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This guideline primarily focuses on the diagnosis and treatment of cutaneous manifestations of Lyme borreliosis. It was approved in 2016 by 22 interdisciplinary medical societies and 2 patient organisations. Since then, a systematic literature review and evaluation has been conducted and published by the German Cochrane Centre, Freiburg (Cochrane Germany) for the further development to stage S3 for the treatment of erythema migrans []. In 2018, the same interdisciplinary guideline group published the guideline ‘Neuroborreliosis’, AWMF register number 030-071, development stage S3 [].

The updated version of this guideline incorporates international publications on cutaneous manifestations of Lyme borreliosis up to 2022. There have been no significant changes regarding diagnosis and treatment. Cochrane’s network meta-analysis on the treatment of erythema migrans has shown that oral penicillin V is just as effective as doxycycline and amoxicillin. A Slovenian study of patients with acrodermatitis chronica atrophicans, carried out over the last 30 years, has found that constitutional symptoms and atrophy are becoming less frequent [], most likely due to improvements in early detection.

Borrelia burgdorferi infection, hard-bodied tick borreliosis, Lyme disease, cutaneous Lyme borreliosis, erythema migrans disease, erythema migrans, erythema chronicum migrans, lymphadenosis cutis benigna, borrelial lymphocytoma, multiple erythemata migrantia, multiple erythema migrans, acrodermatitis chronica atrophicans

Lyme borreliosis is the infectious disease most frequently transmitted by ticks in Europe. The Borrelia migrate from the hard-bodied tick Ixodes ricinus into the bite wound during the act of blood feeding. There the Borrelia are either killed off by the (non-specific, innate) immune system, or a localised infection occurs which leads to illness in a small percentage of those infected. Most often the skin becomes inflamed, typically in the form of erythema migrans or, seldom, as borrelial lymphocytoma. In the course of the infection, the Borrelia can disseminate and attack various organs. They primarily affect the skin, joints and nervous system. Acrodermatitis chronica atrophicans can develop as a chronic or late-stage skin infection.

Recommendations for confirming a clinical diagnosis Recommendations for stage-appropriate laboratory testing: serological detection of IgM and IgG Borrelia antibodies using the 2-step ELISA/immunoblot process; prudent use of procedures for molecular and culture-based diagnostic testing Treatment of localised, early-stage infections (erythema migrans, erythema chronicum migrans and Borrelia lymphocytoma) Treatment of disseminated early infections (multiple erythemata migrantia, flu-like symptoms) Treatment of late-stage infections (acrodermatitis chronica without neurological manifestations) Treatment of late-stage infections (acrodermatitis chronica with neurological manifestations) Recommendations for observing tick bites Information sheet for patients (Annex 1 in )

Prof Dr med. Heidelore Hofmann – coordinator German Society for Hygiene and Microbiology (DGHM) German Society of Neurology (DGN) – coordinator German Society of Paediatrics and Adolescent Medicine (DGKJ) and German Society of Paediatric Infectiology (DGPI) German United Society of Clinical Chemistry and Laboratory Medicine and German Society for Rheumatology and Clinical Immunology (DGRh) German Society of Infectious Diseases (DGI)

The German Association of Psychiatry, Psychotherapy and Psychosomatics (DGPPN) Borreliosis and FSME Association Germany (BFBD) Action Alliance Against Tick-Borne Infections Germany (OnLyme-Aktion) German Society for Occupational and Environmental Medicine (DEGAM) Paul Ehrlich Society for Chemotherapy (PEG) Prof Dr med. Constanze Hausteiner-Wiehle German Society of Psychosomatic Medicine and Medical Psychotherapy (DGPM) and the German College of Psychosomatic Medicine (DKPM) German Society of Oto-Rhino-Laryngology, Head and Neck Surgery German Society of Cardiology and Cardiovascular Research (DGK) German Society for Occupational and Environmental Medicine (DGAUM) AWMF Institute for Medical Knowledge Management

