub ahead of print]
Clinical aspects of neuroborreliosis and post-Lyme disease syndrome in adult patients.
Pfister HW, Rupprecht TA.
Department of Neurology, Ludwig-Maximilians-University, Klinikum Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany.

The diagnostic criteria of active neuroborreliosis include inflammatory changes of the cerebrospinal fluid (CSF) and an elevated specific Borrelia CSF-to-serum antibody index, indicating intrathecal Borrelia antibody production. Patients with neuroborreliosis are usually treated with intravenous ceftriaxone for 2-3 weeks. In case of allergy, doxycycline may be used. Treatment efficacy is detected by the improvement of the neurological symptoms and the normalization of the CSF pleocytosis. The measurement of serum and CSF antibodies is not suitable for follow-up, because they frequently persist. Post-Lyme disease (PLD) syndrome is characterized by persistent complaints and symptoms after previous treatment for Lyme borreliosis, e.g., musculoskeletal or radicular pain, dysaesthesia, and neurocognitive symptoms that are often associated with fatigue. There is no formal definition of the PLD syndrome, and its pathogenesis is unclear. Recent controlled studies do not support the use of additional antibiotics in these patients, but recommend primarily symptomatic strategies.

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Compr Ther. 2005 Winter;31(4):284-90.
Current diagnosis and treatment of lyme disease.
Smith RP.
Maine Medical Center Research Institute, Vector-Borne Disease Laboratory, and Division of Infectious Disease, Maine Medical Center, South Portland, 04106, USA. smithr@mmc.org

In more than 80% of cases, Lyme disease presents with an erythema migrans rash, but its characteristics can vary. Carditis, cranial palsies, lymphocytic meningitis, oligoarticular arthritis are manifestations of disseminated infection. Serological tests are helpful, but must be interpreted with caution. Standard antibiotic treatment regimens are highly effective.

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Int J Epidemiol. 2006 Jan 4; [Epub ahead of print]
Towards landscape design guidelines for reducing Lyme disease risk.
Jackson LE, Hilborn ED, Thomas JC.
National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.

BACKGROUND: Incidence of Lyme disease in the US continues to grow. Low-density development is also increasing in endemic regions, raising questions about the relationship between development pattern and disease. This study sought to model Lyme disease incidence rate using quantitative, practical metrics of regional landscape pattern. The objective was to progress towards the development of design guidelines that may help minimize known threats to human and environmental health. METHODS: Ecological analysis was used to accommodate the integral landscape variables under study. Case data derived from passive surveillance reports across 12 counties in the US state of Maryland during 1996-2000; 2137 cases were spatially referenced to residential addresses. Major roads were used to delineate 514 landscape analysis units from 0.002 to 580 km(2). RESULTS: The parameter that explained the most variation in incidence rate was the percentage of land-cover edge represented by the adjacency of forest and herbaceous cover [R(2) = 0.75; rate ratio = 1.34 (1.26-1.43); P < 0.0001]. Also highly significant was the percentage of the landscape in forest cover (cumulative R(2) = 0.82), which exhibited a quadratic relationship with incidence rate. Modelled relationships applied throughout the range of landscape sizes. CONCLUSIONS: Results begin to provide quantitative landscape design parameters for reducing casual peridomestic contact with tick and host habitat. The final model suggests that clustered forest and herbaceous cover, as opposed to high forest-herbaceous interspersion, would minimize Lyme disease risk in low-density residential areas. Higher-density development that precludes a large percentage of forest-herbaceous edge would also limit exposure.

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Compr Ther. 2005 Winter;31(4):284-90.
Current diagnosis and treatment of lyme disease.
Smith RP.
Maine Medical Center Research Institute, Vector-Borne Disease Laboratory, and Division of Infectious Disease, Maine Medical Center, Portland, ME.

In more than 80% of cases, Lyme disease presents with an erythema migrans rash, but its characteristics can vary. Carditis, cranial palsies, lymphocytic meningitis, oligoarticular arthritis are manifestations of disseminated infection. Serological tests are helpful, but must be interpreted with caution. Standard antibiotic treatment regimens are highly effective.

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Ther Umsch. 2005 Nov;62(11):751-5.
[Lyme borreliosis--treatment and prevention]
[Article in German]
Bassetti S.
Klinik fur Infektiologie, Universitatsspital Basel, Basel. sbassetti@uhbs.ch

Several antimicrobials are effective for the treatment of all stages of Lyme borreliosis. Parenteral therapy is usually only required for neuroborreliosis and cardiac disease with 3rd degree atrioventricular block, while oral antibiotics are sufficient for most other manifestations. In the past years a trend of prolongation of treatment can be noted. However, no evidence from controlled clinical studies is available to suggest that extension of treatment is beneficial. The risk of developing Lyme borreliosis in Switzerland is low. Prophylactic antibiotic treatment after a tick bite is not recommended.

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Curr Neurol Neurosci Rep. 2005 Nov;5(6):446-52.
Central nervous system lyme disease.
Halperin JJ.
Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA. halperin@nshs.edu.

Nervous system infection with Borrelia burgdorferi frequently causes meningitis and rarely causes encephalomyelitis. Altered cognitive function also can occur in the absence of central nervous system infection. Recently developed serodiagnostic tools, such as the C6 assay, and appropriate use of Western blotting promise to improve diagnostic accuracy. Treatment trials have demonstrated the efficacy of relatively brief courses of oral antimicrobial agents, even in peripheral nervous system infection and meningitis. Several well-performed studies have clearly shown that prolonged antimicrobial treatment of "post-Lyme disease" is ineffective. Diagnosis and treatment of Lyme disease continue to improve.

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Ther Umsch. 2005 Nov;62(11):745-9.
[Late manifestations of Lyme borreliosis]
[Article in German]
Rossi M.
Abteilung Infektiologie, Kantonsspital Luzern, Luzern. marco.rossi@ksl.ch

Month to years after an early local or an early disseminated infection some patients develop late manifestations of lyme borreliosis. Most frequently involved organs are the skin (acrodermatitis chronica atrophicans), joints (Lyme arthritis) and the nervous system. A history of exposure and the clinical picture may suggest Lyme borreliosis, however, confirmation by serological and other tests is needed. Antibiotic treatment during early stages normally prevents development of late manifestations. Late stages persist if not treated. By adequate antimicrobial therapy they are treatable and usually show a good prognosis. Recovery may be delayed, some patients suffer from residual difficulties. Currently there is no accepted case definition for a "post lyme syndrome". The term "chronic Lyme disease" suggests (a never proven) persistent infection by viable bacteria. Repeated and prolonged antibiotic treatments are not indicated.

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CNS Drugs. 2005;19(12):1009-32.
Tick-borne encephalopathies : epidemiology, diagnosis, treatment and prevention.
Gunther G, Haglund M.
Infectious Diseases, Department of Medical Sciences, Akademiska Sjukhuset, Uppsala University Hospital, Uppsala, Sweden. goran.gunther@akademiska.se

Tick-borne encephalopathies constitute a broad range of infectious diseases affecting the brain and other parts of the CNS. The causative agents are both viral and bacterial. This review focuses on the current most important tick-borne human diseases: tick-borne encephalitis (TBE; including Powassan encephalitis) and Lyme borreliosis. Rocky Mountain spotted fever (RMSF) and Colorado tick fever (CTF), less common tick-borne diseases associated with encephalopathy, are also discussed. TBE is the most important flaviviral infection of the CNS in Europe and Russia, with 10 000-12 000 people diagnosed annually. The lethality of TBE in Europe is 0.5% and a post-encephalitic syndrome is seen in over 40% of affected patients, often producing a pronounced impairment in quality of life. There is no specific treatment for TBE. Two vaccines are available to prevent infection. Although these have a good protection rate and good efficacy, there are few data on long-term immunity. Lyme borreliosis is the most prevalent tick-borne disease in Europe and North America, with >50 000 cases annually. Localised early disease can be treated with oral phenoxymethylpenicillin (penicillin V), doxycycline or amoxicillin. The later manifestations of meningitis, arthritis or acrodermatitis can be treated with oral doxycycline, oral amoxicillin or intravenous ceftriaxone; intravenous benzylpenicillin (penicillin G) or cefotaxime can be used as alternatives. The current use of vaccines against Lyme borreliosis in North America is under discussion, as the LYMErix vaccine has been withdrawn from the market because of possible adverse effects, for example, arthritis. RMSF and CTF appear only in North America. RMSF is an important rickettsial disease and is effectively treated with doxycycline. There is no treatment or preventative measure available for CTF.

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J Chemother. 2005 Sep;17 Suppl 2:3-16.
Review of treatment options for lyme borreliosis.
Taylor RS, Simpson IN.
Micron Research Ltd, Ely, UK. rod.taylor@micron-research.com

Lyme borreliosis (Lyme disease) is the most common tick-borne bacterial infection and the incidence is increasing in parts of Europe and the USA. Prompt antimicrobial therapy using oral agents such as doxycycline or amoxicillin is successful among more than 90% of patients. Inadequate penetration of oral agents into the CNS may result in the development of overt neuroborreliosis. The parenteral agent ceftriaxone is the drug of choice for severe acute and chronic infections, due to good penetration into CSF, convenient single daily dosage regimen and proven high efficacy in clinical trials involving a wide variety of disseminated infections. Regardless of therapeutic agent, there appears to a small minority of patients (<10%) who do not respond; such cases may be due to long-term persistence of borrelial cysts and to misdiagnoses based solely on seropositivity. Several adjunct therapies are available, including hyperbaric oxygen therapy and immune system supplements, but clinical trials have yet to be conducted.

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Dermatology. 2005;211(2):123-7.
Gabapentin for the symptomatic treatment of chronic neuropathic pain in patients with late-stage lyme borreliosis: a pilot study.
Weissenbacher S, Ring J, Hofmann H.
Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany.

BACKGROUND: Chronic neuropathic pain occurs in 10-15% of patients with neuroborreliosis and is difficult to treat. OBJECTIVE: We evaluated the effect of gabapentin monotherapy on residual pain in patients with neuroborreliosis after intravenous ceftriaxone treatment. METHODS: Ten patients with neuroborreliosis and a long-lasting history of neurologic symptoms were treated with gabapentin, starting with 300 mg/day. Doses were raised over a period of 4-12 weeks to the individually effective and tolerated maximum dose (500-1,200 mg). Treatment was maintained until pain disappeared and then gradually reduced in dose over weeks. If symptoms recurred, the doses were raised again. Therapy was maintained over an average of 1-2 years. RESULTS: Pain quality and pain quantity were evaluated using the McGill pain questionnaire and a visual analogue scale. There was an improvement of 'crawling' and 'burning' pain sensations, neck and radiating lumbar pain in 9/10 (90%) patients as well as a positive effect on mood, general feeling of health and quality of sleep in 5/10 (50%) patients. The average dose leading to a clear-cut pain reduction was 700 mg. CONCLUSIONS: In an open pilot study (10 patients), gabapentin monotherapy which has to our knowledge not been published as treatment of chronic neuropathic pain in patients with late Lyme borreliosis is efficacious in treating pain associated with neuroborreliosis and can thus improve quality of life in these patients. (c) 2005 S. Karger AG, Basel

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Hautarzt. 2005 Aug;56(8):783-96.
[Lyme borreliosis Cutaneous manifestation.]
[Article in German]
Hofmann H.
Klinik und Poliklinik fur Dermatologie und Allergologie Technische Universitat Munchen, .

Lyme borreliosis is a tick transmitted infectious disease caused by different genospecies of Borrelia burgdorferi sensu lato. In USA only one species B. burgdorferi sensu stricto is prevalent, whereas in Europe at least 5 different pathogenic species could be identified. The most prevalent species are B. afzelii and B. garinii. Infection is not always causing disease. In early infection, a localized skin inflammation, called erythema migrans, occurs around the tick bite, hematogenous dissemination of Borrelia causes flu like symptoms up to meningitis and multiple erythemata migrantia on the skin. In late stage multiple organ systems can be affected, in Europe especially the skin with various forms of acrodermatitis chronica atrophicans, the central and peripheral nervous system, joints and heartmuscle. Lyme borreliosis can be diagnosed by the typical history, the clinical symptoms and the elevated Borrelia specific IgM- and IgG-antibodies in serum and CSF according to the MIQ guidelines, in special cases B. burgdorferi can be cultivated or DNA detected by PCR. Therapy of choice for early infection is oral antibiotics like doxycycline, amoxicillin and cefuroxime for at least 10 days up to 21 days. Late stage infections should be treated for 3-4 weeks. Patients with neurological symptoms should be treated intravenously with ceftriaxone or penicillin G.

