Global risk assessment of Lyme borreliosis transmission

Diagnosis and Treatment of Lyme Disease

Lyme disease is the most common vector-borne disease in the United States. A cluster of children in Lyme, Connecticut, who had unexplained arthritis was reported by one of their parents in the mid-1970s. Investigation of this "epidemic" of arthritis led to the description of "Lyme" arthritis in 1976 and ultimately to the discovery of its bacterial etiology. Both the reported incidence of the disease and its geographic range have increased dramatically in recent years. Perhaps even more striking has been the increase in publicity about the illness in the consumer media, which has been accompanied at times by near-hysteria about both its risks and its complications. This publicity,combined with a very high frequency of misdiagnoses in people whose symptoms are due to other causes, has resulted in a degree of anxiety about Lyme disease (among both patients and physicians) out of proportion to the morbidity it causes.Lyme disease is caused by the spirochete Borrelia burgdorferi, a fastidious, microaerophilic bacterium that replicates very slowly and requires special media to grow in the laboratory. B burgdorferi is transmitted by ticks of the Ixodid species—in the United States, primarily Ixodes scapularis (previously called Ixodes dammini), the deer tick. Lyme disease occurs most commonly in areas where deer ticks are abundant and where the prevalence of B burgdorferi in these ticks is high (20% to 50%)—southern New England, southeastern New York, New Jersey, eastern Pennsylvania, eastern Maryland, Delaware, and parts of Minnesota and Wisconsin. Lyme disease is rare in the Pacific states because although Ixodes pacificus (the Western black-legged tick)can transmit B burgdorferi, very few (<2%) of these ticks are infected with the organism. People who have increased occupational,recreational, or residential exposure to tick-infested woodlands and fields(the preferred habitat of ticks) in endemic areas are at increased risk of developing Lyme disease.The life cycle of Ixodid ticks consists of three stages—larva, nymph, and adult—that occur during a 2-year period(Fig. 1). Each stage feeds only once. The adult female lays eggs in the spring, and the larvae emerge in the early summer. They overwinter and emerge the following spring as nymphs. In the fall, the nymphs molt and become adults. The adults spend the winter on an animal host, a favorite being the white-tailed deer (hence the name, the deer tick). In the spring, the females lay their eggs and die, completing the 2-year life cycle.Most larvae (98%) are not infected with B burgdorferi because transovarial transmission rarely occurs. The larvae feed on a wide variety of small mammals (such as Peromyscus leucopus, the white-footed mouse) that are important natural reservoirs for B burgdorferi and thereby may become infected. A tick can acquire infection with B burgdorferi at each stage in its life cycle, so the proportion of adult ticks that is infected is higher than that of either nymphs or larvae. However, most cases of Lyme disease occur after the bites of nymphal-stage ticks because they are more abundant than adult ticks, they are more difficult to detect due to their small size, and humans frequently enter tick-infested habitats at times of the year when they are prevalent.A number of factors are associated with the risk of transmission of B burgdorferi from ticks to humans. First, a tick has to be infected to transmit the organism. The proportion of infected ticks varies greatly both by geographic area and stage of tick in its life cycle. I pacificusoften feeds on lizards, which are not a competent reservoir for B burgdorferi. Consequently, only 1% to 3% of these ticks, even in the nymphal and adult stages, are infected with B burgdorferi. By contrast, I scapularis feeds on small mammals that are competent reservoirs for B burgdorferi. As a result,in endemic areas, rates of infection of I scapularis are approximately 2% for larvae, 15% to 30% for nymphs, and 30% to 50% for adults. Infection rates as high as 60% to 90% have been reported in selected areas.Lyme disease occurs throughout the world. In Europe, most cases are seen in the Scandinavian countries and in central Europe (especially Germany, Austria,and Switzerland), although cases have been reported throughout the continent. The incidence of Lyme disease varies tremendously from region to region and even within local areas. Information about the true incidence of the disease is complicated by reliance, in most instances, on passive reporting of cases as well as by the high frequency of misdiagnosis. Further, studies have indicated that as many as 50% of patients who develop serologic evidence of recent infection with B burgdorferi may be asymptomatic.In 1995, 11,603 cases of Lyme disease were reported to the United States Centers for Disease Control and Prevention (CDC) by 43 states and the District of Columbia, which was the second highest number reported since surveillance began in 1982 (although it was an 11% decrease from the 13,043 cases reported in 1994)(Fig. 2). More than 75% of the reported cases occurred in just 63 counties(Fig. 3). In Connecticut, which has the highest incidence of Lyme disease in the United States, the reported annual incidence of Lyme disease in 1995 was 47.1/100,000 persons and varied from 7.5/100,000 persons in Hartford County to 129.7/100,000 persons in Wyndham County. In certain towns in which the disease is hyperendemic (eg, Lyme), the annual incidence may be as high as 1,000/100,000 persons or more. The incidence of Lyme disease is highest among children. The reported incidence among children 5 to 10 years of age in Connecticut in 1995 was 79/100,000 per year. Because not all cases of Lyme disease are reported, these figures undoubtedly are underestimates.B burgdorferi is transmitted when an infected tick inoculates the organism into the blood vessels of the skin of its host. The risk of transmission from infected deer ticks is related to the duration of feeding. It takes hours for the mouth parts of ticks to implant fully in the host and much longer (days) for the tick to become fully engorged. Experiments with animals have shown that nymphal-stage ticks must feed for 36 to 48 hours or longer and adult ticks must feed for 48 to 72 hours or longer before the risk of transmission of B burgdorferi from infected ticks becomes substantial. The duration of time that a tick has fed can be estimated from indices of engorgement derived from experiments with animals. Based on these indices, there is evidence that approximately 75% of persons who recognize that they have been bitten by a deer tick remove the tick fewer than 48 hours after it has begun to feed. Indeed, the majority of persons who develop Lyme disease do not recall a tick bite. Unrecognized tick bites probably are associated with greater risk because unrecognized ticks may feed longer. A history of a tick bite is an indication that the person is at risk and should not be assumed to be the only exposure.Like other spirochetes, B burgdorferi is a cylindrically shaped organism, and its cell membrane is covered by flagella and a loosely associated outer membrane. The three major outer-surface proteins,OspA, OspB, and OspC (which are highly charged basic proteins of molecular weights of about 31, 34, and 23 kd, respectively), as well as the 41-kd flagellar protein, are important targets of the immune response of humans. Differences in the frequency of certain clinical manifestations of Lyme disease in Europe and in the United States (eg, the greater frequency of neuritis in European patients) have been attributed to differences in the molecular structure of different strains of B burgdorferi.After B burgdorferi is inoculated by the tick into the skin, it begins to spread locally. The inflammation results in a single erythema migrans rash in approximately two thirds of patients who become symptomatic. Days to weeks later, the spirochete may disseminate via either the bloodstream or the lymphatics to many other sites, including the skin(almost 25% of patients develop multiple erythema migrans), eye, muscle,bone, synovial tissue, central nervous system, and heart. Although it may be possible to isolate the organism from cultures of tissue, the small numbers that are present and the fastidious nature of its