Five of the six human-pathogenic genospecies from the Borrelia (B.) burgdorferi sensu lato complex have been isolated in Europe: B. afzelii is the most common, followed by B. garinii , B. bavariensis , B. burgdorferi sensu stricto and B. spielmanii [], [], [], []. Human pathogenicity has yet to be confirmed for B. val a isiana , B. lusitaniae and B. bissettiae . All of the species that have been confirmed to be human-pathogenic can be found in Europe with the exception of B. mayonii ; in the USA only B. burgdorferi sensu stricto and B. mayonii are found, and in Asia all of the species are found with the exception of B. burgdorferi sensu stricto and B. ma yo nii . The various genospecies of the B. burgdorferi sensu lato complex are genetically very heterogenic [] and exhibit an organotropism in human infections. Erythema migrans is caused by all 5 genospecies present in Europe, in rare cases possibly also by the relapsing fever Borrelia B. miyamoto i []. Acrodermatitis chronica atrophicans is almost exclusively caused by B. afzelii ; B. garinii and B. bavariensis are often found in conjunction with neurological manifestations, and B. burgdorferi sensu stricto mainly affects the joints [], []. B. spielmanii has so far only been isolated from erythema migrans [], [].

Lyme borreliosis predominantly occurs between the 40 th and 60 th parallels of the northern hemisphere. Few relevant epidemiological investigations have been conducted in Europe. A population-based study in southern Sweden found an incidence of 69 per 100,000 inhabitants []. In a prospective, population-based study of the region around Würzburg over a 12-month period, 313 cases of Lyme borreliosis were identified, which corresponds to an incidence of 111 per 100,000 inhabitants []. In terms of early manifestations, localised erythema migrans was diagnosed in 89% of patients and disseminated erythema migrans in a further 3%. Borrelial lymphocytoma was established in 2% of patients, early-stage neuroborreliosis in 3%, and carditis in <1%. With regard to the late forms of the disease, Lyme arthritis occurred in 5% of patients and acrodermatitis chronica atrophicans in 1%. No chronic neuroborreliosis was identified.

Currently there is an obligation to report Lyme borreliosis in nine states in Germany (see Annex 4 in ) []. Epidemiological data obtained through this partial reporting obligation are only based on the clearly diagnosable manifestations, such as erythema migrans, acute neuroborreliosis and acute Lyme arthritis. Thus, it can be assumed that there is a considerable underreporting of cases [], []. A secondary analysis of health insurance data based on the ICD 10 coding A 69.2 (G) found much higher case numbers []. A recent study of billing data from statutory health insurances between 2010 and 2019 found that the annual incidence of newly diagnosed Lyme borreliosis cases ranged between 240 per 100,000 insured persons in 2011 and 158 per 100,000 insured persons in 2015 []. It can therefore be concluded that the incidence of Lyme borreliosis cannot be conclusively established using the current epidemiological data. Data published to date in Germany indicate that the incidence of Lyme borreliosis is somewhere between 60,000 and 200,000 cases per year, or around 72 to 241 cases per 100,000 inhabitants.

A major, nation-wide seroprevalence study of children (KIGGS) and adults (DEGGS) found that the percentage of Borrelia-specific antibodies in serum rises as population age increases. In 14- to 17-year-olds it is as high as 7%, while in adults, the percentage of Borrelia antibodies is even higher. In the cohort of 70- to 79-year-olds, 24.5% of men and 16.4% of women are seropositive (Figure 1 ) []. A comparison between two nationally conducted seroprevalence studies (1997–1999 and 2008–2011) shows an annual seroconversion rate of 0.45% (95% CI: 0.37–0.54) of the previously seronegative population. The annual seroreversion rate of the previously seropositive population was 1.47% (95% CI: 1.24–2.17). There was no significant change in seroprevalence between the two study periods []. A prospective study of the incidence of Lyme borreliosis in southern Sweden and Finland (2008–2009) revealed that a Borrelia burgdorferi infection occurred in 78 (5%) of the 1,546 people bitten by a tick. Of these, only 45 (3%) experienced a seroconversion and 33 (2%) developed an infection. Erythema migrans was diagnosed in 28 patients, one person had borrelial lymphocytoma, two people had an acute case of neuroborreliosis, and 2 had non-specified symptoms which were diagnosed as Lyme borreliosis [].

