Course of Borrelia burgdorferi DNA shedding in urine after treatment

Diagnosis of Lyme borreliosis by urine polymerase chain reaction (PCR) has been recognized as having better diagnostic sensitivity in patients with erythema migrans than serological methods. We made serial tests with 192 urine specimens from 70 patients with erythema migrans and 60 urine specimens from 21 patients with acrodermatitis chronica atrophicans to evaluate the course of positive urine PCR after antibiotic treatment. Before treatment, urine samples from patients with erythema migrans showed a positive PCR in 27/34 samples (79%), and those from patients with acrodermatitis chronica atrophicans in 7/11 (63%). The specificity of bands was proven by hybridization with GEN-ETI-KTM-DEIA kit in 40/41 samples. Borrelia DNA in urine decreased gradually within the observation period of one year in both patients with erythema migrans and acrodermatitis chronica atrophicans, and persisted without clinical symptoms in 4/45 patients with erythema migrans (8%) after 12 months. Urine PCR can serve as a diagnostic method in early Lyme borreliosis and also in seropositive patients with unclear clinical symptoms.     

Skin Manifestations of Lyme Borreliosis

Lyme borreliosis is a multisystem infectious disease caused by tick-transmitted spirochetes of the Borrelia burgdorferi sensu lato complex. The three characteristic cutaneous manifestations are erythema migrans, borrelial lymphocytoma, and acrodermatitis chronica atrophicans. Erythema migrans occurs in acute Lyme borreliosis, lymphocytoma is a subacute lesion, and acrodermatitis is the typical manifestation of late Lyme borreliosis. Clinical appearances of erythema migrans and lymphocytoma (when located on the ear or breast) are characteristic, whereas acrodermatitis is often confused with vascular conditions. The diagnosis of erythema migrans is made clinically. Serologic analyses often yield false-negative results and are not required for the diagnosis. However, serologic proof of the diagnosis in lymphocytoma (approximately 90% positive) and acrodermatitis (100% positive) is mandatory. Histopathologic examination often adds substantial information in patients with skin manifestations of Lyme borreliosis and is recommended in clinically (and serologically) undecided cases of erythema migrans or lymphocytoma and is obligatory in acrodermatitis. Polymerase chain reaction for Borrelia-specific DNA (rather than culture of the spirochete) and immunohistochemical investigations (lymphocytoma) are sometimes necessary adjuncts for the diagnosis. Antibacterial treatment is necessary in all patients to eliminate the spirochete, cure current disease, and prevent late sequelae. Oral doxycycline, also effective against coinfection with Anaplasma phagocytophilum, is the mainstay of therapy of cutaneous manifestations of Lyme borreliosis. Other first-line antibacterials are amoxicillin and cefuroxime axetil. Erythema migrans is treated for 2 weeks, lymphocytoma for 3-4 weeks, and acrodermatitis for at least 4 weeks.     

Dermatological manifestations of Lyme borreliosis

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.     

Lyme borreliosis in children. Epidemiology, diagnosis, clinical treatment, and therapy

In Europe, Lyme borreliosis is the most common disease communicated by ticks and especially affects the skin, nervous system, joints, and heart. It is caused by at least four species of the spirochete Borrelia burgdorferi. The various pathologies are classified as early forms (erythema migrans, borrelia lymphocytom, early neuroborreliosis, carditis) or late forms (arthritis, acrodermatitis chronica atrophicans, chronic neuroborreliosis). The accuracy of serodiagnosis is 20-50% with erythema migrans, 70-90% with early neuroborreliosis, and nearly 100% with Lyme arthritis. Following special indications, the agent is confirmed by skin biopsy or spinal or joint puncture. Oral therapy is performed with amoxicillin, doxycycline, and cefuroxime, and intravenous therapy uses ceftriaxone, cefotaxime, or penicillin G. All in all, the prognosis of treated Lyme borreliosis is good. In childhood permanent defects are extremely rare, even following long-term manifestation at an early age.     