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Wien Klin Wochenschr. 2005 Jun;117(11-12):393-7.
A comparison of two treatment regimens of ceftriaxone in late Lyme disease.
Dattwyler RJ, Wormser GP, Rush TJ, Finkel MF, Schoen RT, Grunwaldt E, Franklin M, Hilton E, Bryant GL, Agger WA, Maladorno D.
Division of Rheumatology, Allergy and Immunology, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA. Raymond_Dattwyler@nymc.edu

BACKGROUND: The optimal duration of treatment for patients with late Lyme disease is unresolved. METHODS: In a prospective, open label, randomized, multi-center study, a 14 day course of ceftriaxone was compared to 28 days of therapy. Entry criteria included objective abnormalities compatible with late Lyme disease and serologic reactivity to Borrelia burgdorferi. Randomization took place prior to obtaining serologic results. Clinical response was rated as cure; improvement; failure; or not assessable. RESULTS: Of the 201 patients randomized, 21 patients in the 14 day group and 37 in the 28-day group were excluded from the study for failure to meet serologic criteria. Of those who met serologic criteria, 80 patients received 14 days and 63 received 28 days of ceftriaxone. At time of last evaluation, there were 5 treatment failures in the 14 day group and none in the 28 day group (p = 0.07). Clinical cure rates were 76% for the 14 day group and 70% for the 28 day group (p = NS). Therapy was discontinued due to adverse events for a significantly greater proportion of patients in the 28-day group compared to the 14-day group (p < 0.02). CONCLUSIONS: Ceftriaxone for 14 days eradicated the signs and symptoms of late Lyme disease in the majority of evaluable patients. Although there were more failures in the 14-day group than in the 28-day group, this study did not have the power to determine if a clinical subset of patients may benefit from 28 days of therapy.

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Wien Klin Wochenschr. 2005 Jun;117(11-12):385-91.
Prevention of Lyme borreliosis.
Wormser GP.
Division of Infectious Diseases, Department of Medicine, New York Medical College, Westchester Medical Center, Valhalla, New York 10595, USA. Gary_Wormser@NYMC.edu

Lyme borreliosis, the most common tick-borne disease in both North America and Europe, is acquired through the bite of certain tick species in the genus Ixodes. The number of Ixodes ticks in the environment can be reduced by relatively simple interventions such as removing leaf litter and brush, which increases exposure of the tick to sun and air and takes advantage of the tick's vulnerability to desiccation, or by application of acaricides to property. Deer elimination or exclusion, application of topical acaricides to mice or deer, and application of systemic acaricides to deer are more complex approaches. However, none of these methods for reducing tick numbers, nor any of the recommended personal prevention measures, such as reducing the amount of exposed skin, use of tick repellents on exposed skin or clothing, and frequent tick checks to remove attached ticks expeditiously, has been demonstrated to decrease significantly the incidence of Lyme borreliosis in humans. Only two strategies have been shown to do so. A recombinant outer surface protein A (OspA) vaccine was approximately 80% effective in clinical trials in the United States, and a single 200 mg dose of doxycycline given within 72 hours of an I. scapularis tick bite, was shown to be 87% effective. The OspA vaccine is no longer manufactured due to poor sales. Consequently, single-dose doxycycline prophylaxis is rapidly gaining acceptance in the United States. Limiting single-dose doxycycline to just the highest risk tick bites can be accomplished if the health care provider has learned to differentiate engorged from unengorged I. scapularis ticks. Limitations of single-dose doxycycline prophylaxis are that the majority of patients with Lyme borreliosis do not recall a tick bite, and that there is no evidence that other Ixodes transmitted infections, such as human granulocytic ehrlichiosis, would be prevented. A safe, effective, inexpensive and well-accepted vaccine would be welcome.

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Scand J Infect Dis. 2005;37(6-7):449-54.
Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis.
Borg R, Dotevall L, Hagberg L, Maraspin V, Lotric-Furlan S, Cimperman J, Strle F.
Department of Infectious Diseases, Sahlgrenska University Hospital, Goteborg, Sweden. rebecca.borg@infect.gu.se

This prospective, open-label, non-randomized trial at the University Departments of Infectious Diseases in Ljubljana, Slovenia, and Goteborg, Sweden, was conducted to compare the kinetics of the cerebrospinal fluid (CSF) mononuclear cell count after 10-14 d of ceftriaxone or doxycycline for treatment of Lyme neuroborreliosis. 29 patients were treated with intravenous ceftriaxone 2 g daily in Ljubljana and 36 patients with oral doxycycline 400 mg daily in Goteborg. The study protocol included lumbar puncture before and 6-8 weeks after treatment initiation. There was a marked decrease (1.2 log10 x 10(6)/l) of the median CSF mononuclear cell count following treatment. With the assumption of a linear regression of the logarithmic mononuclear cell counts between the 2 lumbar punctures, no significant difference between the 2 antibiotic treatments could be found. All patients were clinically much improved after treatment. At 6 months follow-up 23 (79%) of the ceftriaxone- and 26 (72%) of the doxycycline-treated patients were completely recovered. Intravenous ceftriaxone or oral doxycycline was found to be effective, safe, and convenient for treatment of Lyme neuroborreliosis.

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Dermatology. 2005;211(2):123-7.
Gabapentin for the symptomatic treatment of chronic neuropathic pain in patients with late-stage lyme borreliosis: a pilot study.
Weissenbacher S, Ring J, Hofmann H.
Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany.

Background: Chronic neuropathic pain occurs in 10-15% of patients with neuroborreliosis and is difficult to treat. Objective: We evaluated the effect of gabapentin monotherapy on residual pain in patients with neuroborreliosis after intravenous ceftriaxone treatment. Methods: Ten patients with neuroborreliosis and a long-lasting history of neurologic symptoms were treated with gabapentin, starting with 300 mg/day. Doses were raised over a period of 4-12 weeks to the individually effective and tolerated maximum dose (500-1,200 mg). Treatment was maintained until pain disappeared and then gradually reduced in dose over weeks. If symptoms recurred, the doses were raised again. Therapy was maintained over an average of 1-2 years. Results: Pain quality and pain quantity were evaluated using the McGill pain questionnaire and a visual analogue scale. There was an improvement of 'crawling' and 'burning' pain sensations, neck and radiating lumbar pain in 9/10 (90%) patients as well as a positive effect on mood, general feeling of health and quality of sleep in 5/10 (50%) patients. The average dose leading to a clear-cut pain reduction was 700 mg. Conclusions: In an open pilot study (10 patients), gabapentin monotherapy which has to our knowledge not been published as treatment of chronic neuropathic pain in patients with late Lyme borreliosis is efficacious in treating pain associated with neuroborreliosis and can thus improve quality of life in these patients. Copyright (c) 2005 S. Karger AG, Basel.

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Paediatr Drugs. 2005;7(3):163-76.
Tick-borne infections in children: epidemiology, clinical manifestations, and optimal management strategies.
Buckingham SC.
Department of Pediatrics, Division of Infectious Disease, University of Tennessee Health Science Center and Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, Tennessee, USA. sbuckingham@utmem.edu

Ticks can transmit bacterial, protozoal, and viral infections to humans. Specific therapy is available for several of these infections. Doxycycline is the antimicrobial treatment of choice for all patients, regardless of age, with Rocky Mountain spotted fever, human monocytic ehrlichiosis, or human granulocytic ehrlichiosis. Chloramphenicol has been used to treat these infections in children but is demonstrably inferior to doxycycline. In patients with Mediterranean spotted fever, doxycycline, chloramphenicol, and newer macrolides all appear to be effective therapies. Therapy of Lyme disease depends on the age of the child and stage of the disease. For early localized disease, amoxicillin (for those aged <8 years) or doxycycline (for those aged >/=8 years) is effective. Doxycycline, penicillin V (phenoxymethylpenicillin) or penicillin G (benzylpenicillin) preparations, and erythromycin are all effective treatments for tick-borne relapsing fever. Hospitalized patients with tularemia should receive gentamicin or streptomycin. Doxycycline and ciprofloxacin have each been investigated for the treatment of tularemia in outpatients; however, these agents do not yet have established roles in the treatment of this disease in children. Combination therapy with clindamycin and quinine is preferred for children with babesiosis; the combination of azithromycin and atovaquone also appears promising. Ribavirin has been recently shown to markedly improve survival in patients with Crimean-Congo hemorrhagic fever. The role of antiviral therapy in the treatment of other tick-borne viral infections, including other hemorrhagic fevers and tick-borne encephalitis, is not yet defined.

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Enferm Infecc Microbiol Clin. 2005 Apr;23(4):232-40.
[Diseases produced by Borrelia.]
[Article in Spanish]
Escudero-Nieto R, Guerrero-Espejo A.
Laboratorio de Espiroquetas y Patogenos Especiales. Servicio de Bacteriologia. Centro Nacional de Microbiologia. ISCIII. Majadahonda. Madrid. Spain.

Lyme borreliosis, caused by Borrelia burgdorferi sensu lato, is a multi-organ infection with dermatological, rheumatological, neurological, and cardiac manifestations. The main characteristic is a skin lesion, named erythema migrans. Relapsing fever, caused by numerous species of Borrelia, is characterized by a periodic cycle of acute and afebrile episodes. The serological diagnosis of these infections has limited value in sensitivity, specificity and predictive values. Lyme borreliosis is usually diagnosed by recognition of a characterisic clinical picture with serological confirmation, and the diagnosis of relapsing fever relies on direct observation of spirochetes in peripherical blood. The elected treatment is almost always tetracycline for the young or for adults but not for pregnant women, although betalactamic (such as penicillin or 3rd generation cephalosporin for the central nervious system) or macrolides are indicated in several situations. The prognosis, with adequate treatment, is good. In the majority of Spanish regions, due to the low incidence of these diseases, the prophylactic antimicrobial treatment after a tick bite is not indicated.

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Curr Treat Options Neurol. 2005 Mar;7(2):167-170.
The Therapy of Lyme Neuroborreliosis.
Pachner AR.
Department of Neurology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA. pachner@umdnj.edu.

The challenge for the neurologist in the treatment of Lyme neuroborreliosis is not in the treatment per se, but in the diagnosis. Neurological manifestations of Lyme disease can present in many forms, and diagnostic techniques which detect the spirochete directly; the culture or polymerase chain reaction of the spirochete in cerebrospinal fluid, are of disappointingly low yield. Therefore, the diagnosis is frequently not easy. After the diagnosis is made, antibiotic therapy is straightforward; Lyme neuroborreliosis should be treated with at least 2 weeks of antibiotics. In the United States, intravenous therapy with ceftriaxone or penicillin for 2 weeks is the standard, whereas in Europe oral doxycycline therapy is commonly administered. Either is effective, and my choice of therapy generally depends on the patient. Many patients have symptoms which continue after antibiotic therapy referable to persistent inflammation, and, for those patients, I will commonly prescribe nonsteroidal anti-inflammatory medications.

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Rev Med Suisse. 2005 Jan 12;1(2):134, 136-9.
[Infectious diseases in the ambulatory care setting]
[Article in French]
Zanetti G.
Service des maladies infectieuses, et Division autonome de medecine, preventive hospitaliere, CHUV, 1011 Lausanne. Giorgio.Zanetti@chuv.hospvd.ch

Hot topics in infectiology mainly include emerging diseases, particularly those caused by antibiotic-resistant bacteria. Prudent use of antibiotics is therefore mandatory. Among new classes of antibiotics for outpatients therapy are linezolid (for resistant, Gram-positive bacterial, and telithromycine (for treatment of respiratory tract infections). This review also addresses the following topics: short course of doxycycline for treatment of early Lyme disease in adults, recommendations against the widespread use of fluoroquinolones for community-acquired pneumonia, prevention of Herpes simplex type 2 transmission with valacyclovir, management of acute, symptomatic hepatitis C, and the absence of an established link between vaccines and chronic diseases.

