SeminarLyme borreliosis
Section snippets
Frequency
Although Lyme borreliosis is the most commonly reported tick-transmitted disease in the northern hemisphere, few data are available about its actual frequency in several regions. In the USA, the disease has been reportable on a standardised basis since 1991.7 Cases were reported from 45 states with an overall incidence of six per 100 000 population, amounting to 98 in Connecticut. In the European Union the list of reportable communicable diseases is still in preparation, but Lyme borreliosis is
Causative agents
The agents of Lyme borreliosis are borrelia, bacteria of the spirochaete family, which are grouped in the Borrelia burgdorferi sensu lato species complex and further divided into at least 11 different genomic species (table 1), including the human pathogens Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii, and possibly Borrelia bissettii.13 Borrelia are thin, elongated, motile bacteria with a fragile, fluid outer membrane surrounding the protoplasmic cylinder.14 In the
Animal reservoir and vectors
Borrelia can survive and multiply in vertebrate reservoirs, from which they are taken up by ticks.21 In Europe small mammals such as mice and voles provide reservoirs for B afzelii, B burgdorferi sensu stricto, and B garinii serotype 4, and birds are resevoirs for B garinii and B valaisiana.21, 22 Rodents and birds also form the reservoir for B burgdorferi sensu stricto in North America.23
Distribution of Lyme borreliosis in the northern hemisphere is tied to the activity of the vector ticks of
Pathogenesis
Borrelia are highly motile and invasive, and localise in selected tissues. They spread through tissues and can directly transcytose endothelial layers.28 Borrelia facilitate invasion by binding host-derived plasmin. In vitro, they can also bind integrins, decorin, and glycosaminoglycans. Complement activation and serum resistance might also have a role in the pathogenesis.29, 30, 31 Lipoproteins, expressed during infection, activate several cell types—including macrophages, endothelial cells,
Clinical characteristics and diagnosis
When diagnosing Lyme borreliosis one should remember that there is no disease without signs or symptoms, and thus there is no diagnosis in the absence of clinical manifestations. Infection alone may not produce clinical signs. Clinical signs and symptoms form a basis for the recognition of the disease, and good knowledge of clinical features is important for diagnosing Lyme borreliosis; however these features differ somewhat in the USA and Europe. It is tempting to assess and interpret European
Skin
Skin is the most frequently affected tissue in Lyme borreliosis (figure 1). Erythema migrans, borrelial lymphocytoma (formerly lymphadenosis benigna cutis), and acrodermatitis chronica atrophicans are manifestations of Lyme borreliosis38, 42, 43 that were well known as distinct skin entities long before the discovery of the causative agents.44, 45, 46 Borrelial lymphocytoma and acrodermatitis chronica atrophicans are almost never seen in the USA, probably because of a firm association of these
Nervous system
Neuroborreliosis can arise at any time during the course of Lyme borreliosis. Early neuroborreliosis typically features aseptic meningitis, and involvement of cranial and peripheral nerves.59, 60 Diagnosis is not straightforward in the absence of one or more of these features.38, 43, 60 Usually, the most pronounced clinical symptom is pain as a result of radiculoneuritis. Patients have severe pain, usually in the thoracic or abdominal region, which is often beltlike and most pronounced during
Lyme carditis
Lyme carditis is characterised by changing atrioventricular blocks as a result of conduction disturbances.43, 60, 66 The course is usually favourable. In patients treated with antibiotics, and even in those who are not, heart-related symptoms and electrocardiogram abnormalities usually disappear within 3–6 weeks.67, 69, 70 Admission to hospital and permanent ECG surveillance are needed in patients who have degree I atrioventricular block with PQ interval longer than 0–30 s, degree II or III
Joints
Lyme arthritis usually consists of intermittent attacks of inflammation of one or more joints. It is the most frequent clinical sign of disseminated Lyme borreliosis in the USA,43 and emerges in 70% of patients with untreated erythema migrans.72 In Europe, patients with Lyme arthritis seem to be less common than in the USA. Joint involvement is usually asymmetrical. Onset of arthritis is acute, with effusion and warm but normally-coloured skin.43 The condition is frequently monoarticular or
Eye
Eye problems in Lyme borreliosis seem to be very rare and are usually associated with other signs of the disease.75, 76 Eyes can be affected primarily as a result of the inflammation of eye tissue such as conjunctivitis, keratitis, iridocyclitis, retinal vasculitis, chorioiditis, and optic neuropathy (extremely rarely episcleritis, panuveitis, panophthalmitis); or secondarily as a result of extraocular manifestations of Lyme borreliosis such as pareses of cranial nerves and orbital myositis.75,
Other rare manifestations
