Lyme borreliosis A69.2

Authors: Prof. Dr. med. Peter Altmeyer, Dr. med. Rupert Florian

Our authors

Last updated on: 29.10.2020

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Synonym(s)

Dermatoborreliosis; Erythema migrans disease; Lyme borreliosis; Lyme disease; Lyme disease chronic; Neuroborreliosis; Tick-borne Lyme disease

Definition
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Lyme disease" includes all clinical manifestations of human beings caused by infections with B. burgdorferi s.l. (see below Borrelia bacteria) according to the definition made in 1985 in Vienna at the "Second International Symposium on Lyme Disease and Related Disorders". According to this, Lyme disease in humans is a multisystemic spirochetosis, which can progress both as a mild local infection and as a stadium-like chronic multisystemic spirochetosis. Lyme borreliosis is the most common tick-borne infectious disease. The causative agent is transmitted by ticks(Ixodes ricinus, the common wood tick).

Pathogen
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  • Borrelia burgdorferi (see below Borrelia burgdorferi): thread-like, winding, lively moving spirochetes. Carriers are ticks (Ixodes ricinus, I. dammini and others), which are ubiquitous in Central, Eastern and Northern Europe and America, rarely also insects, e.g. Stomoxys calcitrans.
  • About 5-40% of the ticks are infected with Borrelia, with adult ticks being infected to about 20%, nymphs to 10% and larvae to about 1%. Diaplacental infection is possible.
  • In Europe 5 pathogenic species of B. burgdorferi have been described so far:
    • B. afzelii
    • B. garinii
    • B. bavariensis
    • B. burgdorferi sensu stricto
    • B. spielmanii
  • Borrelia burgdorferi sensu lato is transmitted in Europe by tick bites. In the USA only B. burgdorferi sensu stricto is observed.

Occurrence/Epidemiology
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Most common tick-borne disease in Europe and North America. About 5-35% of ticks are infected with Borrelia bacteria. In Europe all 3 groups of Borrelia occur. Furthermore on the west and east coast of the USA. Borrelia infections also occur in China.

Incidence: There are only rough estimates of the incidence of human Lyme disease in Germany, as up to now only a few federal states (Berlin, Brandenburg, Mecklenburg-Western Pomerania, Rhineland-Palatinate, Saarland, Saxony, Saxony-Anhalt, Thuringia) are obliged to notify the authorities. Notifiable manifestations of Lyme disease are the erythema migrans, early neuroborreliosis and acute Lyme arthritis.

In 2009, the annual incidence in the new federal states was 34.7 notifiable cases per 100,000 inhabitants. Results from two population-based prospective cohort studies in Southern Germany showed annual incidences of between 111 and 260 cases per 100,000 inhabitants. The number of new cases per year in Germany is estimated at 50,000 to 100,000.

On average, adult ticks are infected to 20%, nymphs to 10% and larvae to only about 1%. After a tick bite, 1.5-6% of those affected can be expected to be infected (seroconversion) and 0.3-1.5% can expect a manifest disease. The risk of infection is greatest from the end of May to the end of July; infections in autumn or on warm winter days are less frequent.

Manifestation
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All age groups are affected.

Clinical features
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Classification into 3 stages, where each stage can represent the initial manifestation of the disease and stages can be skipped (see Table 1):

  • Stage I (localized early infection): The main symptom is the erythema chronicum migrans. Possibly accompanying: regional swelling of the lymph nodes, mild general symptoms (fever, fatigue, headache). In this stage of the disease the borrelia serology is mostly negative. The clinical findings are diagnostic.
  • Stage II (disseminated early infection; 6-8 weeks after the tick bite). Often no clinical symptoms):
    • Non-specific exanthema, cheek erythema, erythema nodosum, arthralgia, myalgia, myo-/pericarditis, recurrent hepatitis, conjunctivitis, possibly panophthalmitis, lymph node and spleen swelling. Under certain circumstances severe feeling of illness.
    • Lymphadenosis cutis benigna (lymphocytoma)
    • Early neuroborreliosis: Meningopolyneuritis Garin-Bujadoux-Bannwarth (severe nocturnal headaches, unilateral radiculitis with painful paralysis, possibly discrete encephalitis)
    • The (rare) multiple occurrence of the clinically classic "erythema chronicum migrans" is to be seen as a cutaneous sign of the dissemination of the Borrelia infection. More often, in the context of disseminated early infection, large, homogeneously bright red, sharply defined, less symptomatic circular or oval erythema are present; not infrequently, they are also only discreetly perceptible or only visible when warm. In children the face is usually also affected (differential diagnosis!).
  • Stage III (late infection with organ manifestation): In this stage neurological symptoms in the form of a Bannwarth syndrome occur in Europe. In the USA Lyme arthritis is more frequently observed. Stage III is always accompanied by a positive borreliosis serology. A serological negative result excludes the disease!
    • Clinical-dermatological leading symptom of stage III in Europe is acrodermatitis chronica atrophicans (for clinic and differential diagnosis see there).
    • Rarely a nodular panniculitis is observed as a hyperergic reaction to a Borrelia infection.
    • Lyme arthritis is characterized by a typical joint attack pattern with mono- or oligoarthritis
    • A double infection with the early summer meningoencephalitis virus is very rare. Clinical sign is the picture of "Progressive Encephalomyelitis", similar to Encephalomyelitis disseminata (Multiple Sclerosis).