Roxithromycin in Lyme borreliosis: discrepant results of an in vitro and in vivo animal susceptibility study and a clinical trial in patients with erythema migrans.

A new semisynthetic macrolide roxithromycin was evaluated for its potential use in the treatment of Lyme borreliosis. Using a macro-dilution broth technique, Borrelia burgdorferi was shown to be susceptible to roxithromycin with a minimal bactericidal concentration (MBC) of 0.06-0.25 microgram/ml. A systemic B. burgdorferi infection was established in gerbils; a dosage of greater than or equal to 25 mg/kg/day roxithromycin for 10 days eliminated the infection. A single blind, randomized multicenter study was performed to evaluate the efficacy of roxithromycin 150 mg b.i.d. versus phenoxymethyl-penicillin 1 g b.i.d. for 10 days in patients with uncomplicated erythema migrans. The study was interrupted when 19 patients had enrolled because of five treatment failures. All 5 patients had received roxithromycin; three patients had persisting or recurrent erythema migrans, one developed a secondary erythema migrans-like lesion and severe arthralgia and one developed neuroborreliosis. B. burgdorferi was isolated from skin biopsies after roxithromycin therapy from two patients with persistent erythema migrans and both isolates were still highly susceptible to roxithromycin (MBC = 0.03 microgram/ml). No treatment failures were seen in 10 patients treated with phenoxymethyl-penicillin. Roxithromycin is thus not recommended for treatment of Lyme borreliosis.     

What should be known about the activity of the Reference Center of the Ministry of Health and Social Welfare of the Republic of Croatia for Diagnosis of Lyme Disease

Lyme borreliosis is very important for dermatovenereologists because of its skin manifestations that include erythema chronicum migrans, lymphadenosis benigna cutis, and aerodermatitis chronica atrophicans. In Croatia, the spirochete Borrelia burgodorferi was first isolated in 1991 at University Department of Dermatology and Venereology, Zagreb University Hospital Center. In October 2003, the Laboratory of Clinical Immunology, Immunofluorescence and Serodiagnosis was of the Ministry of Health and Social Welfare of the Republic of Croatia appointed Reference Center for the Diagnosis of Syphilis and Lyme Disease. Results of immunofluorescence diagnosis of Lyme disease are reported and areas in Croatia endemic for Lyme borreliosis are presented.     

Lyme borreliosis. Cutaneous manifestation

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.     

Solitary crythcma migrans: a clinical, laboratory and epidemiological study of 77 Dutch patients

Regional variations in the clinical spectrum of Lyme borreliosis have been described previously. These may be related to strain variations, or reflect selection bias. We compared the clinical and epidemiological profiles of Dutch patients presenting with solitary erythema migrans alone, with the profiles in other European studies, and studies from the U.S.A., and cultured Borrelia burgdorferi from erythema migrans to identify the genospecies. Seventy-seven consecutive patients with a final diagnosis of erythema migrans were admitted into the study. Various clinical and epidemiological data were obtained, and serum was evaluated for antibodies to Borrelia burgdorferi with an enzyme-linked immunosorbent assay. Skin biopsy specimens were taken from the border of the erythema migrans and cultured in modified Kelly's medium. The different genospecies of Borrelia burgdorferi were identified by reactivity with monoclonal antibodies H3TS, LA-26, LA-31 and D6, and by rRNA gene restriction patterns. Patients were treated with tetracycline or doxycycline, and were seen for follow-up 6 weeks after treatment, Long-term follow-up was by telephone interview. A tick bite had been noticed by 45% of the patients. The onset of erythema migrans occurred in 97% of these patients within 3 months of the tick bite. Erythema migrans was present for 1–319 days (median 2 months). No concomitant manifestations were spontaneously reported. Borrelia burgdorferi was cultured from 52 (84%) of 62 skin biopsy specimens. Fifty isolates (96%) were identified as Borrelia burgdorferi group VS461. No therapy failures occurred among patients treated with tetracycline (follow-up 1–4 years, median 27 months) or doxycycline (follow-up 6–31 months, median 19 months). The clinical and epidemiological profile of Dutch patients with erythema migrans alone did not differ from that reported in other European studies. The predominant organism isolated from erythema migrans lesions was Borrelia burgdorferi group VS461. Multiple skin lesions and concomitant clinical manifestations appear to be more frequent in patients in the U.S.A. However, selection bias cannot be excluded. At present, Borrelia burgdorferi sensu stricto is the only genospecies identified in the U.S.A. Hence, regional variations in the clinical spectrum of Lyme borreliosis may be the result of different genospecies.     