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Emerg Infect Dis. 2005 Jan;11(1):36-41.
Hypersensitivity to ticks and Lyme disease risk.
Burke G, Wikel SK, Spielman A, Telford SR, McKay K, Krause PJ; Tick-borne Infection Study Group.
Connecticut Children's Medical Center, Hartford, Connecticut, USA.

Although residents of Lyme disease-endemic regions describe frequent exposure to ticks, Lyme disease develops in relatively few. To determine whether people who experience cutaneous hypersensitivity against tick bite have fewer episodes of Lyme disease than those who do not, we examined several factors that might restrict the incidence of Lyme disease among residents of Block Island, Rhode Island. Of 1,498 study participants, 27% (95% confidence interval [CI] 23%-31%) reported > or = 1 tick bites, and 17% (95% CI 13%-21%) reported itch associated with tick bite in the previous year. Borrelia burgdorferi infected 23% (95% CI 20%-26%) of 135 nymphal Ixodes scapularis (I. dammini) ticks. The likelihood of Lyme disease infection decreased with >3 reports of tick-associated itch (odds ratio 0.14, 95% CI 0.94-0.03, p = 0.01). Prior exposure to uninfected vector ticks protects residents of disease-endemic sites from Lyme disease.

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Med Hypotheses. 2005;64(3):438-48.
Chronic Lyme borreliosis at the root of multiple sclerosis - is a cure with antibiotics attainable?
Fritzsche M.
Clinic for Internal and Geographical Medicine, Soodstrasse 13, 8134 Adliswil, Switzerland.

Apart from its devastating impact on individuals and their families, multiple sclerosis (MS) creates a huge economic burden for society by mainly afflicting young adults in their most productive years. Although effective strategies for symptom management and disease modifying therapies have evolved, there exists no curative treatment yet. Worldwide, MS prevalence parallels the distribution of the Lyme disease pathogen Borrelia (B.) burgdorferi, and in America and Europe, the birth excesses of those individuals who later in life develop MS exactly mirror the seasonal distributions of Borrelia transmitting Ixodes ticks. In addition to known acute infections, no other disease exhibits equally marked epidemiological clusters by season and locality, nurturing the hope that prevention might ultimately be attainable. As minocycline, tinidazole and hydroxychloroquine are reportedly capable of destroying both the spirochaetal and cystic L-form of B. burgdorferi found in MS brains, there emerges also new hope for those already afflicted. The immunomodulating anti-inflammatory potential of minocycline and hydroxychloroquine may furthermore reduce the Jarisch Herxheimer reaction triggered by decaying Borrelia at treatment initiation. Even in those cases unrelated to B. burgdorferi, minocycline is known for its beneficial effect on several factors considered to be detrimental in MS. Patients receiving a combination of these pharmaceuticals are thus expected to be cured or to have a longer period of remission compared to untreated controls. Although the goal of this rational, cost-effective and potentially curative treatment seems simple enough, the importance of a scientifically sound approach cannot be overemphasised. A randomised, prospective, double blinded trial is necessary in patients from B. burgdorferi endemic areas with established MS and/or Borrelia L-forms in their cerebrospinal fluid, and to yield reasonable significance within due time, the groups must be large enough and preferably taken together in a multi-centre study.

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Eur J Dermatol. 2004 Sep-Oct;14(5):296-309.
Dermatological manifestations of Lyme borreliosis.
Mullegger RR.
Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. robert.muellegger@meduni-graz.at

Lyme borreliosis is a multisystem infectious disease caused by the tick-transmitted spirochete Borrelia burgdorferi sensu lato. About 80% of all Lyme borreliosis cases represent skin manifestations (dermatoborrelioses). The three characteristic dermatoborrelioses are erythema migrans, borrelial lymphocytoma, and acrodermatitis chronica atrophicans, which occur in different stages of the disease. Erythema migrans is the hallmark of early Lyme borreliosis, whereas acrodermatitis chronica atrophicans is the characteristic manifestation of late Lyme borreliosis. Several spirochetal factors (e.g. infection with different genospecies, co-infection with other tick-transmitted pathogens) as well as host factors (e.g. cytokine patterns at the site of infection) influence the course of the disease. Diagnosis in the early stage of Lyme borreliosis relies on the clinical picture, whereas serological, molecular, microbiological, and histopathological findings are important adjuncts in the diagnosis of later stages of the infection. Antibiotic treatment is necessary for all stages and manifestations of Lyme borreliosis. Doxycycline is the antibiotic of choice for most patients with dermatoborrelioses.

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Ceska Slov Farm. 2004 Jul;53(4):159-64.
[Pharmacological aspects of Lyme borreliosis]
[Article in Czech]
Dvorakova J, Celer V.
Ustav humanni farmakologie a toxikologie VFU a FF, Brno. celer@vfu.cz

Clinical signs of Lyme boreliosis in humans are versatile and in their whole scope they finally affect the nervous system, heart, and joints. The therapeutic effect of antibiotics is maximal in the first acute stage of the disease when doxycycline and amoxiciline are administered. These antibiotics possess a comparable in vitro effect, tissue penetration, pharmacokinetics, and therapeutic effect. The treatment of disseminated infections in the second stage, such as neuroborreliosis, carditis, and iritis, is difficult and with relative success they are treated with large doses of penicillin G, or cefriaxon, and doxycycline. The treatment of the third stage of borreliosis aims at chronic inflammatory changes in the affected organs. Antibiotics, however, are successfully effective only in 50% of cases. Administration of antibiotics, such as tetracycline, cefuroxim, doxycycline, or large doses of penicillin is a long-term one, coming up to four weeks. A special therapeutic regimen is used in pregnant women and children.

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Eur J Med Res. 2004 Jul 30;9(7):334-6.
Clinical effects of fluconazole in patients with neuroborreliosis.
Schardt FW.
Betriebsarztliche Untersuchungsstelle, Bayerische Julius-Maximilians-Universitat, Wurzburg, Germany. Fritz.Schardt@mail.uni-wuerzburg.de

Eleven patients with neuro-borreliosis had been treated with 200 mg fluconazole daily for 25 days after an unsuccessful therapy with antibiotics. At the end of treatment eight patients had no borreliosis symptoms and remained free of relapse in a follow-up examination one year later. In the remaining four patients, symptoms were considerably improved. At the end of therapy immune reactivity (IgM+) disappeared in three patients. Since borrelia spp. are almost exclusively localised intracellular, they may depend on certain metabolites of their eucaryotic host cell. Inhibition of P450 and other cytochromes by fluconazole may incapacitate Borrelia upon longterm exposure.

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Recenti Prog Med. 2004 Sep;95(9):403-13.
[Tick-borne infections]
[Article in Italian]
Calza L, Manfredi R, Chiodo F.
Sezione di Malattie Infettive, Dipartimento di Medicina Clinica Specialistica e Sperimentale, Policlinico S. Orsola, Alma Mater Studiorum Universita, Bologna. calza@med.unibo.it

Ticks are obligate, blood-sucking ectoparasites that are the most common agents of vector-borne infectious disease in the United States and European countries. Ticks play an important role in transmitting several infectious agents, such as viruses, bacteria, spirochetes, rickettsia, and parasites, and tick bites cause a variety of acute and chronic infectious diseases, including Lyme disease, tick-borne relapsing fever, Rocky Mountain and Mediterranean spotted fevers, ehrlichiosis, Q fever, tularemia, babesiosis, and tick-borne viral encephalitis. Since its identification nearly 30 years ago, Lyme disease has continued to spread, and it is now the most commonly reported arthropod-borne illness in American and European countries. Rickettsial infections are widely distributed throughout the world and have a remarkable influence on public health and military activities as a possible biological weapon. Tick-borne encephalitis virus is endemic in central, eastern and northern Europe and may cause a wide spectrum of clinical forms, ranging from asymptomatic infection to severe meningo-encephalitis. This article reviews the epidemiology, microbiology, clinical manifestation, diagnosis and treatment of the major tick-borne infectious diseases in the United States and Europe.

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Curr Infect Dis Rep. 2004 Aug;6(4):298-304.
Central Nervous System Lyme Disease.
Halperin JJ.
Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA. halperin@nshs.edu

Nervous system infection with Borrelia burgdorferi frequently causes meningitis and rarely causes encephalomyelitis. Altered cognitive function also can occur in the absence of central nervous system infection. Recently developed serodiagnostic tools, such as the C6 assay, and appropriate use of Western blotting, promise to improve diagnostic accuracy. Treatment trials have demonstrated the efficacy of relatively brief courses of oral antimicrobial agents, even in peripheral nervous system infection and meningitis. Several well-performed studies have clearly shown that prolonged antimicrobial treatment of "post-Lyme disease" is ineffective. Diagnosis and treatment of Lyme disease continue to improve.

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Nervenarzt. 2004 Jun;75(6):553-7.
[Clinical courses of acute and chronic neuroborreliosis following treatment with ceftriaxone]
[Article in German]
Kaiser R.
Neurologische Klinik, Stadtisches Klinikum Pforzheim. Kaiser.Neurologische_Klinik@Stadt-Pforzheim.de

Between 1990 and 2000, a total of 101 patients with acute (n=86) or chronic (n=15) neuroborreliosis (proven by clinical data, pleocytosis in the CSF, and elevated Borrelia burgdorferi-specific antibody indices) were treated with 2 g of ceftriaxone per day for either 2 or 3 weeks. The patients were reexamined clinically and serologically after 3, 6, and 12 months. Six (12) months after the antibiotic treatment, about 93% (95%) of the patients with acute neuroborreliosis and 20% (66%) of the patients with chronic neuroborreliosis were cured. One year after treatment, four patients with acute neuroborreliosis still suffered from facial palsy and five with chronic neuroborreliosis still had moderate spastic ataxic gait disturbance. The prognosis of facial palsy in neuroborreliosis is quite similar to that in idiopathic facial palsy, while that in chronic neuroborreliosis largely depends on the time elapsed before diagnosis.

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Expert Rev Anti Infect Ther. 2004 Aug;2(4):533-57.
Treatment of Lyme disease: a medicolegal assessment.
Johnson L, Stricker RB.
California Pacific Medical Center, 450 Sutter Street, Suite 1504, San Francisco, CA 94108, USA. rstricker@usmamed.com.

Lyme disease is the most common tick-borne disease in the world today. Despite extensive research into the complex nature of Borrelia burgdorferi, the spirochetal agent of Lyme disease, controversy continues over the diagnosis and treatment of this protean illness. This report will focus on two aspects of the treatment of Lyme disase. First, the medical basis for diagnostic and therapeutic uncertainty in Lyme disease, including variability in clinical presentation, shortcomings in laboratory testing procedures, and design defects in therapeutic trials. Second, the standard of care and legal issues that have resulted from the clinical uncertainty of Lyme disease diagnosis and treatment. Specifically, the divergent therapeutic standards for Lyme disease are addressed, and the difficult process of creating treatment guidelines for this complex infection is explored. Consideration by healthcare providers of the medicolegal issues outlined in this review will support a more rational approach to the diagnosis and treatment of Lyme disease and related tick-borne illnesses.

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Rev Neurol (Paris). 2004 Sep;160(8-9):833-5.
[Ataxic sensory neuropathy and Lyme disease]
[Article in French]
Thouvenot E, Hadjout K, Grosleron S, Blard JM, Pages M.
Service de Neurologie A.

Introduction: The clinical spectrum of peripheral neuropathies in Lyme disease is very wide. We report a case which was revealed by an ataxic sensory neuropathy. Observation: A 77-year-old patient presented with a subacute ataxic sensory neuropathy which occurred 2 weeks after a skin lesion involving the right lower limb. He fully recovered after specific antibiotic treatment. EMG was suggestive of a predominantly axonal neuropathy. Diagnosis of Lyme disease was assessed by progressive elevation of serum antibodies, demonstration of a lymphocytic meningitis and intrathecal synthesis of antibodies. CONCLUSION: Lyme disease may be added to the list of diseases which may induce subacute sensory neuropathies.