Case reports of patients with myositis, osteomyelitis, diffuse fasciitis, eosinophilic fasciitis, and panniculitis, have been interpreted as manifestations of Lyme borreliosis.43, 79, 80 Most investigators believe that borrelial infection does not have a direct causative association with fibromyalgia;38, 81 however, fibromyalgia seems to be triggered by infection with B burgdorferi sensu lato.81 Borrelial isolation has been reported from lesional tissue of patients with granuloma annulare,
Non-specific symptoms
Some patients with early and late forms of Lyme borreliosis report several non-specific complaints such as malaise, fatigue, nervousness, mild to moderate mental alteration, depression, headache, myalgia, and arthralgia. B burgdorferi sensu lato can sometimes trigger musculoskeletal, neurocognitive, or fatigue symptoms, but this occurrence is unusual, and these symptoms do not differ from those triggered by some other infections or by stressful physical or emotional events.38, 85
Microbiological diagnosis
Microbial or serological confirmation of infection is needed for all manifestations of Lyme borreliosis except for typical early skin lesions. Ideally, detection of the causative agent by culture or by amplification of specific nucleic acid sequences from lesional skin, other tissue, cerebrospinal fluid, synovial fluid, or blood would prove the association. However, direct detection is most successful in early skin manifestations, which are usually identified clinically.86 In neuroborreliosis,
Treatment
Treatment with antibiotics is beneficial for all clinical manifestations of Lyme borreliosis (table 3). However, such therapy is most effective early in the course of the illness.6 Only antibiotics that have been shown to have in-vitro activity against borrelia and were effective in clinical studies should be used. The result of treatment depends not only on the location, extent, and duration of clinical manifestations but also on several other factors including the choice of antibiotic,
Early localised disease
Patients with solitary erythema migrans lesions and borrelial lymphocytoma are treated with oral antibiotics. Parenteral therapy with ceftriaxone or penicillin G should be used only in those with multiple erythema migrans lesions, although recent findings in the USA suggest that doxycycline is as effective as ceftriaxone in such patients.96 Pregnant women97 and immunodeficient patients98 with erythema migrans might also benefit from parenteral treatment, but there are not enough data to confirm
Early disseminated and late disease
Nervous system involvement and severe Lyme carditis are usually treated with ceftriaxone or penicillin G intravenously for 2-3 weeks and only exceptionally orally with doxycycline. For the treatment of acrodermatitis chronica atrophicans and arthritis doxycycline, amoxicillin, or ceftriaxone are recommended.
Asymptomatic but seropositive individuals
No reliable data support the use of antibiotics in people who are seropositive for borrelia but have no clinical signs and symptoms of Lyme borreliosis. Asymptomatic seropositivity may often occur in people from endemic areas. Although no studies have been done in such individuals, they might later develop manifestations of the infection, and in the USA doxycycline is sometimes given to individuals with asymptomatic seropositivity in an effort to prevent this happening. In Europe, the
Post-treatment chronic disease
Some patients treated with standard courses of antibiotics for established acute Lyme borreliosis recover only partly and can have ongoing long-lasting symptoms such as persistent fatigue, myalgias, arthralgias, paraesthesias or dysaesthesias, or memory and mood disturbances. This syndrome is called post-treatment chronic Lyme borreliosis. Many such patients have been treated with repeated courses of antibiotics for weeks, months, or even years. Results from the USA have shown that treatment of
Treatment failure
One of several potential reasons for antibiotic treatment failure is persistence of borrelia in tissues. Clinical and experimental data show that borrelia can remain in tissues even after recommended treatment34, 101, 102 but the precise magnitude of this problem is difficult to assess. However, microbiological evidence of treatment failure after recommended courses of antibiotic therapy has been quite rare. Persistence of symptoms after treatment should not be equated with microbiological
Prevention
Recommendations for avoidance of infected ticks are important but mostly impractical. Prophylactic antibiotic treatment within 72 h of a tick bite with one dose of 200 mg of doxycycline has been shown to prevent Lyme borreliosis in 87% of individuals.105 Consequently, experts at the Centers for Disease Control and Prevention in the USA recommend—among other public health strategies to prevent Lyme disease in communities—to “encourage prophylactic treatment of bites from deer ticks under certain
Tick removal
Ideally, an attached tick should be removed as soon as possible with forceps, grasping as close as possible next to the skin and then carefully pulling it out. The site of the bite could then be disinfected. Medical care should be sought only exceptionally, for example if the tick is attached on a skin area which is difficult to reach or where it is very sensitive (figure 2). Sometimes a tick needs to be removed with the aid of a magnifying lens and surgical equipment. Application of oil,
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