Failure of Borrelia burgdorferi to survive in the skin of patients with antibiotic-treated Lyme disease.

BACKGROUND: Borrelia burgdorferi has been cultivated from clinically normal skin (previous erythema migrans sites) after antibiotic therapy for Lyme disease. OBJECTIVE: We investigated the possibility of similar findings in 13 of our patients with antibiotic-treated Lyme disease from whom B. burgdorferi was cultivated from their erythema migrans lesions before antibiotic therapy. METHODS: After treatment with doxycycline or a combination of amoxicillin and probenecid, skin biopsy specimens were obtained from clinically normal skin adjacent to the previous biopsy sites and cultured. RESULTS: B. burgdorferi was not cultivated from these posttreatment biopsy sites. CONCLUSION: The failure of B. burgdorferi to survive in the former erythema migrans sites of our antibiotic-treated patients, as well as their favorable clinical response, supports the use of doxycycline or combined amoxicillin and probenecid in the treatment of early Lyme disease but does not preclude the survival of the organism in other tissues.     

Atypical Lyme borreliosis in an HIV-infected man

We report the fourth case of Lyme borreliosis in a man infected with human immunodeficiency virus (HIV). The erythema chronicum migrans was persistent, overlapping with meningoradiculitis. Repeated immunofluorescence tests for Borrelia burgdorferi sensu lato remained negative in both sera and cerebrospinal fluid (CSF), the enzyme-linked immunosorbent assay was weakly positive in serum and CSF and a Western blot was positive. The skin infiltrate was composed mostly of T lymphocytes with a CD4/CD8 ratio of 0.5. The course of the disease was favourable after treatment with intravenous ceftriaxone. Further studies are necessary to evaluate whether HIV infection influences, as does syphilis, the course and response to treatment of Lyme borreliosis. Serological tests are insufficiently sensitive and the Western blot assay is necessary to confirm Lyme disease in HIV-positive patients.     

Lyme-Borreliose

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.     

Vesicular erythema migrans.

BACKGROUND--Lyme disease is the most common vector-borne disease in the United States. The characteristic rash, erythema migrans, is an early sign of the disease. Clinical criteria remain the "gold standard" for diagnosis at this stage of illness. OBSERVATIONS--Five (8%) of 65 patients with erythema migrans seen in a Lyme disease diagnostic center in Westchester County, New York, had a lesion with vesicles. Borrelia burgdorferi was cultured from two of five. In one case the positive culture came from a swab of the blister fluid. CONCLUSIONS--Recognition of erythema migrans and its variants is important, since early treatment of Lyme disease may prevent late complications. Vesicular erythema migrans should be added to the differential diagnosis of inflammatory vesicular rashes in the appropriate clinical setting.     

Use of an autologous antigen in the serologic testing of patients with erythema migrans of Lyme disease

We attempted to detect an early rise in antibody titers to Borrelia burgdorferi in the serum of patients with erythema migrans of Lyme disease by utilizing B. burgdorferi isolates obtained from patients' own skin lesions instead of the B31 reference strain. B. burgdorferi was isolated from nine of 23 skin biopsy specimens submitted for culture. Elevated antibody titers were not detected in any of the 23 acute serum samples by immunofluorescence assay. The antigens derived from patient isolates were no more effective than the reference strain in detecting antibodies in patients with early Lyme disease.     