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Curr Infect Dis Rep. 2004 Aug;6(4):298-304.
Central Nervous System Lyme Disease.
Halperin JJ.
Department of Neurology, North Shore University Hospital, Manhasset, NY 11030, USA. halperin@nshs.edu

Nervous system infection with Borrelia burgdorferi frequently causes meningitis and rarely causes encephalomyelitis. Altered cognitive function also can occur in the absence of central nervous system infection. Recently developed serodiagnostic tools, such as the C6 assay, and appropriate use of Western blotting, promise to improve diagnostic accuracy. Treatment trials have demonstrated the efficacy of relatively brief courses of oral antimicrobial agents, even in peripheral nervous system infection and meningitis. Several well-performed studies have clearly shown that prolonged antimicrobial treatment of "post-Lyme disease" is ineffective. Diagnosis and treatment of Lyme disease continue to improve.

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Eur J Clin Microbiol Infect Dis. 2004 Aug;23(8):615-8. Epub 2004 Jul 08.
Pre-treatment and post-treatment assessment of the C(6) test in patients with persistent symptoms and a history of Lyme borreliosis.
Fleming RV, Marques AR, Klempner MS, Schmid CH, Dally LG, Martin DS, Philipp MT.
Department of Medicine, Boston University Medical Center, 650 Albany Street, Room 620, Boston, MA 02118, USA.

It was recently reported that antibody to C(6), a peptide that reproduces an invariable region of the VlsE lipoprotein of Borrelia burgdorferi, declined in titer by a factor of four or more in a significant proportion of patients after successful antibiotic treatment of acute localized or disseminated Lyme borreliosis. The present study evaluated the C(6) test as a predictor of therapy outcome in a population of patients with post-treatment Lyme disease syndrome. The serum specimens tested were from patients with well-documented, previously treated Lyme borreliosis who had persistent musculoskeletal or neurocognitive symptoms. All of the patients had participated in a recent double-blind, placebo-controlled antibiotic trial in which serum samples were collected at baseline and 6 months thereafter, i.show $132#e. 3 months following treatment termination. In this patient population no correlation was found between a decline of C(6) antibody titer of any magnitude and treatment or clinical outcome. Antibodies to C(6) persisted in these patients with post-treatment Lyme disease syndrome following treatment, albeit at a markedly lower prevalence and titer than in untreated patients with acute disseminated Lyme disease. The results indicate that C(6) antibody cannot be used to assess treatment outcome or the presence of active infection in this population.

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Clin Microbiol Infect. 2004 Jul;10(7):598-614.
Lyme borreliosis: from infection to autoimmunity.
Singh SK, Girschick HJ.
Paediatric Rheumatology, Children's Hospital, University of Wurzburg, Wurzburg, Germany.

Lyme borreliosis in humans is an inflammatory disease affecting multiple organ systems, including the nervous system, cardiovascular system, joints and muscles. The causative agent, the spirochaete Borrelia burgdorferi, is transmitted to the host by a tick bite. The pathogenesis of the disease in its early stages is associated largely with the presence of viable bacteria at the site of inflammation, whereas in the later stages of disease, autoimmune features seem to contribute significantly. In addition, it has been suggested that chronic persistence of B. burgdorferi in affected tissues is of pathogenic relevance. Long-term exposure of the host immune system to spirochaetes and/or borrelial compounds may induce chronic autoimmune disease. The study of bacterium-host interactions has revealed a variety of proinflammatory and also immunomodulatory-immunosuppressive features caused by the pathogen. Therapeutic strategies using antibiotics are generally successful, but chronic disease may require immunosuppressive treatment. Effective and safe vaccines using recombinant outer surface protein A have been developed, but have not been propagated because of fears that autoimmunity might be induced. Nevertheless, new insights into the modes of transmission of B. burgdorferi to the warm-blooded host have been generated by studying the action of these vaccines.

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Int J Med Microbiol. 2004 Apr;293 Suppl 37:80-5.
Problems in the study and prophylaxis of mixed infections transmitted by ixodid ticks.
Korenberg EI.
Gamaleya Research Institute for Epidemiology and Microbiology, Russian Academy of Medical Sciences, Moscow, Russia. focus@edkor.msk.ru

The spread of mixed infections with natural focality transmitted by ixodid ticks is a normal phenomenon attributable to trends in the relationships of different pathogens in the vector organism and ecosystem as a whole. Any disease developing as a result of tick bite should be regarded as a potentially mixed infection. Clinically, tick-borne mixed infections proceed more severely than the corresponding diseases caused by a single agent. The residual course of the disease may sometimes be accounted for by the persistence of two or even several pathogens. This implies the necessity of a comprehensive approach to the study, diagnosis, treatment, management and prophylaxis of infections belonging to this group.

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Cent Eur J Public Health. 2004 Mar;12(1):6-11.
Long term and repeated electron microscopy and PCR detection of Borrelia burgdorferi sensu lato after an antibiotic treatment.
Honegr K, Hulinska D, Beran J, Dostal V, Havlasova J, Cermakova Z.
Department of Infectious diseases, University Hospital, Hradec Kralove, Czech Republic.

The diagnosis of Lyme disease in 18 patients has been proved by detection of Borrelia burgdorferi sensu lato when using immunoelectron microscopy or detecting its nucleic acid by PCR in the plasma or the cerebrospinal fluid. The positive results occurred in the plasma or in the cerebrospinal fluid in the period of 4-68 months after an antibiotic treatment. The typical clinical manifestations of Lyme disease were observed in 9 patients and non-specific symptoms in another 9 patients. According to presented results we can recommend repeated examination using PCR of the plasma and other biological specimens in the individuals with persistent or recurring complaints after an acute form of Lyme disease and its antibiotic treatment. Also examination of the cerebrospinal fluid with non-specific symptoms and simultaneously displayed pathology electroencephalogram and/or magnetic resonance imaging findings can be advantageous.

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Nat Rev Immunol. 2004 Feb;4(2):143-52.
Elucidation of Lyme arthritis.
Steere AC, Glickstein L.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. asteere@partners.org

Before the first description of Lyme arthritis in 1976, patients with this disease were often thought to have juvenile or adult rheumatoid arthritis. It is now known that Lyme arthritis is caused by a tick-borne spirochete that disseminates to joints, where it induces marked pro-inflammatory responses. In most patients, the arthritis resolves with antibiotic treatment. However, in the United States, about 10% of patients with Lyme arthritis develop persistent synovitis, which lasts for months or even several years after the apparent eradication of the spirochete from the joint with antibiotic therapy. The elucidation of Lyme arthritis, from acute infection to chronic synovitis, might help in our understanding not only of this entity, but also of other forms of chronic inflammatory arthritis, including rheumatoid arthritis.

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Joint Bone Spine. 2004 Jan;71(1):39-43.
Good outcomes of Lyme arthritis in 24 patients in an endemic area of Switzerland.
Renaud I, Cachin C, Gerster JC.
Internal Medicine Department, CHUV, 1011 Lausanne, Switzerland.

OBJECTIVE: To describe outcomes of treated Lyme arthritis in an endemic area of western Switzerland, where some of the first cases of Lyme disease outside the United States were reported. PATIENTS AND METHODS: We retrospectively studied 24 patients (15 males and nine females, mean age 38.7 years) managed by rheumatologists between 1994 and 1999 for Borrelia burgdorferi arthritis manifesting as monoarthritis (n = 20), oligoarthritis (n = 3), or polyarthritis (n = 1). The knee was affected in 20 (85%) patients. Nine patients reported a history of tick bite and four of erythema chronicum migrans. All the patients but one had a high titer of antibodies to B. burgdorferi by ELISA and all but two had a positive immunoblot test (22 positive for all three types of B. burgdorferi found in Switzerland and one positive only for B. burgdorferi sensu stricto). Joint fluid PCR for B. burgdorferi was done in nine patients and was positive in six. RESULTS: All 24 patients received antibiotic therapy, orally (n = 10) or parenterally (n = 14). A second course of antibiotic therapy was used in four patients with persistent arthritis. A rapid response was noted in 13 patients. Intraarticular glucocorticoid therapy or a synoviorthesis was required in nine patients. After a mean follow-up of 40 months (range, 6-84 months), none of the patients had chronic arthritis but two reported persistent muscle or joint pain. CONCLUSION: Recurrent or chronic arthritis, which has been reported in treated patients in the United States, did not occur in our series. This may be ascribable to differences in B. burgdorferi subtypes, as in the United States only B. burgdorferi sensu stricto is found.

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Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1303-8. Epub 2004 Jan 23.
An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope.
Willett TA, Meyer AL, Brown EL, Huber BT.
Department of Pathology, Tufts University School of Medicine, 150 Harrison Avenue, Boston, MA 02111, USA.

The antigenic component of a common Lyme disease vaccine is recombinant outer surface protein A (rOspA) of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Coincidentally, patients with chronic, treatment-resistant Lyme arthritis develop an immune response against OspA, whereas those with acute Lyme disease usually do not. Treatment-resistant Lyme arthritis occurs in a subset of Lyme arthritis patients and is linked to HLA.DRB1*0401 (DR4) and related alleles. Recent work from our laboratory identified T cell crossreactivity between epitopes of OspA and lymphocyte function-associated antigen 1alpha(L) chain (LFA-1alpha(L)) in these patients. We generated a form of rOspA, FTK-OspA, in which the LFA-1alpha(L)/rOspA crossreactive T cell epitope was mutated to reduce the possible risk of autoimmunity in genetically susceptible individuals. FTK-OspA did not stimulate human or mouse DR4-restricted, WT-OspA-specific T cells, whereas it did stimulate antibody responses specific for WT-OspA that were similar to mice vaccinated WT-OspA. We show here that the protective efficacy of FTK-OspA is indistinguishable from that of WT-OspA in vaccination trials, as both C3H/HeJ and BALB/c FTK-OspA-vaccinated mice were protected from Bb infection. These data demonstrate that this rOspA-derived vaccine lacking the predicted cross-reactive T cell epitope, but retaining the capacity to elicit antibodies against infection, is effective in generating protective immunity.

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Infect Immun. 2004 Sep;72(9):4956-65.
Treatment of mice with the neutrophil-depleting antibody RB6-8C5 results in early development of experimental lyme arthritis via the recruitment of Gr-1- polymorphonuclear leukocyte-like cells.
Brown CR, Blaho VA, Loiacono CM.
Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65211, USA. BrownChar@missouri.edu

Recently, we demonstrated that blocking the entry of neutrophils into Borrelia burgdorferi-infected joints in mice deficient in the chemokine receptor CXCR2 prevented the development of experimental Lyme arthritis. Neutrophils were marginalized in blood vessels at the site of infection but could not enter the joint tissue. In the present study, we treated both genetically arthritis-resistant DBA/2J (DBA) and arthritis-susceptible C3H/HeJ (C3H) mice with the neutrophil-depleting monoclonal antibody RB6-8C5 (RB6) to determine the effect on arthritis development. Surprisingly, both DBA and C3H mice treated with RB6 developed arthritis at 1 week postinfection, approximately 1 week earlier than the control-treated C3H mice. The early development of arthritis in the RB6-treated mice was accompanied by an influx into the joints of cells with ring-shaped polymorphonuclear leukocyte (PMN) cell morphology that were negative for the Gr-1 neutrophil maturation marker. RB6 treatment of mice also resulted in increased numbers of B. burgdorferi cells in the joints at 7 days postinfection and earlier expression of the chemokines KC and monocyte chemoattractant protein 1 in the joints compared to control-treated animals. Together, these results suggest that recruitment of neutrophils or PMN-like cells into an infected joint is a key requirement for Lyme arthritis development and that altered recruitment of these cells into the joints of arthritis-resistant mice can exacerbate the development of pathology.

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Clin Microbiol Infect. 2004 Jul;10(7):598-614.
Lyme borreliosis: from infection to autoimmunity.
Singh SK, Girschick HJ.
Paediatric Rheumatology, Children's Hospital, University of Wurzburg, Wurzburg, Germany.