B. burgdorferi is transmitted to birds, mammals and humans from hard-bodied ticks of the I. ricinus/I. persulcatus spp. complex during the blood meal. In Europe it is primarily transmitted from I. ricinus , in northeastern Europe and Asia from I. persulcatus , and in the USA predominantly from I. scapularis . Often the patient does not recall being bitten by a tick []. Ticks suck blood in the course of their cycle of development from larva to nymph to adult tick and before they lay eggs. It is at this time that they can acquire and/or transmit Borrelia. Small rodents – particularly mice – and birds are the primary reservoirs. Birds contribute to the geographical spread of the infected ticks. In Germany, ticks are ubiquitously infected with Borrelia, however percentages can vary greatly from region to region, even between areas very close in proximity (e.g. 4–21%, []).

The successful transmission from tick to mammal is the result of a specific, highly complex vector-pathogen interaction. First the Borrelia are activated in the tick’s gut. Then they migrate to the salivary glands where they bind immunosuppressive salivary proteins to their surface []. Finally, they are secreted with the saliva into the bite wound where they are – at least partially – protected from the host’s immune system by immunomodulating substances from the tick’s saliva. This is most likely what allows them to reach a sufficiently high infection dose. A similar transmission through blood-sucking insects is close to impossible due to the short blood sucking time (lack of vector competence in insects for B. burgdorferi ). Xenobiotic tests reveal that it can take hours for the Borrelia to be transferred depending on the species []. See the guideline report for the dissenting opinion of the Borreliosis and FSME Alliance of Germany on transmission from mosquitos []. When there is an increased occupational risk of a tick bite, cases of Lyme borreliosis (occupational disease 3102, diseases transmitted from animals to humans) should be reported to the accident insurer by the attending physician or employer as an occupational disease in line with Art. 202 of the Social Security Code VII (see Annex 4 in ).

The pathogenesis of the borrelial infection is primarily determined by two factors: The pathogen’s evasion strategies [], [], [], [] The quality of the host’s immune response [], [], [], [], [], [], [], [] Moreover, the salivary proteins released by the tick during the blood meal have also been found to have immunosuppressive effects [], [], [], [], [], [], [], [], []. Host-specific inflammatory reactions in the skin have also been found to influence the course of the infection [], []. Some of the many strategies the Borrelia use to evade the host’s immune system include the ability to mask their cell surface with proteins/inhibitors from the tick or the host, and to modify their phenotype expression of cell surface proteins (outer surface protein: osp) depending on their environment [], [], [], []. Several Borrelia species form a resistance to complement-mediated lysis by binding the regulators of the complement cascade (factor H) to their surface [], [], [], [], []. By binding to plasminogens, Borrelia are capable of breaking down collagen, fibronectin and laminin [], [], [], [], [] and disseminating in the skin.

The innate immune system recognises the Borrelia mainly by their surface proteins (osp lipoproteins) [], [], [], [], []. This interaction leads to the activation of soluble factors, such as the complement system, as well as to the activation of target cells, like macrophages and dendritic cells, and to the induction of inflammatory cytokines [], [], [], []. As the infection progresses, specific immune responses are generated, particularly the activation of T helper cells and B lymphocytes, and the production of Borrelia-specific antibodies [], [], [], []. In reservoir hosts, like wild mice, the antibodies that form during an infection are able to prevent disease, however they are unable to eliminate the pathogen. In contrast, the antibodies that form in human patients are often unable to prevent disease. Antibodies against certain Borrelia antigens have, however, also been shown to protect against subsequent infection in humans (see vaccines). Humans do not acquire permanent immunity following a wild-type infection. As a result, reinfections can occur.