in vitro growth makes recovery of the spirochete difficult. Nevertheless, B burgdorferi has been isolated from the blood or from tissue at all stages of the illness.The pathogenesis of the symptoms late in the course of Lyme disease appears to be related to long-term persistence of organisms in tissues. It is likely that relatively few organisms actually invade the host, but mediators of inflammation amplify the inflammatory response and lead to much of the tissue damage. The spirochete prefers cell surfaces, but it will adhere to a wide variety of cell types, which may explain why it can cause clinical manifestations in such a broad array of organ systems. Because the organism may persist in tissues for prolonged periods of time, symptoms may appear very late in the course of infection. The symptoms of Lyme disease are due to inflammation, mediated by interleukin-1 and other lymphokines, that is a direct result of the presence of the organism. However, in a small subset of patients who have refractory symptoms despite antimicrobial treatment (such as recurrent Lyme arthritis), the symptoms may have an immunogenetic basis. There is substantial evidence that patients who have a high prevalence of the HLA-DR2, DR3, and DR4 allotypes may be genetically predisposed to develop chronic recurrent Lyme arthritis long after the bacteria have been killed.The clinical manifestations of Lyme disease generally are divided into two stages: early and late. Early Lyme disease often is subdivided further into early localized and early disseminated disease. The usual clinical manifestations of the different stages of Lyme disease are shown in Table 1. The skin is the initial target organ for infection by B burgdorferi. The first clinical manifestation is the typical annular rash, erythema migrans. It usually occurs 7 to 14 days after the tick bite, although its onset has been reported as few as 3 days and as many as 4 weeks later. The rash may be uniformly erythematous(Fig. 4)or it may appear as a target lesion with variable degrees of central clearing(Fig. 5). Occasionally there may be vesicular or necrotic areas in the center of the rash. The rash may be itchy, painful, or asymptomatic and may be accompanied by systemic symptoms, such as fever, myalgia, headache, or malaise. If the patient is not treated, the rash gradually expands (hence,the name "migrans"), sometimes to more than 1 ft in diameter. It will persist for at least 1 to 2 weeks and usually for longer. Approximately two thirds of children who have Lyme disease will have single erythema migrans.A substantial proportion of children (nearly 25%) in the United States who are acutely infected with B burgdorferidevelop multiple erythema migrans lesions, a manifestation of early disseminated disease that occurs approximately 3 to 10 weeks after initial infection. The secondary skin lesions, which may develop several days or even weeks after the first lesion, are smaller than the primary lesion. Fever and myalgia usually accompany the rash. Patients also may complain of headache, neck pain, or malaise, and conjunctivitis and regional lymphadenopathy may develop. Occasionally, when the erythema migrans rash resolves, new evanescent lesions, which usually are small (1 to 3 cm)erythematous annular lesions, appear and disappear over several weeks. These lesions may appear at different sites but generally do not expand.At this stage of the illness, aseptic meningitis may occur, although it is rare (about 1% of all patients). DNA of B burgdorferi has been found in the cerebrospinal fluid of patients at this stage of the illness. Focal neurologic manifestations, specifically cranioneuropathies, also may occur. Seventh-nerve palsy (facial palsy) is relatively common, affecting about 3% of children, and may be the presenting as well as the only manifestation of Lyme disease. The palsy usually lasts from 2 to 8 weeks before complete resolution (with or without treatment). Rarely, the palsy may resolve only partially or not at all. Bannworth syndrome (meningopolyneuritis)has been reported more commonly as a manifestation of Lyme disease in Europe. Encephalitis, with or without focal neurologic signs, occasionally occurs.Arthritis is the classic manifestation of late Lyme disease, occurring in about 7% of affected children. Patients who have arthralgia, a common, nonspecific symptom that frequently is present among patients who have early Lyme disease as well as those who do not have Lyme disease,should be differentiated from those who have objective evidence of synovitis(eg, an effusion), which is the hallmark of late Lyme disease. The arthritis occurs weeks to months after the initial infection. Primarily the large joints, especially the knee (which is affected in more than 90% of the cases), are involved. Although the affected joint is swollen and tender, the patient usually does not experience the exquisite pain that is typical of acute bacterial arthritis. Joint swelling generally resolves within 1 to 2 weeks (although it may last for several weeks) before recurring, often in other joints. Although the large joints are involved most commonly, any joint, including small ones, may be affected. If untreated, the episodes of arthritis often increase in duration, sometimes lasting for months. However,the disease usually resolves eventually, even in patients who are untreated and who have had many recurrences of arthritis. Most patients will not have a history of erythema migrans because those who have the rash usually are treated with antimicrobials and do not develop late manifestations of disease.Late central nervous system manifestations of Lyme disease(sometimes termed tertiary neuroborreliosis) rarely have been reported in children. In adults, chronic demyelinating encephalitis, polyneuritis, and impairment of memory have been attributed to Lyme disease, although there is controversy about the frequency with which such late manifestations occur,especially among patients who have been treated. Other very rare manifestations of late Lyme disease include acrodermatitis chronica atrophicans (a chronic, atrophic sclerotic lesion of the skin) and borrelia lymphocytoma, a localized, subcutaneous nodular lesion that usually occurs in either the earlobe or the breast.In the largest prospective study of children who had Lyme disease(a community-based study of 201 children in Connecticut), the initial manifestations of disease were: single erythema migrans (66%),multiple erythema migrans (23%), arthritis (7%), facial palsy (3%), aseptic meningitis (1%), and carditis(0.5%). Erythema migrans was more likely to occur on either the head or neck in younger children and on the extremities in older children,a finding similar to that recently reported from Europe. Only about one third of the children who had a single erythema migrans rash had positive serology for B burgdorferi at the time of presentation compared with almost 90% of the children who had multiple erythema migrans.More than 25% of the children had early disseminated Lyme disease at the time that they presented to a physician, and 89% had either single or multiple erythema migrans.Because clinical syndromes caused by congenital infection have been recognized with other spirochetal infections such as syphilis, the possible transmission of B burgdorferi from an infected pregnant woman to her unborn fetus has been of concern. Although case reports have been published in which B burgdorferi has been identified from several abortuses and from a few live-born children who had congenital anomalies, the placentas, abortuses, and tissues from affected children did not show histologic evidence of inflammation. In addition, no consistent pattern of congenital malformations (as would be expected in a"syndrome" due to congenital infection) has been identified. In two small longitudinal studies conducted by the CDC of pregnant women who developed Lyme disease, the adverse outcomes could not be attributed to infection with B burgdorferi. Furthermore, sero-surveys conducted in endemic areas found no difference in the prevalence of congenital malformations among the offspring of women who had serum antibodies against B burgdorferi and those who had no such antibodies.To assess the prevalence of clinically significant neurologic disorders attributable to congenital infection with B burgdorferi, two investigators conducted a survey of