Post Lyme disease: Even after healing of the Borrelia typical HV by an adequate antibiotic therapy a general feeling of illness with muscle and joint pain can persist for months.

Notice! Lyme disease does not have to go through every stage, but can skip a stage or become clinically manifest only with stage II or III!

Laboratory
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  • Antibodies can be detected in 50% of patients in the first 2 weeks after infection, after > 4 weeks in 80% of patients. Serological parameters cannot distinguish between an active and a past infection (antibodies remain for months to years even after adequately treated infection).
  • The guidelines of the microbiological quality standards (MiQ = acronym for "Quality standards in microbiological-infectiological diagnostics") recommend the detection of separate IgG and IgM antibodies with a sensitive ELISA and, in case of positivity, analysis with a specific immunoblot.
  • Due to the diagnostic gap of 2-5 weeks for IgM and 2-3 months for IgG, a detection of Borrelia antigens by PCR from infected skin material is possible.
    • Experimental: Attempt to culture the pathogen from bioptic material (Barbour-Stoenner-Kelly medium in microaerophilic environment at a temperature of 33 °C).

      IgM Western blot positive for detection of 1 or more bands of: p17, OspC, p39,p41
      IgG Western Blot

      positive for detection of 2 or more bands of: p14, p17, OspC, p30, p39, p43, p58, p83/100

      and detection of 1 or more bands of: dpbA (osp17), p17b, p21, OspC, p58, p30, p39, p43, p83/100 (Pbi, Borrelia garinii)

  • The interpretation of the findings is based on the fact that the antibody prevalence of the normal population is about 1% in infants and >25% in persons >60 years of age.
  • Neuroborreliosis: For the detection of neuroborreliosis the determination of the CSF-serum-index has a high diagnostic value. It is determined whether the CSF antibody (intrathecal formed AK) is produced against Borrelia bacteria. In connection with a lymphocytic pleocytosis (usually the leukocyte count is < 1000/ul, in case of clear lymphocytosis), protein elevation (1 g/l and more) and barrier disorder, the diagnosis can be secured in most cases. Sometimes AK is already found when the serum antibody test is still negative or is still in the borderline range.

Histology
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Diagnosis
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The clinical picture is in many cases diagnostically groundbreaking for dermatological clinical pictures. Also important: medical history (often positive regarding tick bite ). Proof of infection by positive Borrelia serology; if necessary biopsy with detection of the Borrelia antigen by PCR.

Differential diagnosis
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Early Infection:

Disseminated early infection:

  • Erythema anulare centrifugum. Multiple, partly anular, partly polycyclic, slowly centrifugally growing, typically surface smooth, little or no itching plaques. The palpation is almost pathognomonic: with a rough border wall. Histology is often characteristic. In this phase of Lyme disease a positive serology is to be expected.
  • Drug exanthema, maculo-papular: Serological evidence of Borrelia infection can always be provided in this phase of infection.
  • In case of facial erythema in children: Erythema infectiosum: Acute clinical picture with butterfly-shaped redness and swelling of the cheeks (in 75% of the patients: slap face; slapped cheek appearance).

Late infection of the skin

Complication(s)
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Development of cutaneous B-cell lymphomas has been described in individual cases.

Therapy
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Stage I:

  • In case of localized early infection (erythema chronicum migrans) oral doxycycline therapy (2x100mg/day p.o. or 200mg 1x/day p.o.) over 14 days. A higher dosage is not necessary.
  • Alternative: Amoxicillin (e.g. Amoxicillin ratiopharm) 3 times/day 500 (-750) mg p.o. over 14 days
  • Alternatively: Cefuroxime (e.g. Cefuhexal) 2 times/day 500 mg p.o. for 14 days.
  • Alternatively: Azithromycin 2x250mg p.o. for 10 days.
  • children:
    • Amoxicillin 50 mg/kg bw/day p.o. divided into 3 daily doses over 14 days
    • Alternatively: Cefuroxime (e.g. Cefuhexal) 20-30 mg/kg bw p.o. divided into 2 daily doses over 14 days.
    • From the 9th year of life onwards Doxycyclin (e.g. Doxycyclin AL) 2 times/day 100 mg p.o. or 4 mg/kg bw/day over 14 days. Doxycycline is contraindicated in children <8 years of age.