Abstract Lyme borreliosis in humans is an inflammatory disease affecting multiple organ systems, including the nervous system, cardiovascular system, joints and muscles. The causative agent, the spirochaete Borrelia burgdorferi, is transmitted to the host by a tick bite. The pathogenesis of the disease in its early stages is associated largely with the presence of viable bacteria at the site of inflammation, whereas in the later stages of disease, autoimmune features seem to contribute significantly. In addition, it has been suggested that chronic persistence of B. burgdorferi in affected tissues is of pathogenic relevance. Long-term exposure of the host immune system to spirochaetes and/or borrelial compounds may induce chronic autoimmune disease. The study of bacterium-host interactions has revealed a variety of proinflammatory and also immunomodulatory-immunosuppressive features caused by the pathogen. Therapeutic strategies using antibiotics are generally successful, but chronic disease may require immunosuppressive treatment. Effective and safe vaccines using recombinant outer surface protein A have been developed, but have not been propagated because of fears that autoimmunity might be induced. Nevertheless, new insights into the modes of transmission of B. burgdorferi to the warm-blooded host have been generated by studying the action of these vaccines.

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Clin Diagn Lab Immunol. 2004 Jul;11(4):808-10.
Long-term effects of immunization with recombinant lipoprotein outer surface protein a on serologic test for lyme disease.
Fawcett PT, Rose CD, Maduskuie V.
Immunology Laboratory, Department of Research, A. I. duPont Hospital for Children, 1600 Rockland Rd., Wilmington, DE 19803. pfawcett@nemours.org

Immunization with recombinant lipoprotein outer surface protein A vaccine is known to interfere with some serologic tests for Lyme disease. We tested sera from 152 vaccine recipients by using in-house and commercial Western blot assays and found that vaccination caused interference in up to 25% of recipients and can persist for over 6 years.

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Vector Borne Zoonotic Dis. 2004 Summer;4(2):143-8.
Precipitation and the occurrence of lyme disease in the northeastern United States.
McCabe GJ, Bunnell JE.
US Geological Survey, Denver Federal Center, Colorado 80225, USA. gmccabe@usgs.gov

The occurrence of Lyme disease is a growing concern in the United States, and various studies have been performed to understand the factors related to Lyme disease occurrence. In the United States, Lyme disease has occurred most frequently in the northeastern United States. Positive correlations between the number of cases of Lyme disease reported in the northeastern United States during the 1992-2002 period indicate that late spring/early summer precipitation was a significant climate factor affecting the occurrence of Lyme disease. When late spring/early summer precipitation was greater than average, the occurrence of Lyme disease was above average, possibly due to increased tick activity and survival rate during wet conditions. Temperature did not seem to explain the variability in Lyme disease reports for the northeastern United States.

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MMWR Morb Mortal Wkly Rep. 2004 May 7;53(17):365-9.
Lyme disease—United States, 2001-2002.
Centers for Disease Control and Prevention (CDC).

Lyme disease (LD) is caused by the spirochete Borrelia burgdorferi and is transmitted through the bite of Ixodes spp. ticks. CDC began LD surveillance in 1982, and the Council of State and Territorial Epidemiologists designated LD a nationally notifiable disease in 1991. This report summarizes the analysis of 40,792 cases of LD reported to CDC during 2001-2002. The results of that analysis indicate that annual LD incidence increased 40% during this period. The continued emergence of LD underscores the need for persons in areas where LD is endemic to reduce their risk for infection through integrated pest management, landscaping practices, repellent use, and prompt removal of ticks.

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Am Fam Physician. 2004 Apr 15;69(8):1935-7.
Identifying the vector of Lyme disease.
Lo Re V 3rd, Occi JL, MacGregor RR.
Division of Infectious Diseases, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. vincent.lore@uphs.upenn.edu

Lyme disease is the most common vector-borne illness in the United States. It is caused by the spirochete Borrelia burgdorferi, which is transmitted by the deer tick. Deer ticks have a four-stage life cycle (egg, larva, nymph, and adult), and nymphal ticks transmit B. burgdorferi to humans more frequently than adult ticks. Transmission of this spirochete typically requires a minimum of 24 to 48 hours of tick attachment. Early stages of Lyme disease are characterized by a hallmark rash, erythema migrans. The overall risk of acquiring Lyme disease is low in a person who has a deer tick bite. If erythema migrans develops at the site of the bite, treatment may include doxycycline in persons who are at least eight years of age. Administration of amoxicillin is appropriate for pregnant women or children younger than eight years. For those who are allergic to these medications, cefuroxime axetil may be used.

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Ned Tijdschr Geneeskd. 2004 Apr 3;148(14):659-63.
[Guideline 'Lyme borreliosis']
[Article in Dutch]
Speelman P, de Jongh BM, Wolfs TF, Wittenberg J; Kwaliteitsinstituut voor de Gezondheidszorg (CBO).
Academisch Medisch Centrum/Universiteit van Amsterdam, afd. Infectieziekten, Tropische Geneeskunde & Aids, Amsterdam.

Borrelia burgdorferi is the causative bacterial agent of Lyme borreliosis, a tick-transmitted infectious disease. The Dutch Institute for Health Care Improvement (CBO) has now issued a guideline on 'Lyme borreliosis'. Lyme borreliosis is classified as 'early', 'early disseminated', 'late' or as 'post-infectious complaints and symptoms'. Erythema migrans is the most common manifestation of early Lyme borreliosis. Frequent neurological manifestations of 'early disseminated Lyme borreliosis' include meningoradiculitis, meningitis and peripheral facial palsy, but Lyme carditis and arthritis also occur. Late Lyme borreliosis is characterised by skin abnormalities (acrodermatitis chronica atrophicans), chronic neuroborreliosis or chronic arthritis. Confirmation serology with respect to Borrelia is the most commonly used laboratory technique, but in early Lyme borreliosis the immune response may be absent. In addition, the mere presence of antibodies in the serum is no proof of an active infection with Borrelia and serology may yield false-positive reactions. Doxycycline and ceftriaxone are the most commonly used antibiotics in the various stages of Lyme borreliosis. Lyme borreliosis may be prevented by avoiding high-risk areas, keeping the skin covered as much as possible, and inspection of the skin after possible exposure to remove ticks within 24 hours. Laboratory tests after a tick bite are not recommended, nor is prophylactic treatment with antibiotics.

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Nat Rev Immunol. 2004 Feb;4(2):143-52.
Elucidation of Lyme arthritis.
Steere AC, Glickstein L.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. asteere@partners.org

Before the first description of Lyme arthritis in 1976, patients with this disease were often thought to have juvenile or adult rheumatoid arthritis. It is now known that Lyme arthritis is caused by a tick-borne spirochete that disseminates to joints, where it induces marked pro-inflammatory responses. In most patients, the arthritis resolves with antibiotic treatment. However, in the United States, about 10% of patients with Lyme arthritis develop persistent synovitis, which lasts for months or even several years after the apparent eradication of the spirochete from the joint with antibiotic therapy. The elucidation of Lyme arthritis, from acute infection to chronic synovitis, might help in our understanding not only of this entity, but also of other forms of chronic inflammatory arthritis, including rheumatoid arthritis.

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Expert Rev Vaccines. 2003 Oct;2(5):683-703.
Progress and controversy surrounding vaccines against Lyme disease.
Hanson MS, Edelman R.
MedImmune, Inc., Gaithersburg, MD 20878, USA, currently Consultant, LTS Corporation, Bethesda, MD 20814, USA. drmarkhanson@yahoo.com

Less than 20 years elapsed between the 1982 report of the identification and isolation of Borrelia burgdorferi and the licensure and marketing in the USA of a prophylactic vaccine against this pathogen. However, the manufacturer removed the vaccine from the market under 4 years after its release. The low demand undoubtedly was the result of limited efficacy, need for frequent boosters, the high price of the vaccine, exclusion of children, fear of vaccine-induced musculoskeletal symptoms and litigation surrounding the vaccine. Second-generation polyvalent outer surface protein (Osp)C vaccines may overcome some of these concerns but the precise antigenic components required for efficacy are uncertain. The development of the next generation of Lyme disease vaccines is in its infancy.

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Lancet. 2003 Nov 15;362(9396):1639-47.
Lyme borreliosis.
Stanek G, Strle F.
Department of Hygiene and Medical Microbiology of the University Vienna, 1095 Wien, 15, Kinderspitalgasse, Austria. gerold.stanek@univie.ac.at

Lyme borreliosis is the most common tick-transmitted disease in the northern hemisphere and is caused by spirochaetes of the Borrelia burgdorferi species complex. A complete presentation of the disease is an extremely unusual observation in which a skin lesion results from a tick bite and is followed by heart and nervous system involvement, and later on by arthritis. Late involvement of eye, nervous system, joints, and skin can also occur. The only sign that enables a reliable clinical diagnosis of Lyme borreliosis is erythema migrans. Other features of some diagnostic value are earlobe lymphocytoma, meningoradiculoneuritis (Garin-Bujadoux-Bannwarth syndrome), and acrodermatitis chronica atrophicans. The many other symptoms and signs have little diagnostic value. Microbial or serological confirmation of borrelial infection is needed for all manifestations of the disease except for typical early skin lesions. However, even erythema migrans might not be pathognomonic for Lyme borreliosis, especially in the southern part of the USA where there is no microbiological evidence for infection with the agent. Treatment with antibiotics is beneficial for all stages of Lyme borreliosis, but is most successful early in the course of the illness. Prevention relies mainly on avoiding exposure to tick bites but there is some interest in chemoprophylaxis and also in vaccine development following initial disappointments.

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Lancet Infect Dis. 2003 Aug;3(8):489-500.
Lyme borreliosis.
Hengge UR, Tannapfel A, Tyring SK, Erbel R, Arendt G, Ruzicka T.
Department of Dermatology, Dusseldorf, Germany. ulrich.hengge@uni-duesseldorf.de <ulrich.hengge@uni-duesseldorf.de>

Lyme borreliosis is a multi-organ infection caused by spirochetes of the Borrelia burgdorferi sensu lato group with its species B burgdorferi sensu stricto, Borrelia garinii, and Borrelia afzelii, which are transmitted by ticks of the species Ixodes. Laboratory testing of Lyme borreliosis includes culture, antibody detection using ELISA with whole extracts or recombinant chimeric borrelia proteins, immunoblot, and PCR with different levels of sensitivity and specificity for each test. Common skin manifestations of Lyme borreliosis include erythema migrans, lymphocytoma, and acrodermatitis chronica atrophicans. The last two conditions are usually caused by B garinii and B afzelii, respectively, which are seen more frequently in Europe than in America. Late extracutaneous manifestations of Lyme borreliosis are characterised by carditis, neuroborreliosis, and arthritis. We present evidence-based treatment recommendations for Lyme borreliosis and review the prevention of Lyme borreliosis, including the Lyme vaccines.

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Ann Intern Med. 2003 May 6;138(9):697-704.
Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind,
placebo-controlled trial.
Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, Dornbush R, Singh B, Nadelman RB.
Division of Infectious Diseases, New York Medical College, Room 245, Munger Pavilion, Valhalla, New York 10595, USA.

BACKGROUND: Treatment of patients with early Lyme disease has trended toward longer duration despite the absence of supporting clinical trials. OBJECTIVE: To evaluate different durations of oral doxycycline treatment and the combination of oral doxycycline and a single intravenous dose of ceftriaxone for treatment of patients with early Lyme disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single-center university hospital. PATIENTS: 180 patients with erythema migrans. INTERVENTION: Ten days of oral doxycycline, with or without a single intravenous dose of ceftriaxone, or 20 days of oral doxycycline. MEASUREMENTS: Outcome was based on clinical observations and neurocognitive testing. Efficacy was assessed at 20 days, 3 months, 12 months, and 30 months. RESULTS: At all time points, the complete response rate was similar for the three treatment groups in both on-study and intention-to-treat analyses. In the on-study analysis, the complete response rate at 30 months was 83.9% in the 20-day doxycycline group, 90.3% in the 10-day doxycycline group, and 86.5% in the doxycycline-ceftriaxone group (P > 0.2). The only patient with treatment failure (10-day doxycycline group) developed meningitis on day 18. There were no significant differences in the results of neurocognitive testing among the three treatment groups and a separate control group without Lyme disease. Diarrhea occurred significantly more often in the doxycycline-ceftriaxone group (35%) than in either of the other two groups (P < 0.001). CONCLUSIONS: Extending treatment with doxycycline from 10 to 20 days or adding one dose of ceftriaxone to the beginning of a 10-day course of doxycycline did not enhance therapeutic efficacy in patients with erythema migrans. Regardless of regimen, objective evidence of treatment failure was extremely rare.