all pediatric neurologists in areas of the United States in which Lyme disease is endemic (Connecticut, Rhode Island, Massachusetts, New York, New Jersey, Wisconsin, and Minnesota). Of the 162 respondents to the survey (92%), none had seen a child who had a clinically significant neurologic disorder attributable to congenital Lyme disease or whose mother had Lyme disease during her pregnancy.There is no definitive evidence that B burgdorferi causes congenital disease, although the existence of such a syndrome also has not been excluded. If it does exist, congenital Lyme disease must be extremely rare. Finally, it should be noted that transmission of Lyme disease through breastfeeding never has been documented.The diagnosis of Lyme disease, especially in the absence of the characteristic rash, may be difficult because the other clinical manifestations of disease are not specific. Seventh-nerve palsy due to Lyme disease is indistinguishable from idiopathic Bell palsy, and Lyme arthritis may mimic either septic arthritis or pauciarticular juvenile rheumatoid arthritis. The clinical manifestations of Lyme meningitis may be difficult to distinguish from those of viral meningitis. Even the diagnosis of erythema migrans can be difficult because the rash initially may be confused with nummular eczema, granuloma annulare, an insect bite,ringworm, or cellulitis. However, the relatively rapid expansion of erythema migrans helps to distinguish it from these other conditions.Routine laboratory tests rarely are helpful in diagnosing Lyme disease because the associated abnormalities are nonspecific. The peripheral white blood cell count may be either normal or elevated. The erythrocyte sedimentation rate usually is elevated. The white blood cell concentration in joint fluid in patients who have Lyme arthritis may range from 25,000 to 125,000/mL, often with a preponderance of polymorphonuclear cells. When the central nervous system is involved, there usually is a with a of the of for B burgdorferi is and patients must an such as a or a to tissue or fluid for such tests are indicated only in rare including the that are on of of B burgdorferi have not been shown to be to be clinically studies in that is very Consequently, laboratory of Lyme disease usually on the of antibodies to B burgdorferi in the is well that the and of tests for Lyme disease The of is much than that of tests by that and the in the A study of the was conducted by the of and in with the In this and the CDC the (as by to of antibodies against B burgdorferi in of (with and to which the were The of the results in the laboratory with different as well as the of the results from different the were The of the of the from to and from to The investigators that with these for Lyme disease will result in a high rate of This is consistent with other reports of the of most tests for Lyme disease.The of Western the of serologic for Lyme disease. from the on of Lyme Disease in that a when tests for Lyme a either an or an and that result is positive or a Western to the If the or the is an is not The a of the concentration of antibodies against B burgdorferi. The about the of the that antibodies against of the spirochete are Most the presence of antibodies against at least either three or proteins of B least one of which is a more molecular outer for the to be tests are not for the diagnosis of early localized Lyme disease because only a of patients who have single erythema migrans will have a positive of tests very on the prevalence of the infection among patients who are because many including have the that nonspecific symptoms (eg, or may be manifestations of Lyme disease, parents of children who have only nonspecific symptoms frequently for Lyme disease tests for Lyme disease on such patients). Lyme disease will be the cause of the nonspecific symptoms in very of these children. However, because the of even tests for Lyme disease rarely 90% to of the tests in children who have no or symptoms of Lyme disease will be the majority of these will be Nevertheless, Lyme disease frequently is on these and such children often are treated with a patient has a positive serologic for antibodies to B burgdorferi, it is possible that Lyme disease may not be the cause of that In to the that the result is positive (a common the patient may have been infected with B burgdorferi and the symptoms may be to the infection. serum antibodies to B they may persist for many years despite treatment and clinical In addition, because a substantial proportion of people who become infected with B burgdorferi never develop symptoms, there will be a rate in endemic areas of When patients who had Lyme disease asymptomatic and untreated or clinically and develop any of symptoms and are for antibodies against B symptoms may be attributed to Lyme disease because of the positive should not tests for Lyme disease either for patients who have not been in endemic areas or for those who only nonspecific In the highly of certain proteins of B burgdorferi will become for in which will be more than for the treatment of children who have Lyme have been from studies of no clinical of treatment have been conducted among children. younger than years of age should not be treated with because it may cause of also is results with have been There is for new because the results of treatment with or have been so such as arthralgia, and myalgia may persist after a course of treatment for Lyme disease has been These nonspecific symptoms, which may accompany or more symptoms and of Lyme disease but almost never are the presenting resolve over several weeks. There is evidence that such symptoms are related to persistence of B burgdorferi, and there is no evidence that of antimicrobials their Because antibodies against B burgdorferi persist even after treatment of symptoms, there is no to tests of against B is a that Lyme disease is difficult to and that chronic recurrences are In the for treated children is The most common for treatment is the patient actually does not have Lyme In a of children who were treated for erythema all were well and none had developed symptoms of late disease at a of more than 3 years later. In a prospective study of 201 children who had Lyme disease had either early localized or early disseminated all were clinically at a of years later. The long-term for patients who are treated for late Lyme disease also is Although arthritis does especially among patients who have the or most children who are treated for Lyme arthritis are Indeed, long-term of children with Lyme disease before its cause was recognized of either were not treated with antimicrobials or were treated years after the onset of indicated that the arthritis multiple even in children who never were treated. of investigators tests on children to 4 years after they were treated and found no evidence of any long-term of the infection. Other investigators who are a community-based study of the long-term outcomes of persons who have Lyme disease have found no evidence of impairment of normal in children 4 to 10 years after endemic areas it is very common for children to be bitten by deer bites often However, the risk of Lyme disease is 1% to even in areas in which Lyme disease is of the it is highly Consequently, the of antimicrobial (the of which is for persons who have been bitten by a deer tick is not a tick is tests such as the is not although it may important The for infection of humans of either a positive or a result is The may be positive even only very few organisms are Furthermore, the no about either the of the or the duration of both of which may be of the risk of In addition, and results are more to Lyme disease is to (such as long when tick-infested areas and to for and remove ticks after time in such areas. may but they may be from the skin, and frequently or in large may significant especially in have to develop an against Lyme disease. against outer A against Lyme disease in animal proteins have been developed and are being in in humans. Because the spirochete in ticks and in stages of illness but not at the time of initial infection in is that the by the tick blood during before it inoculates the spirochete into humans. of B burgdorferi occurs in the tick. Even the is found to be it likely will be because the risk of disease is in most and outcomes among persons who the disease are rare. that other are being