Long-term prognosis of patients treated for erythema migrans in France

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.     

Kinderdermatologie

We review important aspects of bacterial skin diseases in children, most commonly caused by Staphylococcus aureus, group A β-hemolytic streptococci (Streptococcus pyogenes) and Borrelia burgdorferi. For early diagnosis of Lyme borreliosis in children it is important to be familiar with the variable clinical presentation of erythema migrans and early hematogenic dissemination with multiple erythemata migrantia. Treatment of impetigo in children requires consideration of concomitant diseases, the specific pathogen as well as local resistance patterns. Recently retapamulin has been released as a new antibiotic for topical use in impetigo contagiosa. Perianal streptococcal disease has been underdiagnosed and is an important differential diagnosis of perianal skin disease in children. Diagnosis is made by culturing group A β-hemolytic streptococci; a 2-week course of oral penicillin represents the treatment of choice.     

Downregulation of class II molecules on epidermal Langerhans cells in Lyme borreliosis

BACKGROUND: Borrelia burgdorferi can be isolated from the skin of patients with acrodermatitis chronica atrophicans (ACA), a late-stage manifestation of Lyme borreliosis; despite a marked T-cell infiltrate in lesional skin and high antibody titres in patients' sera. OBJECTIVES: To determine whether antigen-presenting Langerhans cells (LCs), which reportedly show signs of injury in erythema chronicum migrans (ECM), the early stage of disease, are altered in ACA. PATIENTS/METHODS: We studied the immunophenotype of cutaneous leucocytes on cryostat sections of lesional skin from both ECM and ACA patients. RESULTS: The total number of CD1a+ cells evaluated by semiautomatic image analysis was lower in ECM (594 +/- 263 cells mm(-2) epidermis) than in ACA (835 +/- 317 cells mm(-2) epidermis). HLA-DR expression was remarkably downregulated on CD1a+ LCs to 29% in ECM and 18% in ACA, whereas in normal skin, most of the epidermal CD1a+ dendritic cells were HLA-DR+. The inflammatory infiltrate was mainly composed of CD68+ macrophages and CD45RO+ memory T cells, with a predominance of CD4+ helper T cells. CONCLUSIONS: It is conceivable that the downregulation of major histocompatibility complex class II molecules on LC in both the early and late skin manifestations of Lyme borreliosis is indicative of a poorly effective anti-B. burgdorferi immune response and thus at least partly responsible for the insufficient elimination of this micro-organism from ACA skin.     

The impact of immunosuppression on erythema migrans. A retrospective study of clinical presentation, response to treatment and production of Borrelia antibodies in 33 patients

BACKGROUND: Little is known about the potential influence of immunosuppression on erythema migrans, the hallmark of early Lyme borreliosis. METHODS: We performed a retrospective study to assess the impact of immunosuppression on erythema migrans in 33 patients with a malignant or autoimmune disease, chronic infection, or immunosuppressive therapy for organ transplantation. Only patients with active disease status and/or current immunosuppressive therapy were included. Pre-treatment clinical parameters, such as presentation of the skin lesion and presence of extracutaneous signs and symptoms, the disease course during a median follow-up of 9 months after therapy and serum anti-Borrelia burgdorferi antibodies before therapy and by the end of follow-up in the 33 immunosuppressed patients were statistically compared with 75 otherwise healthy patients with erythema migrans. The 75 control patients were matched for sex, age and antibiotic therapy. RESULTS: With the exception of the site of erythema migrans lesions, which were found more often on the trunk than on the legs in the immunosuppressed patients (vice versa in immunocompetent patients), we found no significant differences for all investigated parameters between the two groups. CONCLUSIONS: It appears that immunosuppression does not influence clinical presentation, response to therapy, or production of anti-B. burgdorferi antibodies of patients with erythema migrans. It is thus not necessary to treat immunosuppressed patients with erythema migrans differently from immunocompetent patients.     