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Clin Ther. 2003 Jan;25(1):210-24.
An open-label, nonrandomized, single-center, prospective extension, clinical trial of booster dose schedules to assess the safety profile and immunogenicity of recombinant outer-surface protein A (OspA) Lyme disease vaccine.
Schoen RT, Deshefy-Longhi T, Van-Hoecke C, Buscarino C, Fikrig E.
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA. Robert.Schoen@yale.edu

BACKGROUND: An efficacy trial of an outer-surface protein A (OspA) Lyme disease vaccine demonstrated tolerability and efficacy against laboratory-confirmed Lyme disease after a primary series of 3 doses at 0, 1, and 12 months.OBJECTIVES: This extension of the efficacy study assessed the immunogenicity and tolerability of booster vaccinations administered at 24 and/or 36 months after the first vaccination. METHODS: This open-label, nonrandomized, single-center, prospective extension, clinical trial was conducted in the general community in New Haven, Connecticut, where Lyme disease is endemic. Blood samples (to determine anti-OspA titer) were collected before administration of the booster doses at months 24 and 36, and at 1 and 12 months after each booster dose was administered. Immune response was assessed via total immunoglobulin G (IgG) anti-OspA antibody titers and the proportion of subjects with titers >or=1400 EL.U/mL. Adverse events (AEs) were recorded by the study volunteers on diary cards. RESULTS: A total of 318 volunteers (173 women and 145 men) received at least 1 booster dose of Lyme disease vaccine, administered at 12 or 24 months after the third vaccination of the primary series (months 24 and 36, in relation to the primary series). Eighty-eight subjects of those who received a month-24 booster received a second booster dose at month 36 (12 months after the first booster). Overall, the mean age of the volunteers was 55 years (range, 19 to 73 years). The demographic characteristics of the groups were similar. Most AEs were limited induration and were rated by investigators and subjects as mild to moderate in severity. Administration of I or 2 booster doses did not elicit any patterns of AEs different from those reported in the efficacy trial. After the first booster dose, all volunteers had an anamnestic response and positive test results for total IgG antibody. Geometric mean titers increased at least 12-fold 1 month after the first booster dose at month 24 or 36. More than 96% of volunteers had titers>1400 EL.U/mL and 100% had titers >400 EL.U/mL (minimum seroprotective level) 1 month after the booster dose at month 24 or 36. CONCLUSIONS: All booster doses were well tolerated, and the incidence of AEs did not increase after the second booster dose. The immune response generated after the 3-dose primary series waned; booster doses administered at 12 and/or 24 months after the primary series increased antibody levels above seroprotective levels.

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Rev Neurol (Paris). 2003 Jan;159(1):23-30.
[Lyme borreliosis]
[Article in French]
Tranchant C, Warter JM.
Service des maladies du Systeme Nerveux et du Muscle, Hopitaux Universitaires, Strasbourg.

Lyme disease is a multisystemic disease caused by a spirochete, Borrelia Burgdorferi that is transmitted by ticks. A clinical diagnosis is easy when a tick bite is followed 3 weeks later by erythema migrans, than by involvement of nervous system, joints or heart. In case of neuroborreliosis, serological tests, performed in blood and cerebro-spinal fluid, support the diagnosis and patients recover rapidly with antibacterial treatments. However an accurate diagnosis remains sometimes problematic, especially distinction between a coincidental positive serologic test and a nervous system Lyme borreliosis which require antibiotics. Furthermore, the role of autoimmunity in the pathophysiology of late Lyme disease, antibiotic choice in early disease, duration of treatment, and utility of vaccination are discussed.

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Scand J Infect Dis. 2003;35(2):129-31.
Clinical outcome of erythema migrans after treatment with phenoxymethyl penicillin.
Bennet L, Danell S, Berglund J.
Lyckeby Primary Health Care Centre, Karlskrona, Sweden. louise.bennet@ltblekinge.se

In a 5 y retrospective follow-up study in southern Sweden of 708 adult individuals with erythema migrans as the single manifestation of Lyme borreliosis, the clinical outcome and the antibiotic treatment were studied. 80% were treated with phenoxymethyl penicillin, 15% with doxycycline and 5% with other antibiotics. Phenoxymethyl penicillin and doxycycline were extremely effective: 98 and 94% of the individuals reported complete recovery without complications. Few individuals reported the development of new symptoms following treatment and none developed any late manifestation of Lyme borreliosis during the observation period. Thus, in the area studied the treatment of the early localized manifestation of Lyme borreliosis (erythema migrans) with antibiotics was extremely successful. The current Swedish recommendation to use phenoxymethyl penicillin, when no sign of disseminated infection or coinfection with other tick-borne pathogens is present, seems excellent.

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Wien Klin Wochenschr. 2002 Jul 31;114(13-14):515-23.
Solitary borrelial lymphocytoma in adult patients.
Maraspin V, Cimperman J, Lotric-Furlan S, Ruzic-Sabljic E, Jurca T, Picken RN, Strle F.
University Medical Centre Ljubljana, Department of Infectious Diseases, Ljubljana, Slovenia. vera.maraspin@kclj.si

During the period from 1986 to 2000, 85 adult patients with solitary borrelial lymphocytoma were diagnosed at the Department of Infectious Diseases, University Medical Centre Ljubljana, Slovenia. There were 36 (42.4%) females and 49 (57.6%) males with a median age of 49 (15-74) years. Borrelial lymphocytoma was located on the breast (nipple--areola mammae region) in 68 (80%) patients, on the ear lobe in eight (9.4%), and in other locations in nine (10.6%). A concomitant erythema migrans enabling clinical diagnosis of Lyme borreliosis was registered or reported in 67 (78.8%) patients. Fifteen (17.6%) patients had no accompanying symptoms, 34 (40%) reported local and constitutional symptoms, 23 (27.1%) recounted only local symptoms, and 13 (15.3%) patients had solely constitutional symptoms. Clinical findings indicating early disseminated borrelial infection were observed at the first visit in 12 (14.1%) patients: six (7.1%) had multiple erythema migrans, one had meningitis, one meningoradiculitis and arthritis, one radiculoneuritis and arthritis, one peripheral facial palsy and concomitant meningitis, and two arthritis. In addition, one of the patients with borrelial lymphocytoma on the breast had acrodermatitis chronica atrophicans. A seropositive response to borrelial antigens was found in 30 (35.3%) patients at the initial examination. In 11/46 (23.9%) patients, infection with Borrelia burgdorferi sensu lato was confirmed by isolation of the agent from lymphocytoma tissue. Eight out of nine (88.9%) typed borrelial strains were found to be B. afzelii, and one (11.1%) B. bissettii. Patients were treated with doxycycline, azithromycin, amoxycillin, cefuroxime-axetil, phenoxymethylpenicillin, or ceftriaxone. Median time to complete disappearance of lymphocytoma was 28 days (range 7-270 days) after the institution of antibiotic treatment; disappearance took longer in patients with prolonged duration of the skin lesion prior to treatment. Treatment failure was registered in 11 (12.9%) patients who were later re-treated. The outcome of borrelial infection assessed at the end of a follow-up period of one year was favourable.

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Wien Klin Wochenschr. 2002 Jul 31;114(13-14):498-504.
Solitary erythema migrans in children: comparison of treatment with azithromycin and phenoxymethylpenicillin.
Arnez M, Pleterski-Rigler D, Luznik-Bufon T, Ruzic-Sabljic E, Strle F.
Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia. maja.arnez@kclj.si

OBJECTIVE: To compare clinical effectiveness and side effects of treatment with azithromycin or phenoxymethylpenicillin in children with solitary erythema migrans. METHODS: Consecutive patients younger than 15 years, referred to our institution in 1998 and 1999 with previously untreated typical solitary erythema migrans, were included in this prospective study. Basic demographic features and clinical data were collected by means of a questionnaire. The efficiency of treatment of acute disease, development of later major and/or minor manifestations of Lyme borreliosis and side effects of treatment were surveyed by follow-up visits during the first year. RESULTS: Forty-two patients received azithromycin 20 mg/kg/day for the first day followed by 10 mg/kg/day for a further four days and phenoxymethylpenicillin 100,000 IU/kg/day for 14 days. No differences in demographic and clinical pre-treatment characteristics were present in the two groups, with the exception of the duration of erythema migrans before treatment (3 days in the azithromycin group versus 4 days in the phenoxymethylpenicillin group; p = 0.0320). The clinical course during the post-treatment period revealed no significant differences between the two groups in the duration of EM (3 days versus 4 days; p = 0.2471), the appearance of minor manifestations of Lyme borreliosis (17.5% in the azithromycin group versus 24.4% in the phenoxymethyl-penicillin group; p = 0.6252), or in the emergence of major manifestations of Lyme borreliosis (one patient in each treatment group). One year after antibiotic treatment all patients were asymptomatic. Side effects of treatment were observed in 5.3% of patients treated with azithromycin and in 6% treated with phenoxymethylpenicillin. The appearance of "Herxheimer's reaction" at the beginning of treatment was recorded in 7 out of 42 patients (6%) in each treatment group. CONCLUSIONS: Azithromycin and phenoxymethylpenicillin are equally effective in treatment of children with solitary erythema migrans and have comparable side effects.

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Curr Neurol Neurosci Rep. 2002 Nov;2(6):479-87.
Lyme disease.
Coyle PK.
Department of Neurology, School of Medicine, State University of New York at Stony Brook, HSC, T-12 Room 020, Stony Brook, NY 11794-8121, USA. pcoyle@notes.cc.sunysb.edu

Lyme disease is due to infection with a tick-borne spirochete, Borrelia burgdorferi. Risk for infection is confined to regions that contain the Ixodid tick vector. Characteristic skin, musculoskeletal, cardiac, ocular, and neurologic disorders are associated with the local, early dissemination and late stages of infection. Neurologic involvement can be seen at all stages, and involves both central and peripheral nervous system syndromes. The inability to easily culture B. burgdorferi and the lack of a reliable active infection assay have contributed to controversies in diagnosis and management. Because the vast majority of patients are seropositive, however, antibody testing is helpful to support the diagnosis of Lyme disease. With appropriate antibiotics, most patients do well. This infection provides an important model system to understand how interactions between an organism, vector, and host lead to disease. It also provides a model to study how infectious agents lead to neurologic disease.

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Ann Pharmacother. 2002 Oct;36(10):1590-7.
Treatment of tick-borne diseases.
Donovan BJ, Weber DJ, Rublein JC, Raasch RH.
Infectious Diseases Pharmacotherapy, Department of Pharmacy, University of North Carolina Hospitals, Chapel Hill, NC, USA.

OBJECTIVE: To review the data regarding the pharmacotherapy of Lyme disease, Rocky Mountain spotted fever (RMSF), and the human ehrlichioses. DATA SOURCES: English-language literature was identified via MEDLINE (1966-January 2002) using the keywords Lyme disease, Rocky Mountain spotted fever, and ehrlichiosis. Textbooks and other pertinent resources were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles identified through the data sources above were evaluated and reviewed if pertinent to the objective. DATA SYNTHESIS: Tick-borne diseases are the most common vector-transmitted diseases in North America. Each disease causes significant morbidity and, in the case of RMSF, mortality if patients go untreated. If the disease syndromes are recognized early and treatment is initiated, complications are greatly reduced. Doxycycline is active against each of the causative organisms, simplifying empiric treatment. CONCLUSIONS: Effective pharmacotherapy exists to treat each of these diseases, assuming diagnosis is made quickly. The beta-lactam and tetracycline antibiotics appear to be the most effective therapy for Lyme disease. The tetracyclines, but not the beta-lactams, are effective for RMSF and the human ehrlichioses. Since Borrelia burgdorferi and the human granulocytic ehrlichiosis agent are becoming more common coinfecting pathogens, tetracycline or doxycycline should be considered the drugs of choice for patients from endemic areas where exposure to both pathogens may have occurred. Doxycycline is the preferred agent because of decreased frequency of administration and adverse effects.