Lyme borreliosis is a multi-organ inflammatory disease. It initially manifests as a localised infection of the skin called erythema migrans. Because of its mild symptoms, this early inflammation of the skin can be overlooked or is not visible. The Borrelia can spread haematogenously. This is clinically recognisable by flu-like symptoms or disseminated erythema on the skin. As the disease progresses, manifestations can appear in other organs, primarily in the nervous system and joints. The disease progresses very differently depending on the individual. Therefore, classifying the disease into stages is not particularly helpful. A distinction between early and late manifestations is preferable since the clinical picture determines both diagnosis and treatment (Table 1 ). European studies show that Lyme borreliosis manifests as a skin disease in 80–90% of patients and affects other organs in around 10–20% of patients [], [], [], []. See the guideline report for the dissenting opinion of the Borreliosis and FSME Alliance of Germany on the frequency of erythema migrans [].

A localised skin infection can occur in the area around the infecting tick bite anywhere from 3 to 30 days following the tick bite []. The extent and duration of the inflammatory reaction varies greatly between individuals. A diagnosis of erythema migrans requires the diameter of the erythema to be more than 5 cm (Figure 2A and B ) []. A clinically clear presentation of a typical erythema migrans is a marginated erythema – not raised, not overheated – with centrifugal dissemination around the tick bite (Figure 2C and D ). Features of a typical solitary erythema migrans Time interval between tick bite and onset of the erythema is typically 3 days to several weeks Increasing centrifugal spread of the erythema (crescendo reaction) Marginated, non-raised erythema that is at least 5 cm in diameter Visible tick bite site at the centre of the erythema

The initial skin infection may be clinically ambiguous. Borrelia have been detected in homogenously red and non-migrating erythema, in patchy and infiltrated erythema (Figure 3B ), in erysipelas-like flaming red erythema (Figure 3A ) and in centrally vesicular erythema (Figure 3D ) [], []. The inflammation can completely disappear in the middle and fade to such as extent that the erythema is only visible around the borders – where the Borrelia are migrating – when heat is applied (Figure 3C ). The erythema can also be haemorrhagic, particularly on the lower extremities (Figure 3E and F ). The centre can turn dark purple in colour (Figure 3F ). The border can be raised or urticarial. The original site of the tick bite is identifiable in the centre as a red papule (Figure 2A and B ) [], []. In the case of multiple erythema migrantia, erythema also develops at sites other than the site of the bite. Without antibiotic treatment the Borrelia can persist for months or years in the skin and the erythema can slowly spread over the body. Often the red border is the only evidence of the inflammatory reaction to the migrating Borrelia. If the erythema migrans persists for several weeks to months, it is referred to as erythema chronicum migrans []: >4 weeks. In most cases (approx. 80%) serological detection of the IgG antibodies (sometimes even the IgM antibodies) is possible [].

The erythema can subside even without antibiotic treatment. Spontaneous healing is possible, however the Borrelia can persist even without a visible inflammatory reaction, and, after a period of latency, this can lead to manifestations in other organs. Variability of the erythema migrans (atypical erythema migrans) Due to the extraordinary variability of the clinical presentation, atypical erythema migrans is difficult for dermatologically inexperienced physicians to diagnose. Therefore, patients with atypical erythema should be referred to a dermatologist. (Strong consensus 13/0/0)