Lyme borreliosis--a review and present situation in Japan

The skin diseases Erythema (chronicum) migrans (ECM, EM), Lymphadenosis benigna cutis (LABC), and Acrodermatitis chronica atrophicans (ACA) have long been described in northern Europe, and dermatologists are very familiar with these manifestations, which have been successfully treated with penicillin for about 40 years without the causative agent being known. Certain neurologic symptoms could be linked to tickbites during the 1920's and later also to EM. In 1977, Steere et al. reported a new form of inflammatory arthritis, mainly in school children in the community of Lyme, Connecticut, U.S.A., which they could also associate with preceding erythema and tickbites. Five years later, Burgdorfer was able to isolate Borrelia spirochetes from Ixodes ticks, which are known to be vectors of Lyme disease as well as of EM and ACA. The following year, Borrelia spirochetes were also isolated from Ixodes ticks and from skin lesions of patients in Sweden and Germany. These findings resulted in a large number of reports of new discoveries related to this infection, which is now known under the names of tick-borne or Lyme borreliosis and, in the U.S., also as Lyme disease or Lyme arthritis. It has proven to be a great imitator disease, mainly through its involvement of the neurological system, and to be far more widespread than previously thought. The full course of the disease is not yet known, however it is clinically, like another spirochetosis, syphilis, divided into early and late stages. Manifestations involve mainly the skin, the joints, the nervous system (Neuroborreliosis), and the heart. Antibiotic treatment is effective, especially in the early stages. Like syphilis, the disease can be self-healing without treatment. People who are exposed to ticks should be aware of the risk of contracting this disease, also in Japan where Ixodes ticks have been shown to be carriers of Borrelia spirochetes. Cases, particularly of EM, but also with neurological symptoms, have already been diagnosed in Hokkaido, Honshu, Shikoku, and Kyushu. As Lyme borreliosis is now proven to exist in Japan, it is beneficial for dermatologists to know about the various presentations of this disease. This paper will briefly summarize the historical background, the clinical stages, the diagnosis, and the treatment of Lyme borreliosis, with a summary of the present situation in Japan.     

Atypical cutaneous lesions of Lyme disease

In 30 patients with Lyme disease, the lesions of erythema chronicum migrans were absent or atypical. Thirty biopsy specimens were obtained from cutaneous lesions of these patients. The predominant histological finding was a superficial dermal and deep perivascular and interstitial infiltrate composed mostly of lymphocytes but containing a few eosinophils and plasma cells. In serial sections with a silver stain, a few Borrelia burgdorferi were found in the biopsy specimens from cutaneous lesions in five patients. Thus, there is evidence that the typical lesions of erythema chronicum migrans of the classical Lyme disease do not develop while Borrelia burgdorferi survive and persist in cutaneous lesions.     

Mini erythema migrans--a sign of early Lyme borreliosis

BACKGROUND: An erythema migrans (EM) remaining smaller than 5 cm in diameter, called mini EM by us, has not been addressed in detail. OBJECTIVE: To study the significance of the mini EM as a sign of Lyme borreliosis. METHODS: Patients with suspected mini EM were retrospectively selected out of 257 consecutive patients with EM. The diagnosis of mini EM rested on the cultivation of Borrelia burgdorferi. Species and subtype analysis of culture isolates was performed using outer surface protein A (OspA) polymerase chain reaction followed by restriction fragment length polymorphism and sequencing of the OspA gene. RESULTS: There was one patient with definite (0.4%) and another patient with a questionable mini EM. Borrelia garinii OspA type 6 was identified in the patient with the definite and B. burgdorferi sensu lato in the patient with the questionable mini EM. CONCLUSION: The mini EM represents an important and apparently uncommon sign of early Lyme borreliosis.