Stage II:

  • Doxycycline once/day 200 mg p.o. for 21 days
  • Alternative: Amoxicillin 3 times/day 750 mg p.o. over 21 days
  • Alternative: Cefuroxime 2x500mg over 21 days
  • Alternatively: Ceftriaxone (e.g. Rocephin, Ceftriaxon® ratiopharm) 1 time / day 2 g i.v. over 21 days.
  • Mild manifestations of stage II should be treated orally over 2 weeks, this also applies to children.
  • Infestation of the central nervous system:
    • In this constellation, the systemic application of cephalosporins such as ceftriaxone, e.g. Rocephin® once/day 2 g i.v. over 21 days, is to be preferred in any case. The antibiotic cycles should be repeated in 3-month intervals depending on the clinic and last at least 14 days due to the generation times of the Borrelia bacteria.
      • Children:
        • Ceftriaxone (e.g. Rocephin, Ceftriaxon ratiopharm) 50-100 mg/kg bw/day i.v. for 14 days.
        • Alternatively: Cefotaxim 200 mg/kg bw/day, max. 3 times/day 2 g i.v. over 14 days (regarding therapy repetitions see above). Benzylpenicillin 500,000 IU/kg bw/day, max. 10 million IU/day, 4-6 ED i.v. over days.
        • From age > 9 years: Doxycycline (e.g. Doxycycline AL) 2 times/day 100 mg p.o. or 4 mg/kg bw/day for 14 days.

Stage III: The duration of a therapy cycle should last 3 to a maximum of 4 weeks. Acrodermatitis chronica atrophicans and Borrelia arthritis can be treated primarily with an oral antibiotic.

  • Doxycycline once/day 200 mg p.o. for 21 days
  • Alternatively: Amoxicillin 3 times/day 750 mg p.o. over 21 days.
  • Alternative: In case of insufficient clinical response, recurrence or complete therapy failure, therapy should be switched to IV treatment, e.g. Ceftriaxone once/day 2 g IV (alternative: Cefotaxime 3 times/day 2 g IV) for 21 days or Penicillin G 4 times/day 5 Mega IV for 21 days.
  • Borrelia carditis: Analogous to clinical stage II.
  • Borrelia arthritis: Analogous to clinical stage II.
  • Notice! Acrodermatitis chronica atrophicans: The activity of the process should be controlled clinically and histologically! Antibody titre controls are not very meaningful for the course of the healing process, therefore it is better to use a Borrelia PCR for this purpose. Skin atrophies are reversible only to a small extent.

    • In children and during pregnancy:
      • Amoxicillin (e.g. Amoxicillin ratiopharm®) 50 mg/kg bw/day p.o. in 3 ED
      • Alternative: Ceftriaxone (e.g. Rocephin®) 20-80 mg/kg bw/day i.v.
      • Alternative: Erythromycin (e.g. Erythro-Hefa® juice) 3 times/day 100-500 mg p.o.
      • Alternative: Clarithromycin (e.g. Klacid®) 15 mg/day/kg bw over 7-10 days.

For immunocompromised patients: Therapy recommendations in the individual stages remain unchanged. Pregnancy:

  • In case of erythema chronicum migrans: Amoxicillin (3 times/day 500 mg p.o. for 2-3 weeks), in case of strict indication cefuroxime 2 times/day 500 mg p.o. for 2-3 weeks); in case of beta-lactam allergy azithromycin is recommended (2 times/day 250 mg p.o. for 2-5 days). Penicillin V is also an alternative.

Post infectious Lyme disease:

  • These post-infectious "rheumatoid" complaints are consistently treated antiphlogistically.

Progression/forecast
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Cheap. Most symptoms are self-limiting. Different course of the disease in Europe and North America. Spontaneous healing in stage 1 (erythema chronicum migrans as sole symptom) is much more frequent in Europe than in the USA, where organ involvement is more prevalent. Typical manifestation of stage 3 of the disease is acrodermatitis chronica atrophicans in Europe and lyme arthritis in North America.

Even after the healing of the skin lesions typical for Borrelia bacteria by an antibiotic therapy carried out lege artis, patients often complain about a general feeling of weakness and illness with muscle and joint complaints for months. These unspecific symptoms are called "postinfectious syndrome". The term "chronic Lyme disease" is misleading for this clinical picture. There are no indications for a pathogen persistence. An antibiotic therapy is not necessary. Instead, long-term antiphlogistic therapy is necessary.

Prophylaxis
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Avoid undergrowth and tall grass in mild weather, wear closed, light-coloured clothing and sturdy shoes. Tuck trouser legs into socks. Rub repellents into legs and arms (effective up to 4 hours). Inspect the entire body after exposure.

