Lyme borreliosis is the most common bite infection in Europe. It is characterised by great clinical, but also bacteriological and antigenic, polymorphism.
Lyme borreliosis is a non-contagious bacterial infection caused by a spirochete, Borrelia burgdorferi sensu lato, which is transmitted to humans by Ixodes tick bites. The disease is present wherever vector agents exist: in Europe (Ixodes ricinus), the USA and Central America (I. scapularis), Asia (I. persulcatis), and in the western USA (I. pacificus).
Ixodes live in wetlands and deciduous forests. These creatures are most active in the spring and early autumn. Humans are an incidental host. The bacterium is present in the tick’s intestine, attached by an OSP A protein, and is transmitted after passing through the salivary glands. The bacterium then diffuses through the skin. The Borrelia species encountered in human pathology are B. afzelii (the main species in France), B. burgdorferi (the main species in the USA) and B. garinii.
The rate of infestation of ticks by Borrelia ranges from 3-30%, with large regional disparities. After being bitten by an infected tick, the risk of transmission (seroconversion) is 10%.
Diagnosis
Diagnosis is based on a number of factors, including the risk of exposure, and clinical and biological findings.
– Risk of exposure
The diagnosis cannot be eliminated purely on the basis that the patient does not remember being written. Populations at risk include forestry professionals and, increasingly so, outdoor leisure enthusiasts, gardeners, campers, hunters, and walkers. High risk regions are mainly Alsace-Lorraine (+++) and Limousin; the risk period is from April to October/November.
– Clinical features
The disease mainly manifests itself on the skin, the nervous system and the joints, and evolves through three phases:
* Early localised form: Erythema migrans (EM)
* Early disseminated forms of Lyme borreliosis (< 6 months after the onset of the first symptoms): EM with multiple locations, borrelial lymphocytoma, early neurological involvement, joint, cardiac and ophthalmological forms.
* Late disseminated forms of Lyme borreliosis (> 6 months after onset of symptoms): Chronic atrophic acrodermatitis (CAA), late neurological involvement, psychiatric disorders.
The majority of infections (92-95%) evolve in an abortive mode (simple seroconversion). In 5-8% of cases, disease occurs, which is a localised infection (erythema migrans) in 85% of cases, and a disseminated infection in 15% of cases. The latter cases heal spontaneously 99% of the time; they develop into chronic manifestations in less than 0.5% of cases.
Erythema migrans (EM) is pathognomonic of borreliosis, but is reported in only 50-60% of cases. It appears on exposed areas at the site of the bite between three and 30 days after being bitten; its growth is annular, centrifugal and not painful. It persists for 3-5 weeks and disappears spontaneously.
Signs of a disseminated infection are primarily neuroborreliosis, which occurs in 48% of cases, and arthritis, in 27% of cases, the other manifestations being rarer (atrophying acrodermatitis or ACA, cardiac attacks, ophthalmological attacks).
Epidemiology
Biological diagnosis
Indirect biological diagnosis: serology
IgM appears in 3-5 weeks, and IgG in 6-8 weeks. If the disease is treated early, IgM and IgG may decrease or never be detected. Once IgM appears, it may persist for a long time after early treatment.
Serology is performed in one or two steps: first the screening test and then, if this is positive, the confirmatory test. It is important to remember that serology is not indicated in the early phase of infection (see below).
The technique used in the first instance is an ELISA technique, the objective of which is to achieve “maximum” sensitivity at the “expense” of specificity. If the ELISA is (+) or (±), a confirmatory technique (Western-blot/immuno-blot/dot-blot) will be used to improve specificity, because cross-reactions with other infectious agents (spirochetes or viral infections) and dysimmune pathologies are frequent.
For Borrelia serology, the recommended European standards are a minimum specificity of 90% for ELISA techniques and 95% for Western blot tests.
Direct biological diagnosis
Direct examination is unsuitable (except in cases of recurrent fevers), because of the rarity of spirochetes, which are intra-tissular.
Culture, which is slow (2-8 weeks) and requires specific media, is reserved for specialised laboratories. Its sensitivity decreases with the evolution of the disease: close to 50% from ME, down to about 20% for ACA, and between 3-17% from CSF and < 1% for arthritis.
Direct PCR testing (PCR Borrelia burgdorferi sensu lato) has the advantage of good sensitivity on skin lesions (ME and ACA: 50-80%) and synovial fluid (60-80%). On the other hand, its sensitivity is very disappointing in CSF (< 10-30%, except in the first weeks of neuroborreliosis) and almost null in blood. Moreover, its positivity does not necessarily indicate an active infection (PCR can remain positive despite a favourable evolution under antibiotic therapy).
In practice, serology is most often used.
Limitations of serological tests
IgM and active infection?
IgM positivity does not always indicate an active infection: it is positive in only 10-15% of culture-positive ACAs. Thus, in CAA, there is no correlation between positive IgM and positive PCR or culture. The same is true of Lyme arthritis (isolated positive IgG is observed in 90% of cases) or in late disseminated manifestations.
Finally, IgM is only of interest for the diagnosis of acute early neuroborreliosis.