The use of serologic testing to diagnose Lyme disease (LD) is a source of controversy. Expert recommendations also discourage the routine use of antibiotic therapy for prophylaxis of LD following tick bites, but the extent to which physicians in endemic areas have adopted these recommendations is not known. To assess the pattern of use of serologic testing and antibiotic therapy for tick bites and LD and associated charges for management in an endemic area. Active surveillance of patient-physician encounters for tick bites and LD. Primary care practices on the Eastern Shore of Maryland. Consecutive sample of 232 patients with tick bites, LD (defined by physician diagnosis in medical record), and suspected LD (physician notation of possible, but not definite LD) seen in 1995. Serologic testing for LD, test results, antibiotic therapy, and direct costs of management. Surveillance identified 142 patients (61.2%) with diagnoses of tick bites, 40 patients (17.2%) with LD, and 50 patients (21.6%) with suspected LD. Of the 142 patients seen for tick bites, 95 (67%) underwent serologic testing for LD. Of these, 93 patients had initial negative or equivocal results; 24 (26%) of the 93 had convalescent testing, with 1 seroconversion. Seventy-eight patients (55%) with a diagnosis of tick bite received antibiotic therapy. No patients with tick bite developed clinical LD. Serologic testing for LD was performed for 36 patients (90%) with a diagnosis of LD and 46 patients (92%) with suspected LD. In most cases, antibiotics were prescribed before serologic test results became available. Convalescent testing was not performed for 37 (86%) of the 43 patients with suspected LD who had initial negative or equivocal results. Of these 37 patients, 25 (68%) did not receive antibiotic therapy. Direct charges for treatment of these 232 patients totaled $47 595, one third of which was attributable to serologic testing. A total of 32% of direct charges were for patients with tick bites, 48% were for patients with LD, and 20% were for patients with suspected LD. In this setting, most patients consulting physicians for tick bites received prophylactic antibiotic therapy of unproven efficacy and underwent unnecessary, costly serologic testing. Despite almost universal use in this study, serologic testing for LD did not appear to influence treatment of patients diagnosed as having LD.