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Med Pregl. 2002 May-Jun;55(5-6):207-12.
[Lyme disease--new findings on its physiopathology, diagnosis, therapy and prevention]
[Article in Serbo-Croatian (Roman)]
Vukadinov J, Sevic S, Canak G, Madle-Samardzija N, Turkulov V, Doder R.
Klinicki centar, Klinika za infektivne bolesti, 21000 Novi Sad, Hajduk Veljkova 1-3.

INTRODUCTION: Lyme disease is a tick-borne disease caused by a spirochete Borrelia burgdorferi, which manifests as a multisystem disease of the skin, nervous system, heart and joints. Recently it is the most common vector-borne disease in Yugoslavia. NEW EPIDEMIOLOGICAL STUDIES: New epidemiological studies revealed that ticks can occasionally be infected not only by Borrelia burgdorferi, but also by some other microbes that can cause diseases in humans. Recently discovered the variable major protein-like sequence, antigenic variation of B. burgdorferi B 31 partly explains the ability of this organism to evade an active immune response. A key role in development of clinical symptoms associated with lyme disease belongs to the connection with ability of B. burgdorferi to induce and activate metallopeptidases and fibrinolytic enzymes, leading to extracellular matrix destruction. DIAGNOSIS AND TREATMENT: Diagnosis of Lyme borreliosis is made on the basis of clinical picture, exposure to ticks in endemic areas and serologic confirmation. It seems that polymerase chain reaction has little role in detection of B. burgdorferi in urine, blood, and spinal fluid samples, but it is most useful in evaluating the effectiveness of antibiotic therapy of Lyme arthritis. Infectious Diseases Society of America had prepared new guidelines for selective treatment of Lyme disease. Vaccination is still the best way of prevention for people living in high-risk areas.

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J Am Board Fam Pract. 2002 Jul-Aug;15(4):277-84.
Lyme disease knowledge, beliefs, and practices of New Hampshire primary care physicians.
Magri JM, Johnson MT, Herring TA, Greenblatt JF.
Epidemic Intelligence Service, Division of Applied Public Health Training, Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA, USA.

BACKGROUND: Lyme disease is the most commonly reported vectorborne illness in the United States and is endemic in many counties in the Northeast, including counties in New Hampshire. Previous studies conducted elsewhere on Lyme disease have indicated substantial differences between physician practices and published consensus guidelines for diagnosis and treatment. METHODS: During 1999, we mailed a 21-item questionnaire to 600 randomly selected family practice physicians, internists, and pediatricians in New Hampshire. RESULTS: Respondents answered a median of 10 (76.9%) of 13 knowledge items correctly. Most physicians (73.6%) underestimated the incidence of erythema migrans among Lyme disease patients, and 41.2% would either test or offer treatment to an asymptomatic patient with deer-tick bite. When surveyed, most respondents (72.4%) planned to recommend Lyme disease vaccine to high-risk persons. Approximately one half (44.8%) reported giving empiric antibiotic treatment of Lyme disease solely because of patient concern. CONCLUSIONS: New Hampshire primary care physicians indicated good knowledge about Lyme disease. Lack of awareness about Lyme disease diagnostic criteria, however, could contribute to misdiagnosis through overreliance on laboratory testing. Lyme disease vaccine appeared to be well accepted by physicians, although the vaccine has since been withdrawn from the US market. Both inappropriate management of tick bite and empiric treatment of unsubstantiated Lyme disease diagnoses were common.

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MMW Fortschr Med. 2002 May 30;144(22):33-6.
[Diagnosis and therapy of neuroborreliosis. On the hunt for the "great imitator"]
[Article in German]
Kursawe HK.
Neurologische Abteilung, St. Josefs-Krankenhaus Potsdam. H.Kursawe@Alexius.de

Neurological manifestations are characteristic of stage 2 and stage 3 borreliosis. In stage 2, some 15% of the patients have neurological symptoms expressed as a triad of aseptic meningitis, cranial neuritis and radiculitis. Stage 3--chronic neuroborreliosis affects some 5% of untreated patients. The condition has its onset at the earliest 6 months after the infection, and is characterized by encephalopathic symptoms, such as fatigue, sleep and memory disturbances, and depressive states. Further manifestations of this stage may be Lyme polyneuropathy, in rare cases also progressive borrelia encephalomyelitis and cerebrovascular neuroborreliosis. The treatment of choice is intravenous administration of cephalosporins over 2-4 weeks. The success of treatment should be assessed on the basis of the clinical course rather than on laboratory results. Patience is required in the treatment of the post-Lyme syndrome, characterized by residual symptoms, recurrences or a relapsing course.

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Pediatrics. 2002 Jun;109(6):1173-7.
Comparative study of cefuroxime axetil versus amoxicillin in children with early Lyme disease.
Eppes SC, Childs JA.
Alfred I. DuPont Hospital for Children, Division of Infectious Diseases, Wilmington, DE 19899, USA. seppes@nemours.org

Cefuroxime axetil has been shown to have efficacy comparable to doxycycline in adults with early Lyme disease (LD). Because of toxicity, doxycycline is usually avoided in children. For children who are unable to tolerate amoxicillin, there is currently no proven alternative oral therapy for LD. This randomized, unblinded study compared 2 dosage regimens of cefuroxime axetil (20 mg/kg/d and 30 mg/kg/d) with amoxicillin (50 mg/kg/d), each given for 20 days. Children were enrolled if they were 6 months to 12 years of age, had erythema migrans, and met other eligibility requirements. Serologic testing occurred at entry and after 6 months. Follow-up evaluations for safety, tolerability, and efficacy occurred at 10 and 20 days, 6 months, and 1 year. Forty-three children were randomized (13 in the amoxicillin group, 15 in each cefuroxime axetil group); 39 completed 12 months of follow-up. At the completion of treatment, there was total resolution of erythema migrans in 67% of the amoxicillin group, 92% of the low-dose cefuroxime group, and 87% of the high-dose cefuroxime group, and resolution of constitutional symptoms occurred in 100%, 69%, and 87%, respectively. All patients had a good outcome, with no long-term problems associated with LD. One patient, who was well at the first 2 follow-up visits, was treated with doxycycline because of new constitutional symptoms. Mild diarrhea occurred in a small number of participants in each group (1 patient was diagnosed and treated for Clostridium difficile-associated diarrhea, which occurred after completing the full course of study medication). No hypersensitivity reactions occurred. The number of patients in this trial was not sufficient to demonstrate a statistically significant difference between the 3 groups; however, both amoxicillin and cefuroxime axetil seem to be safe, efficacious treatments for children with early LD.

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Br J Dermatol. 2002 May;146(5):872-6.
Long-term prognosis of patients treated for erythema migrans in France.
Lipsker D, Antoni-Bach N, Hansmann Y, Jaulhac B.
Services de Dermatologie, de Maladies Infectieuses and Laboratoire de Bacteriologie des Hopitaux Universitaires de Strasbourg, 1 place de l'hopital, 67091 Strasbourg cedex, France. dlipsker@noos.fr

BACKGROUND: The long-term prognosis of patients treated for erythema migrans has only rarely been assessed. OBJECTIVES: To evaluate the clinical characteristics and long-term prognosis of patients treated for erythema migrans in the region of Alsace, France. METHODS: In a prospective study, 56 consecutive patients presenting with erythema migrans at the Strasbourg University Hospital between 1995 and 1999 were examined and a Borrelia burgdorferi enzyme immunoassay was performed. Patients were treated with tetracyclines or amoxycillin. Patients were re-examined 6 weeks later and a telephone interview was performed in summer 2000 to evaluate the long-term outcome. RESULTS: There were 25 women and 31 men of mean age 49 years presenting with single (n = 54) or multiple (n = 2) erythema migrans lesions. At the time of diagnosis, 30% of the patients had systemic signs, myalgias or arthralgias and only 36% of 50 patients were seroreactive against B. burgdorferi. None of the 51 patients evaluated at 6 weeks and none of the 37 patients interviewed after a median delay of 3 years had developed complications attributable to Lyme borreliosis. CONCLUSIONS: The prognosis of patients treated for Lyme borreliosis in this part of France is excellent. Therefore, a complete clinical examination is sufficient as an initial evaluation and long-term follow-up is not necessary.

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Med Clin North Am. 2002 Mar;86(2):297-309.
Lyme arthritis.
Massarotti EM.
Tufts University School of Medicine, Itzhak Perlman Family Arthritis Treatment Center, Division of Rheumatology, New England Medical Center, Boston, Massachusetts, USA. emassarotti@lifespan.org

Infection with B. burgdorferi can cause a large joint inflammatory arthritis in patients who have not been treated for early Lyme disease; the knee is the most common joint affected. The diagnosis depends on a history of known exposure to the spirochete, characteristic clinical features, and serologic studies (ELISA and Western blot) confirming exposure to the spirochete. In most patients, antibiotic therapy is curative, but in a smaller percentage of patients, the presence of the HLA-DR beta 1*0401 haplotype can trigger treatment-resistant arthritis, in which antibiotic therapy is ineffective; in these instances, remittive agents, such as hydroxychloroquine and methotrexate, are indicated. Arthroscopic synovectomy may be considered when antibiotic therapy is not curative. Fibromyalgia can follow infection with B. burgdorferi but is unresponsive to antibiotic therapy; it is treated with tricyclic antidepressants and an exercise program. Lyme arthritis is the only chronic inflammatory arthritis in which the specific cause is known and can be cured. As such, it serves as an excellent model with which to study the pathogenesis of more common inflammatory arthritides, such as rheumatoid arthritis.

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Med Clin North Am. 2002 Mar;86(2):285-96.
Cardiac manifestations of Lyme disease.
Pinto DS.
Harvard Medical School, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. Dpinto@caregroup.harvard.edu

Lyme disease is a vector-borne illness that can affect numerous organ systems during the early disseminated phase, including the heart. The clinical course of Lyme carditis is usually benign with most patients recovering completely. In rare instances, death from Lyme carditis has been reported. The cardinal manifestation of Lyme carditis is conduction system disease, which generally is self-limited. Heart block occurs usually at the level of the atrioventricular node but often is unresponsive to atropine sulfate. Temporary pacing may be necessary in more than 30% of patients, but permanent heart block rarely develops. Myocardial and pericardial involvement can occur but generally is mild and self-limited. Diagnosis is made by associating the clinical and historical features of borreliosis, such as previous tick bite, EM, or neurologic involvement, with electrocardiographic abnormalities and symptoms such as chest pain, palpitations, syncope, and dyspnea. Serologic studies and endomyocardial biopsy can support the diagnosis in the correct clinical setting, and MR imaging, echocardiography, and gallium scanning have utility in selected circumstances. No treatment has been shown clearly to attenuate or prevent the development of Lyme carditis, but mild carditis generally is treated with oral antibiotics and severe carditis with intravenous antibiotics in an effort to eradicate the infection and prevent late complications of Lyme disease. There is conflicting evidence regarding the role that B. burgdorferi plays in the development and progression of chronic congestive heart failure. Because of the significant false-positive ELISA rate in this population and the unclear benefit of antibiotic therapy, confirmatory Western blot analysis is recommended. Routine therapy and screening of patients with idiopathic dilated cardiomyopathy is of limited utility and should be reserved for patients with clear history of antecedent Lyme disease or tick bite.

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Front Biosci. 2003 Sep 1;8:S769-82.
Lyme disease and the heart.
Haddad FA, Nadelman RB.
Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla, New York.

Lyme carditis is typically characterized by varying degrees of intermittent atrioventricular block occurring within weeks of infection with Borrelia burgdorferi. Myocarditis and/or pericarditis may occur. Cardiomyopathy has been associated with B. burgdorferi in Europe, but not in the United States. Patients with unexplained atrioventricular block or myopericarditis should be questioned for recent travel to tick-endemic areas, and for a history of erythema migrans rash, "viral-like" illness, aseptic meningitis, cranial nerve palsy, radiculitis, or oligoarthritis. However, the absence of a recognized tick bite or rash does not rule out Lyme disease. The diagnosis of Lyme carditis should be supported by the presence of concurrent erythema migrans, or by positive results of 2-step laboratory testing for antibodies to B. burgdorferi. False positive results may occur, emphasizing the importance of clinical judgment in attributing specific manifestations to B. burgdorferi infection. Carditis generally resolves spontaneously, but antimicrobial therapy can shorten symptom duration and prevent potential cardiac and non-cardiac sequelae. Cardiac manifestations generally resolve spontaneously, but antimicrobial therapy can shorten symptom duration and prevent potential cardiac and non-cardiac sequelae. The prognosis for Lyme carditis is excellent.