In case of tick bite with tick still present: remove the tick, use thin, firm tweezers, grasp the tick as close as possible to the bite tools and pull it out. The body of the tick should not be squashed or covered with oil or glue to avoid increased secretion of the pathogen-containing saliva.

Lyme borreliosis: The earlier the tick is removed, the less likely it is to transmit the pathogen (from 12 hours after the sting). A general prophylactic intake of antibiotics is not recommended.

A 10% azithromycin gel applied several times every 12 hours at the latest 3 days after the bite can prevent an infection. In a larger study, however, a significance for clinical efficacy could not be established (Schwameis M et al. 2016).

TBE: Vaccination during stay (e.g. holidays) in the endemic area.

Tables
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Stages and clinical manifestations of Lyme borreliosis

Stadium

Incubation period

Skin

Nervous System

Organ Systems

Locomotor system

General symptoms

I

days - weeks

Erythema chronicum migrans, ring-shaped erythema

Meningism

Splenomegaly, Hepatosplenomegaly

Myalgias, Arthralgias

swelling of lymph nodes, fever
, fatigue, nausea

II

weeks - months

Maculo-papular exanthema, lymphocytoma, diffuse erythema

Meningitis, neuritis, radiculitis
(Banwarth syndrome
)

myopericarditis, AV block, pancarditis, eye involvement, hepatitis, microproteinuria, microhaematuria, respiratory tract infections

Arthritis, myalgia, myositis, migratory pain in the musculoskeletal system, osteomyelitis, panniculitis

Severe feeling of illness, swelling of lymph nodes

III

months - years

Acrodermatitischronica
atrophicans, Pseudoscleroderma

Chronic encephalomyelitis, spastic parapareses, ataxic gait, mental disorders

Chronic arthritis, periostitis, arthropathy

Lassitude

Note(s)
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  • The risk of infection after a tick bite can be estimated more accurately by examining the tick for B. burgdorferi (PCR diagnostics). The prophylactic administration of antibiotics in a given case can prevent diseases and save the health care system considerable costs.
  • It is discussed whether an infection with Borrelia burgdorferi plays a pathogenetic role in atrophodermia idiopathica et progressiva. In a study with 17 volunteers 53% IgG antibodies against Borrelia burgdorferi could be detected.
  • After infection and adequate antibiotic treatment of Lyme disease, unspecific symptoms such as impaired performance, fatigue and impaired concentration are often reported. This complex of symptoms is described as post-lymphic syndrome. Whether a new antibiotic therapy cycle should then take place is still open at present.
  • Infection during pregnancy: In some larger epidemiological studies (35,000 pregnant women; 1500 infants and children) no increased risk of malformations, prematurity, fruit death could be proven.
  • Long-term administration of Ceftriaxone is associated with the risk of pseudomembranous colitis caused by Clostridium difficile.
  • A Borrelia infection does not leave a permanent immunity. Reinfections are possible!
  • In a meta-analytical review (19 studies with 2532 patients), no differences in the efficiency of the individual antibiotics (amoxicillin/ doxycycline; cefurroxime axetil; ceftriaxone; azithromycin, phenoxymethylpenicillin, minocycline) could be found. There were also no significant differences in the side effect profile (Torbahn G et al. 2018).

Literature
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  1. Aberer E et al (1988) Neuroborreliosis in morphea and lichen sclerosus et atrophicus. J Am Acad Dermatol 19: 820-825
  2. Bransfield R, Brand S, Sherr V (2001) Treatment of patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345: 1424-1425
  3. Furst B et al (2006) The impact of immunosuppression on erythema migrans. A retrospective study of clinical presentation, response to treatment and production of Borrelia antibodies in 33 patients. Clin Exp Dermatol 31: 509-514
  4. Hofmann H (2012) Variability of cutaneous Lyme disease. dermatologist 63: 381-389
  5. Core A (2011) Tick salvia represses innate immunity and cutaneous inflammation in a murine model of lyme disease. Vector Borne Zooonotic Dis 11: 1343-1350
  6. Logiudice K et al (2003) The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk. Proc Natl Acad Sci USA 100: 567-571
  7. Nau R et al (2009) Lyme disease - current state of knowledge. Dt Medical Journal 106: 72-81
  8. Reed KD (2002) Laboratory testing for Lyme disease: possibilities and practicalities. J Clin Microbiol 40: 319-324
  9. Smith RP et al (2002) Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med 136: 421-428
  10. Schwameis M et al (2016) Topical azithromycin treatment for the prevention of Lyme disease: Results from randomised, placebo-controlled clinical trials. Lancet Infect Dis. doi.org/10.1016/1473-3099
  11. Torbahn G et al (2018) Efficacy and Safety of Antibiotic Therapy in Early Cutaneous Lyme Borreliosis: ANetwork
    Meta-analysis. JAMA Dermatol 154:1292-1303.

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