Epidemiology of Tick Bites and Borreliosis in Children Attending Kindergarten or So-Called “Forest Kindergarten” in Southwest Germany

Human cases of relapsing fever (RF) in North America are caused primarily by Borrelia hermsii and Borrelia turicatae, which are spread by argasid (soft) ticks, and by Borrelia miyamotoi, which is transmitted by ixodid (hard) ticks. In some regions of the United States, the ranges of the hard and soft tick RF species are known to overlap; in many areas, recorded ranges of RF spirochetes overlap with Lyme disease (LD) group Borrelia spirochetes. Identification of RF clusters or cases detected in unusual geographic localities might prompt public health agencies to investigate environmental exposures, enabling prevention of additional cases through locally targeted mitigation. However, exposure risks and mitigation strategies differ among hard and soft tick RF, prompting a need for additional diagnostic strategies that differentiate hard tick from soft tick RF. We evaluated the ability of new and previously described recombinant antigens in serological assays to differentiate among prior exposures in mice to LD, soft or hard tick RF spirochetes. We extracted whole-cell protein lysates from RF Borrelia cultures and synthesized six recombinant RF antigens (Borrelia immunogenic protein A (BipA) derived from four species of RF Borrelia, glycerophosphodiester phosphodiesterase (GlpQ), and Borrelia miyamotoi membrane antigen A (BmaA)) to detect reactivity in laboratory derived (Peromyscus sp. and Mus sp.) mouse serum infected with RF and LD Borrelia species. Among 44 Borrelia exposed mouse samples tested, all five mice exposed to LD spirochetes were correctly differentiated from the 39 mice exposed to RF Borrelia using the recombinant targets. Of the 39 mice exposed to RF spirochetes, 28 were accurately categorized to species of exposure (71%). Segregation among soft tick RF species (Borrelia hermsii, Borrelia parkeri and Borrelia turicatae) was inadequate (58%) owing to observed cross-reactivity among recombinant BipA protein targets. However, among the 28 samples accurately separated to species, all were accurately assigned to soft tick or hard tick RF type. Although not adequately specific to accurately categorize exposure to soft tick RF species, the recombinant BipA protein targets from soft and hard tick RF species show utility in accurately discriminating mouse exposures to LD or RF Borrelia, and accurately segregate hard tick from soft tick RF Borrelia exposure.