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Neurology. 2003 Jun 24;60(12):1923-30.
Study and treatment of post Lyme disease (STOP-LD): A randomized double masked clinical trial.
Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, Dattwyler R, Chandler B.
Departments of Neurology (Drs. Krupp and Coyle, and P. Melville), Preventive Medicine (Drs. Hyman, Grimson, and Ahnn, and B. Chandler), and Medicine (Drs. Dattwyler), Stony Brook University Medical Center, Stony Brook, NY.

OBJECTIVE: To determine whether post Lyme syndrome (PLS) is antibiotic responsive. METHODS: The authors conducted a single-center randomized double-masked placebo-controlled trial on 55 patients with Lyme disease with persistent severe fatigue at least 6 or more months after antibiotic therapy. Patients were randomly assigned to receive 28 days of IV ceftriaxone or placebo. The primary clinical outcomes were improvement in fatigue, defined by a change of 0.7 points or more on an 11-item fatigue questionnaire, and improvement in cognitive function (mental speed), defined by a change of 25% or more on a test of reaction time. The primary laboratory outcome was an experimental measure of CSF infection, outer surface protein A (OspA). Outcome data were collected at the 6-month visit. RESULTS: Patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (rate ratio, 3.5; 95% CI, 1.50 to 8.03; p = 0.001). No beneficial treatment effect was observed for cognitive function or the laboratory measure of persistent infection. Four patients, three of whom were on placebo, had adverse events associated with treatment, which required hospitalization. CONCLUSIONS: Ceftriaxone therapy in patients with PLS with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection in this study. Because fatigue (a nonspecific symptom) was the only outcome that improved and because treatment was associated with adverse events, this study does not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued patients with PLS.

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Med Clin North Am. 2002 Mar;86(2):261-84.
Neurologic aspects of Lyme disease.
Coyle PK, Schutzer SE.
Department of Neurology, School of Medicine, State University of New York, Stony Brook, Stony Brook, New York, USA. pcoyle@notes.cc.sunysb.edu

Lyme disease has emerged as a major infection with frequent neurologic manifestations. These manifestations probably reflect several predominantly indirect pathogenetic mechanisms and involve host, vector, and organism factors. With early diagnosis and appropriate antibiotic treatment, patients do well. Because culture is not reliable, diagnosis has relied on positive serology to document exposure. Serology should improve as second-generation assays become available. Although there is a preventive vaccine based on the lipoprotein OspA, newer vaccines in development may prove more desirable. Lyme disease provides a valuable model to study how infectious pathogens cause neurologic disease.

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Med Clin North Am. 2002 Mar;86(2):239-60.
Erythema migrans.
Edlow JA.
Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. jedlow@caregroup.harvard.edu

EM is the most common manifestation of early Lyme disease, occurring in a high percentage of cases. Because this phase of infection with B. burgdorferi offers an excellent opportunity to treat this potentially systemic infection, front-line physicians must be familiar with its diagnosis. Although much attention has been paid to the classic form--the target lesion or bull's eye--there are variations that are more common. These include uniform coloration, lesions with necrotic or vesicular centers, and lesions with shapes that are not circular or oval. These findings must be interpreted in epidemiologic context. Serologic testing at this phase of the illness should not be done. It is unnecessary and potentially misleading; false-positive and false-negative tests can occur. Diagnosis is clinical. Prompt initiation of appropriate antibiotic therapy for 3 weeks cures most patients at this early stage of the disease. Clinicians should be aware that 15% of patients may be coinfected with a second tick-borne pathogen, which could alter the usual clinical manifestations and the response to treatment.

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Ann Intern Med. 2002 Mar 19;136(6):421-8.
Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans.
Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti DL, Holman MS, Persing DH, Steere AC.
Maine Medical Center, Portland, Maine, USA.

BACKGROUND: Lyme disease has a wide spectrum of clinical manifestations. Diagnosis is usually based on the clinical and serologic picture rather than on microbiological confirmation. OBJECTIVE: To examine the clinical presentation and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. DESIGN: Observational cohort study. SETTING: 31 university-based or clinician-practice sites in 10 endemic states. PARTICIPANTS: 10 936 participants enrolled in a phase III trial of Lyme disease vaccine; 118 participants had erythema migrans in which Borrelia burgdorferi was detected by culture or polymerase chain reaction. MEASUREMENTS: Clinical characteristics and treatment outcome were noted. Skin biopsies of erythema migrans were performed for culture and detection of B. burgdorferi by polymerase chain reaction; serologic responses were determined by Western blot. RESULTS: The 118 patients with microbiologically confirmed erythema migrans presented a median of 3 days after symptom onset. Early erythema migrans commonly had homogeneous or central redness rather than a peripheral erythema with partial central clearing. The most common associated symptoms were low-grade fever, headache, neck stiffness, arthralgia, myalgia, or fatigue. By convalescence, 65% of patients had positive IgM or IgG antibody responses to B. burgdorferi. Most patients responded promptly to antibiotic treatment. CONCLUSIONS: In major endemic areas in the United States, Lyme disease commonly presents as erythema migrans with homogeneous or central redness and nonspecific flu-like symptoms. Clinical outcome is excellent if antibiotic therapy is administered soon after symptom onset.

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Drugs. 2001;61(10):1455-500.
Cefuroxime axetil: an updated review of its use in the management of bacterial infections.
Scott LJ, Ormrod D, Goa KL.
Adis International Limited, Mairangi Bay, Auckland, New Zealand. demail@adis.co.nz

Cefuroxime axetil, a prodrug of the cephalosporin cefuroxime, has proven in vitro antibacterial activity against several gram-positive and gram-negative organisms, including those most frequently associated with various common community-acquired infections. In numerous randomised, controlled trials, 5 to 10 days' treatment with oral cefuroxime axetil (250 or 500 mg twice daily) was an effective treatment in patients with upper (URTI) and lower respiratory tract infections (LRTI) as assessed by clinical and bacteriological criteria. The drug was as effective as several other cephalosporins, quinolones, macrolides and amoxicillin/clavulanic acid. Shorter courses (5 to 10 days') of cefuroxime axetil were at least as effective as a 10 day course. Furthermore, sequential therapy with intravenous cefuroxime (750 mg 2 or 3 times daily for 2 to 5 days) followed by oral cefuroxime axetil (500 mg twice daily for 3 to 8 days) proved an effective treatment in adult patients with community-acquired pneumonia (CAP). This approach provided similar efficacy to intravenous ampicillin/sulbactam followed by oral amoxicillin/clavulanic acid, a full parenteral course of cefuroxime, or intravenous then oral azithromycin or clarithromycin. Additionally, cefuroxime axetil was an effective treatment in patients with genitourinary, skin and soft-tissue infections, and erythema migrans associated with early stage Lyme disease. The drug is well tolerated by adult and paediatric patients, with adverse effects that are consistent with those of other cephalosporins. The majority of adverse events (primarily gastrointestinal disturbances) were mild to moderate in intensity and reversible upon discontinuation of treatment, with very few serious adverse events reported. Conclusions: Cefuroxime axetil is a broad spectrum antibacterial agent with a pharmacokinetic profile that permits convenient twice-daily administration. The drug is an effective and well tolerated treatment in patients with various infections, including otitis media, pharyngitis, sinusitis, CAP and acute exacerbations of chronic bronchitis. Cefuroxime axetil proved effective as a component of intravenous/oral sequential therapy in the treatment of CAP, although there are currently no dosage recommendations available for this regimen in some countries. Cefuroxime axetil may be considered as an empirical therapy for a range of community-acquired infections, including those in which beta-lactamase-producing strains of common respiratory pathogens are identified as the causative organisms. In an era of rapidly emerging bacterial resistance, empirical treatment with bacterial agents, potentially preventing the emergence of bacterial resistance to agents such as cefuroxime axetil may ensure the appropriate use of newer antibacterial agents, potentially preventing the emergence of bacterial resistance to these newer drugs.

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Ann Dermatol Venereol. 2001 May;128(5):627-37.
[Minocycline]
[Article in French]
Bernier C, Dreno B.
Clinique Dermatologique, Hotel-Dieu, Place Alexis Ricordeau, 44093 Nantes Cedex 1.

Minocycline belongs to the second generation class of cyclines. It was synthesized in 1967 and marketed in 1972. Minocycline has an antiinfectious activity with a spectrum similar to that of other cyclines, notably against Chlamydias, Treonema and Proprionibacterium acenes. The antiinflammatory activity is associated with this antiinfectious action is greater than that of first generation cyclines with specifically a modulator effect on epidermal cytokines. The pharmokinetics of minocycline is characterized by an excellent absorption, a long half-life and an important lipophilic property inducing good tissue distribution. Clinical trials of minocycline have mainly been performed in sexually transmissible diseases and in acne, a field where randomized studies are the most frequent. These trials show that the effect of minocycline is not stronger than first generation cyclines or doxycycline, but that the action is quicker than that of tetracycline at the dose of 500 mg a day. Minocycline is also efficient in nocardiasis, mycobacteriosis, leprosy, Lyme disease, pyoderma gangrenosum, autoimmune bullous dermatitis, Carteaud disease, and prurigo. However, the effect of minocycline in these different conditions has always been evaluated in open trials with a small number of patients. The usual side effects of cyclines, i.e. digestive problems, fungal infections, are less frequent than with first generation cyclines. No photosensitivity has been demonstrated although pigmentations have been described. Dizziness is a specific side effect of minocycline. Furthermore, rare but severe side effects have been reported, including hypersensitivity syndrome, autoimmune hepatitis, and lupus. Regular indications for minocycline in dermatology are acne and three sexually transmissible diseases (mycoplasm, chlamydia, treponema). Proposed dosage is 100 mg per day in sexually transmissible disease with a reduction to 50 mg per day after 15 days in acne.

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Scand J Infect Dis. 2001;33(4):259-62.
Follow-up of patients treated with oral doxycycline for Lyme neuroborreliosis.
Karkkonen K, Stiernstedt SH, Karlsson M.
Department of Infectious Diseases, Karolinska Institutet, Huddinge, Sweden.

The clinical outcome for 69 patients treated with oral doxycycline for Lyme neuroborreliosis was studied retrospectively. The clinical follow-up time was 14 d to 2 y (median 7 months). All patients improved during and after treatment. A complete recovery was seen in 56 patients by 14 d to 9 months (median 6 weeks) after therapy, while 13 patients (19%) still had persistent sequelae 1 y after antibiotic treatment. Six patients were retreated because of new or persistent symptoms, but in no patient was a treatment failure proven. A questionnaire was sent to each patient, asking for time to recovery, sequelae and relapse of symptoms. No patient had experienced relapse of symptoms associated with Lyme neuroborreliosis when answering the questionnaire 2-9 y after treatment. Oral doxycycline seems to be an effective, convenient and inexpensive alternative for the treatment of Lyme neuroborreliosis.

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Infect Dis Clin North Am. 2001 Mar;15(1):171-87.
Lyme vaccine: issues and controversies.
Rahn DW.
Department of Clinical Affairs, Medical College of Georgia, Augusta, Georgia, USA.

The development of an effective vaccine for Lyme disease represents a major advance in the control of the most prevalent vector-borne disease in the United States. It has a definite place in the total approach to control of this disease. Its use should be restricted to individuals who are at moderate to high risk of exposure to infected vector ticks. Vaccinated individuals should not be complacent about other personal protection measures, because the vaccine is not uniformly effective and protective antibody levels decay rapidly. Booster doses will be necessary, but the intervals have not yet been determined. There is a theoretical concern about the possible induction of inflammatory arthritis through an autoimmune mechanism, but there is no evidence that this condition has clinical relevance. The impact of the current lawsuits on vaccine recommendations and use remains to be determined. Continued surveillance for rare long-term side effects should address the medical risk issue. Alternative primary vaccine administration schedules are currently under study, and could lead to regimens permitting achievement of protective immunity in 6 months or less. Vaccine is not approved for use in children under the age of 15 years.

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