A positive serology result is not equivalent to a serodiagnosis
A positive serology result simply indicates contact with Borrelia. For example, a seven-year follow-up of asymptomatic Borrelia-infected subjects showed that 95-98% of patients did not develop antibodies to Borrelia (Gern L, 2006).
Persistence of antibodies does not mean persistence of infection
After a well-conducted and effective treatment, the antibodies (IgG and IgM) persist for more than 10 years, hence the risk of overtreatment. Patients should therefore be followed clinically.
HIV-negative patients with the disease?
There is a real time lag between the onset of infection and the appearance of antibodies.
At the ME stage, about 50% of patients are seronegative. Therefore, serology is not recommended at this stage, as it may lead to erroneous diagnostic rejection.
In ACA, the sensitivity of IgG or total Ig is 98-99% and the specificity of IgG is 97%. In the experience of the CNR, of all clinically, histologically, and bacteriologically (culture/PCR positive) confirmed cases of ACA (n=24), serology was positive in all cases.
The same is true for Lyme arthritis: of 48 patients with PCR+ arthritis, all 36 cases for which serology was available were positive.
In neuroborreliosis, the sensitivity of serology in serum is “only” 81% (75-95% of cases depending on the kit used, in early neuroborreliosis). In fact, it is recommended that serum and CSF be tested together (however, Borrelia serology in CSF may be negative in very early neuroborreliosis). Lumbar puncture also allows analysis of the cellular reaction (lymphocytic in neuroborreliosis, with moderate hyperproteinorachy) and determination of intrathecal anti-Borrelia IgG synthesis.
Methods for confirming serology
The immunoblot is a confirmatory method indicated when the first-line serological technique is positive or doubtful. However, it is not more sensitive than ELISA.
It is not indicated if the ELISA is negative. There is no active marker of infection to date (ELISA or immunoblot).
Biological diagnostic strategy: best practice recommendations
Early localised stage
At the stage of early disseminated forms
– Erythema migrans with multiple locations: The diagnosis is clinical, based on the appearance of the lesions and the notion of their progressive centrifugal extension. Serology is not recommended.
– Borrelian lymphocytoma: Serology is recommended in blood: ELISA followed by a Western blot if positive or doubtful. NB: serology may be negative (in 10% of cases). In case of strong clinical suspicion, a serology check three weeks later may be useful.
– Early neurological damage, peripheral or central: An urgent specialised neurological opinion is justified. Serology is recommended in the blood: ELISA followed by a Western blot if positive or doubtful. However, it can be negative. Analysis of cerebrospinal fluid (CSF) is recommended (cytology, biochemistry and serology in CSF with calculation of the blood/CSF comparative active index).
The presence of lymphocytic meningitis and hyperproteinorachia is suggestive of Lyme borreliosis but is not specific; the positivity of the Ac index confirms the diagnosis. In the early phase, these tests may be negative, but their repeated negativity over time should lead to other diagnoses.
In children presenting with isolated and unilateral facial paralysis, without any notion of ME or meningeal signs, only blood serology is recommended in the first instance. If it is positive, a lumbar puncture will be performed in the second phase, in search of a meningeal reaction. If the blood serology is negative, a control blood serology is recommended at three weeks, followed by a lumbar puncture if the control serology is positive.
– Joint involvement: a rheumatological opinion is recommended.
In case of mono or oligoarthritis occurring within six months after a tick bite, a blood serology is recommended (ELISA followed by a Western blot if positive or doubtful) – if necessary, in conjunction with a PCR on the joint fluid.
The diagnosis is evoked if blood serology is positive and PCR negative, or blood serology positive and PCR not performed, or positive PCR on joint fluid.
– Cardiac damage: The main form is an atrioventricular block occurring between four days and seven months after the tick bite. Serology is recommended in blood: ELISA followed by a Western blot if positive or doubtful.
In case of positive serology and conduction or rhythm disorders, a cardiological opinion is recommended.
– Ophthalmological diseases: Serology is recommended in blood: ELISA followed by a Western blot if positive or doubtful. Serology is usually positive. In case of diagnostic doubt, serology in the CSF and PCR in the aqueous humour are recommended, after consultation with an ophthalmologist.
At the stage of late disseminated forms
– Chronic atrophying acrodermatitis: An urgent specialised neurological opinion is justified. Serology is recommended in the blood: ELISA followed by a Western blot if positive or doubtful. A positive blood serology confirms the diagnosis. A negative serology does not support the diagnosis; in this case, a dermatological opinion is recommended, which may lead to a skin biopsy for histological examination and research of B. burgdorferi by culture or PCR.
– Late onset neurological disease: Neurological management is warranted. The diagnosis is based on the anamnesis, biology and imaging. Biologically, serology is recommended in the blood: ELISA followed by a Western blot if positive or doubtful. It is usually positive. CSF analysis is fundamental, showing lymphocytic hypercellularity with (or without) hyperproteinorachy and without hypoglycorachy. A positive Ac index (comparative blood and CSF serology) confirms the diagnosis.
However, a negative Ac index, i.e. the absence of intrathecal production of Ac, is not sufficient to formally eliminate the diagnosis and requires additional examinations in a specialised centre.