Lyme Borreliosis

Lyme arthritis first was described in the United States in 1977 after a report of a cluster of children with arthritis living in Old Lyme, Connecticut.1 In the subsequent 45 years, Lyme disease has come to be recognized as an infectious disease that if left untreated may involve multiple organ systems, including the skin, joints, heart, and nervous system, and is referred to as Lyme borreliosis. The Infectious Diseases Society of America issued guidelines for the management of Lyme disease based on a systematic review of the scientific literature in 2000 and 2006.2,3 The American Academy of Neurology issued guidelines in 2007 for the treatment of nervous system Lyme disease.4 Practice guidelines were affirmed in 2010.5 The current guidelines were published in 2020 by a panel representing the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology, using the Grading of Recommendations, Assessment, Development and Evaluations approach to determine both certainty of evidence and strength of the recommendations.6 More than 33 individuals representing 9 societies, as well as patient representatives and a health care consumer representative, participated in the process.This report extracts recommendations from the 2020 guidelines for the management of pediatric Lyme disease that differ from previous guidelines and reviews treatment recommendations that remain unchanged. Changes in the guidelines include the use of doxycycline in children &lt;8 years of age for postexposure prophylaxis after a nymphal Ixodes scapularis tick bite and for treatment of neuroborreliosis. In addition, we review treatment recommendations for erythema migrans, arthritis, and cardiac disease that remain unchanged. Finally, we note the current status of second-generation vaccine development for the prevention of Lyme disease.In the United States, Lyme borreliosis is caused by the spirochete Borrelia burgdorferi sensu stricto (B burgdorferi in the strict sense), except for a small number of cases caused by Borrelia mayonii in the upper Midwest. Transmission occurs during a bite by an infected tick of the species I scapularis in eastern and upper midwestern states or Ixodes pacificus in the west coast states. Person-to-person transmission of B burgdorferi sensu stricto, including vertical transmission resulting in congenital disease or via transfusion of blood products, has not been documented.Approximately 35 000 cases of Lyme borreliosis are reported annually to the Centers for Disease Control and Prevention Lyme disease surveillance program, although because of likely underreporting, the true number is estimated to be at least three- to 12-fold higher (&gt;400 000 cases annually).7 Lyme borreliosis presents a significant disease burden for those living in the endemic regions of the United States, including the Northeast, Mid-Atlantic, and upper Midwest (Fig 1). Minimal, if any, disease occurs in other areas of the United States except in the west coast states, where a low incidence is recognized.Worldwide, at least 20 different genospecies of Borrelia are recognized and collectively, are referred to as B burgdorferi sensu lato (B burgdorferi in the general sense), although 3 genospecies account for most cases of Lyme borreliosis in humans: B burgdorferi sensu stricto, Borrelia afzelii, and Borrelia garinii. The latter 2 species are found in Europe and Asia and cause certain clinical syndromes such as acrodermatitis chronica atrophicans and borrelial lymphocytoma, which are not seen with B burgdorferi sensu stricto infection in North America. On the other hand, Lyme arthritis is much more common in North America than in Europe.Postexposure prophylaxis is recommended for adults largely on the basis of results from a chemoprophylaxis trial published in 2001.8 Trial results demonstrated that if specific factors are satisfied (the tick is identified as Ixodes species, the bite occurs in a highly endemic area, and the tick was attached for at least 36 hours), the benefit of prophylaxis outweighs the risk of a complication from doxycycline. Doxycycline traditionally has not been used in children &lt;8 years of age because of concern about staining of permanent teeth. However, available data indicate this complication has not been associated with doxycycline, in contrast to older tetracyclines.6 Thus, current guidelines for postexposure prophylaxis (or treatment) of Lyme borreliosis include the use of doxycycline regardless of age.9 Doxycycline is administered as a single dose at 4.4 mg/kg for children up to a maximum of the adult dose of 200 mg (≥45 kg).Single-dose postexposure prophylaxis with amoxicillin is not recommended because of its short half-life (∼60 minutes) relative to that of doxycycline (16–22 hours). Prophylactic antibiotic therapy is not recommended for a tick bite that is equivocal or considered low risk, but the person should be followed for development of erythema migrans or other manifestations of infection. Other tick-borne infections, such as Babesia microti, likely are transmitted in &lt;24 hours, emphasizing the need for prompt tick removal. Whenever possible, avoiding exposure to or prompt removal of ticks is preferred to postexposure prophylaxis.A person with a potential tick exposure in an endemic area who develops erythema migrans should be treated on the basis of the clinical findings. Laboratory testing is not recommended because most people will be seronegative during the early stage of Lyme borreliosis.Selection of an antimicrobial agent for the treatment of erythema migrans (amoxicillin, doxycycline, cefuroxime axetil, or azithromycin) should be based on the following considerations: the presence of extracutaneous manifestations of infection, particularly neurologic involvement (for which doxycycline is the drug of choice); drug allergy history; drug adverse effects; ability to minimize sun exposure (photosensitivity may be associated with doxycycline use); frequency of administration (doxycycline and cefuroxime are administered twice a day, amoxicillin is administered 3 times a day); and the likelihood of coinfection with Anaplasma phagocytophilum or an Ehrlichia muris–like agent (which are sensitive to doxycycline but not to β-lactam antibiotics (Table 1). In most circumstances, a child &lt;8 years of age is treated with oral amoxicillin, and a patient &gt;8 years of age is treated with oral doxycycline.Treatment of erythema migrans results in resolution of the rash within several days of antibiotic initiation and almost always prevents the development of later stages of disease. Among untreated adult patients who had erythema migrans before the cause of the disease was known, ∼5% developed Lyme carditis (mainly atrioventricular conduction abnormalities), 15% develop early neuroborreliosis within weeks, and ∼60% develop monoarticular or pauciarticular arthritis (mostly large joints, particularly the knees) within months.10Patients with possible Lyme arthritis should undergo serum antibody testing rather than polymerase chain reaction or culture of blood or synovial tissue. For patients with Lyme arthritis, oral antibiotic therapy for 28 days is recommended. As with therapy for erythema migrans, children &lt;8 years of age are usually treated with oral amoxicillin and those &gt;8 years of age are treated with oral doxycycline. For patients with Lyme arthritis who have minimal or no response to the initial course of oral antibiotic therapy, a 2- to 4-week course of intravenous (IV) ceftriaxone is recommended over a second course of oral antibiotic. Although rare, especially in prepubertal children, a postinfectious proliferative synovitis may develop after oral and IV therapy. Referral to a rheumatologist is recommended for consideration of treatment with disease-modifying antirheumatic drugs.An electrocardiogram is recommended for patients with signs or symptoms consistent with Lyme carditis, including dyspnea, edema, palpitations, lightheadedness, chest pain, or syncope. Patients with PR interval prolongation &gt;300 milliseconds or other arrhythmias or signs of myopericarditis should be hospitalized for continuous electrocardiographic monitoring. Hospitalized patients with Lyme carditis should be treated with IV ceftriaxone, followed by an oral antibiotic once evidence of clinical improvement is present. An outpatient with Lyme carditis may receive an oral antibiotic instead of an IV antibiotic.Treatment of neuroborreliosis often is the same whether meningitis is present, so the decision to perform a lumbar puncture should be individualized. Performance of a cerebrospinal fluid analysis in patients with suspected neurologic disease is indicated for excluding bacterial, viral, or other etiologies of inflammation. In addition, children with neuroborreliosis may experience a pseudotumor-like syndrome, which can be diagnosed on the basis of the finding of increased intracranial pressure. Children who present with developmental, behavioral, or psychiatric disorders are not recommended to undergo routine testing for Lyme borreliosis, as B burgdorferi infection is unlikely to cause such disorders. For patients with Lyme borreliosis–associated meningitis or cranial neuropathy, oral antibiotic therapy with doxycycline generally is recommended over IV treatment because of ease of administration, a lower likelihood of adverse effects, and evidence of equivalent outcome in European studies.11 For patients with the very rare condition of Lyme disease encephalomyelitis (parenchymal involvement of the brain or spinal cord), IV ceftriaxone is recommended over oral antibiotic therapy. Routine use of corticosteroid therapy for children &lt;16 years of age with cranial neuropathy is not recommended on the basis of lack of evidence of benefit.12Once diagnosed, Lyme borreliosis is a treatable disease, but if misdiagnosed or untreated, the infection can result in complications, excessive health care usage, inappropriate long-term antibiotic administration, and overuse of diagnostic testing. Thus, the burden of disease in endemic areas demonstrates the need for effective prevention strategies. Two recombinant vaccines based on the outer surface protein A (OspA) of the spirochete were developed in the 1990s, and one was licensed for prevention of Lyme borreliosis in 1998 for people 15 to 70 years of age living in areas with high rates of disease.13,14 The licensed vaccine (LYMErix; GlaxoSmithKline) was evaluated in a 3-dose series in a randomized placebo-controlled trial wherein 2 doses were administered in the first year with a booster dose 1 year later. Vaccine efficacy was &gt;75% in the second season of the trial, confirming that serum concentration of antibody against OspA correlated with protection against B burgdorferi infection. However, unsubstantiated concerns about adverse reactions contributed to poor sales of the vaccine, and the vaccine was voluntarily withdrawn by the manufacturer in 2002.15In early-phase trials for preexposure disease prevention, researchers currently are evaluating both active immunization with a modified recombinant OspA vaccine or passive immunization with a long-half-life monoclonal antibody. An investigational, multivalent, subunit, adjuvanted Lyme vaccine (VLA15; produced in a collaboration between Valneva and Pfizer) has received fast-track designation by the US Food and Drug Administration and is being evaluated in an observer-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov identifier: NCT04801420) of seropositive and seronegative participants ≥5 years of age treated with a 2- and 3-dose regimen.16As an alternative to active immunization, seasonal passive administration of a protective antibody at the start of tick season could be an effective strategy for prophylaxis in endemic areas.17 A monoclonal antibody that binds to a protective epitope on OspA may provide protection similar to that of a vaccine. A single dose of a long-half-life antibody at the beginning of the season theoretically would offer immediate protection that persists for the duration of seasonal exposure risk, but the injection would need to be repeated in each subsequent year.The authors thank Paul M. Lantos, MD, for helpful comments regarding this manuscript.