In the early stages of the disease, pseudolymphoma (cutaneous lymphoid hyperplasia) (Figure 4B ) can occur at the site of the tick bite or in the migrating erythema migrans. In most cases it is solitary; in rare cases it is also disseminated. Borrelial lymphocytoma occurs more frequently in children than in adults (in 7% of children and in only 2% of adults with Lyme borreliosis []). The preferred sites in children are the earlobes (Figure 4A and C ), nipples and genitoanal area (Figure 4F ) [], []. The disease was first described as lymphadenosis cutis benigna by Bäferstedt in 1944. B. burgdorferi s.l. is detectable in the pseudolymphomas []. In most cases it is B. afzelii []. Histologically, there are mixed B and T lymphocytic infiltrates. However purely B cell infiltrates can also occur, which are difficult to differentiate from low-grade B cell lymphoma (Figure 4D and E ) []. Borrelial lymphocytoma can also occur in the late stages of the disease within the context of acrodermatitis chronic atrophicans [].

In the case of borrelial lymphocytoma, there is a substantial increase in the number of IgG antibodies in the serum regardless of the duration of the infection [], []. In rare cases, multiple borrelial lymphocytomas can occur in the early disseminated stage or even in the late stages of the disease. Here accurate, histological, immune-histochemical and molecular-genetic clarification is required so that a differential diagnosis can be made from malignant cutaneous lymphomas. Important features of a borrelial lymphocytoma Pseudolymphoma, mostly solitary, more frequent in children Localised, primarily on the earlobes, nipples or in the genital area Histologically, mostly mixed B and T lymphocytic infiltrates

Some patients experience haematogenous dissemination in the early stages of the disease, which is clinically identifiable by flu-like symptoms such as a slight fever, arthralgia, myalgia, headache, lymphadenopathy and multiple erythemata migrantia. This stage is very difficult to diagnose if no erythemas are visible or if they cannot be identified because they have an atypical morphology.

The haematogenous dissemination of the Borrelia in the skin is identifiable by the many sharply defined, symptomless, oval erythemas of varying sizes, i.e., multiple erythemata migrantia (Figure 5B and C ) [], [], []. Children often experience symmetrical erythema on their face, similar to fifth disease (Figure 5A ) [], []. MEM can be associated with systemic symptoms and acute neurological symptoms []. The histological picture is initially atypical. The typical perivascular plasma cell infiltrates can only be found in the advanced stage of the disease. There is usually a highly elevated number of IgM antibodies in the serum, or the antibodies increase rapidly once treatment begins. There is usually an elevated number of IgG antibodies. Borrelia taken from skin lesions, and, in rare cases, blood can be cultivated, or their DNA can be detected by PCR [], []. Important features of multiple erythemata migrantia Symptomless, disseminated round or ovular redness on the skin (strong consensus: 13/0/0) In children, often symmetrical erythema on the face (similar to fifth disease) Possibly associated with systemic or acute neurological symptoms

The disease can manifest in various organs after varying periods of time – from months to years – depending on the individual. Chronic skin infections mostly occur in older patients and more frequently in women [], []. A large retrospective descriptive cohort study conducted over 28 years (1991–2018) of 693 Slovenian patients who presented with ACA has now been published for the first time. Clinical and microbiological findings were anal-ysed. A diagnosis was made after a mean time of 12 months following the onset of changes to the skin. The lower extremities were affected in 70% of cases. In 55% of patients, the ACA was localised to one extremity, in 31.3% to 2, in 5.6% to 3 and in 7.8% to all 4 extremities. Bilateral involvement was observed in 42.1% of cases. Fibroid nodules were also reported in 2.2% of patients, concomitant arthritis in 2.6% and in 20.8% of patients, the ACA was associated with peripheral neuropathy. The neuropathic symptoms only occurred in the extremity affected by the ACA []. Isolated cases have also been reported in children [], [], [], [], [].

Acrodermatitis initially manifests as pink reticular, then increasingly purple, oedematously infiltrated cushion-like erythema, usually on the extremities. The skin is excessively warm, however there is initially no pain apart from a feeling of heaviness. This is the oedematous-infiltrative stage of acrodermatitis chronica (Figure 6A and B ). These purple infiltrates can also appear on the face and be mistaken for lupus erythematosus or cutaneous malignant lymphoma [].