Poly-ticks: Blue State versus Red State for Lyme disease

In selected localities of Ceské Budĕjovice and Ceský, Krumlov districts, well known by stable high incidence of tick-borne encephalitis (TBE) human cases but with low incidence of Lyme borreliosis, monitoring of Borrelia burgdorferi sensu lato (s.l.) in Ixodes ricinus ticks was performed. Research was also aimed at the spread of I. ricinus to mountain areas of this region (National Park Sumava), as well as at investigating this tick for B. burgdorferi s.l. genospecies and TBE virus infection. Altogether 498 nymphs, 88 females and 11 males of I. ricinus from lower locations and 58 nymphs from mountain locations (760-1080 m above sea level) were tested by polymerase chain reaction. In lower locations total prevalence of Borrelia burgdorferi s.l. in Ixodes ricinus ticks was 35%. Single infection of Borrelia afzelii, B. garinii and B. burgdorferi sensu stricto (s.s.) was found in 59, 50 and 63 ticks, respectively (i.e. in 12.8, 11.2 and 14.1%). Double infection was found in 42 ticks (6.0%) and triple infection in three ticks (0.4%). The high frequency of B. burgdorferi s.s. exceeds the as yet reported occurrence in Central Europe. These circumstances are discussed. In mountain locations B. afzelii was found in five ticks, that including two co-infection with B. garinii, in elevations of 762 m and 1024 m above sea level, respectively. This fact signals a real danger of human infections in a region that was previously deemed to be without risk. Moreover, this region is more and more the target destination of tourist activities. The results also suggest that the penetration of infection can be rapid and formation and establishment of natural focus of Lyme borreliosis might be rather quick.

Proposed Lyme disease guidelines focus on appropriate diagnosis, treatment

BackgroundIn France as elsewhere in Europe the most prevalent TBD in humans is Lyme borreliosis, caused by different bacterial species belonging to Borrelia burgdorferi sensu lato complex and transmitted by the most important tick species in France, Ixodes ricinus. However, the diagnosis of Lyme disease is not always confirmed and unexplained syndromes occurring after tick bites have become an important issue. Recently, B. miyamotoi belonging to the relapsing fever group and transmitted by the same Ixodes species has been involved in human disease in Russia, the USA and the Netherlands. In the present study, we investigate the presence of B. miyamotoi along with other Lyme Borreliosis spirochetes, in ticks and possible animal reservoirs collected in France.MethodsWe analyzed 268 ticks (Ixodes ricinus) and 72 bank voles (Myodes glareolus) collected and trapped in France for the presence of DNA from B. miyamotoi as well as from Lyme spirochetes using q-PCR and specific primers and probes. We then compared the French genotypes with those found in other European countries.ResultsWe found that 3% of ticks and 5.55% of bank voles were found infected by the same B. miyamotoi genotype, while co-infection with other Lyme spirochetes (B. garinii) was identified in 12% of B. miyamotoi infected ticks. Sequencing showed that ticks and rodents carried the same genotype as those recently characterized in a sick person in the Netherlands.ConclusionsThe genotype of B. miyamotoi circulating in ticks and bank voles in France is identical to those already described in ticks from Western Europe and to the genotype isolated from a sick person in The Netherlands. This results suggests that even though no human cases have been reported in France, surveillance has to be improved. Moreover, we showed that ticks could simultaneously carry B. miyamotoi and Lyme disease spirochetes, increasing the problem of co-infection in humans.

Background: In Latvia and other endemic regions, a single tick bite has the potential to transmit both tick-borne encephalitis (TBE) and Lyme borreliosis. Objective: To analyse both the clinical features...

Objective In order to offer scientific evidence for prevention and therapy of Lyme disease, we had investigated the natural infection of lyme disease Borrelia burgdorferi(Bb) of 4 ticks in Diebu and Huajian areas of Gansu province. Methods Epidemiology detection of natural infection of lyme disease Bb was accomplished for four dominant tick ( Dermacetor silvarum , Dermacentor nuttalli , Haemaphysalis Japonica and Ixodes Crenulatus ) at Diebu, Diebu forest zone(Qin mountain), north of Min Mountains of Huajian region and Huajian forest zone, north of Qilian Mountains of Sunan region, Gansu, from March to June, 2010. The methods of dispersion of clamp every 10 m which was put in the morning and retrieved at night were used to capture rodent animal and gnawer retrorse hair inspection insect methods were used to collect parasitic tick. Flagging methods were used to collect free tick.Four kinds of live adult ticks were dissected after cleaning and disinfection. Intestinal contents were smeared, lyme disease Bb was observed under dark-field microscope. Etiological agent was cultivated and separated. Separated spirochete was confirmed by spirochete monoclonal and polyclonal antibody. Results The ticks collected were classified as 2 families, 8 genera, 36 species, i.e. Ixodidae 6 genera, 33 species and Argasidae 2 genera, 3 species. The method of dark-field microscope was used to detect the lyme disease spirochete in 201 ticks intestines after dissection of Dermacentor silvarum, Dermacentor nuttalli, Haemaphysalis Japonica and Ixodes Crenulatus, the lyme disease Bb-positive were 25 with positive rate of 12.44％(25/201). The lyme disease Bb was cultivated and separated from 12 ticks with the positive rate of 18.46％(12/65) after inoculation and cultivation of 3 species, 65 ticks of Dermacentor silvarum, Dermacentor nuttalli and Haemaphysalis Japonica. Conclusions Dermacentor silvarum,Dermacentor nuttalli and Haemaphysalis Japonica have different degrees of natural infection of lyme disease Bb. Key words: Ticks; Lyme disease; Borrelia burgdorferi

Committee Opinion No. 399: Management of Tick Bites and Lyme Disease During Pregnancy.

Introduction In the developing world, pregnant women frequently experience a cycle of undernutrition and parasitic infections, resulting in adverse pregnancy outcomes including abortion, malformation, and neonatal death. Although malnutrition in general and parasitic infections specifically are less common in developed countries, no society is immune from their potential effects during pregnancy. Six parasitic infections that have major health, financial, or combined consequences worldwide are Lyme disease, tuberculosis (TB), malaria, syphilis, toxoplasmosis, and schistosomiasis. Lyme Disease In the early 1970s, a mysterious clustering of juvenile rheumatoid-arthritis-like cases occurring in children in and around Lyme, Connecticut, was subsequently recognized as a distinct disease and named Lyme disease. Further investigation revealed that tiny deer ticks infected with a spirochetal bacteria, later named Borrelia burgdorferi , were responsible for the outbreak. Subsequent research has discovered additional vectors, three distinct stages of the disease, and multiple therapy options. Ticks are divided into two families of medical importance: the Ixodidae (hard ticks) and Argasidae (soft ticks). Family Ixodidae contains ticks of the genus Ixodes, which are responsible for transmitting the spirochetal bacteria that cause Lyme disease. Black-legged ticks ( Ixodes scapularis ) transmit B. burgdorferi to humans in the northeastern and north central United States; on the Pacific coast, the bacteria are transmitted to humans by the western blacklegged tick ( I. pacificus ). In other parts of the world, including Europe, Lyme disease is transmitted by I. ricinus and other Ixodes species. The life cycle of ticks is 2 years and includes egg, larva, nymph, and adult. Ixodes scapularis nymphs appear to be the most important vector for transmission of B. burgdorferi . Ixodes ticks are much smaller than common dog and cattle ticks and usually feed and mate on deer during the adult part of their life cycle. The larvae (or seed ticks) are six-legged, whereas adults and nymphs are eight-legged. In their larval and nymphal stages, these ticks are no bigger than a pinhead. According to laboratory studies, a minimum of 36–48 hours of attachment of the tick is required for transmission,3 presumably because of the time required for the bacteria to travel from the midgut of the tick to its salivary glands.