Current perspectives on Lyme Disease

Vesiculobullous Lyme disease: A case series

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

BackgroundThe nervous system is known to be the third most commonly (12–15%) affected site in Lyme disease (LD) in the U.S. Though previous studies reported peripheral neuropathy, encephalopathy, and encephalitis with some frequency in later stage LD, limited contemporary data exist on the frequency, presentation, and outcomes of these entities.MethodsRetrospective review of 1261 patients referred (2000–2013, single center) for presumptive LD was performed for neuroborreliosis. Symptoms less than 3 months were designated early LD. Patients with remote history of treated neuroborreliosis (> 2 years) were excluded. The diagnosis of LD followed CDC criteria. Response to antibiotics was assessed at the last clinical visit.ResultsOf 185 diagnosed with LD, 19% (35/185) had neuroborreliosis, including 29 early LD (ELD) and 6 late LD (LLD). The mean age was 44 yrs (±20) in ELD and 61(±11) in LLD. The median symptom duration was 14d (1–69) in ELD and 182d (140–2570) in LLD. Facial nerve palsy was most common, 54% (19/29 in ELD vs. 0/6 in LLD), followed by meningitis 20% (4/29 vs. 3/6), radiculopathy 20% (6/29 vs. 1/6), encephalopathy 3% (0/29 vs. 1/6), and peripheral neuropathy 3% (0/29 vs. 1/6) (P = 0.001). No encephalitis was identified. The median treatment duration (days) was 30 (10–135) in ELD and 56 (28–230) in LLD. All 35 patients were treated with doxycycline and/or ceftriaxone (16, 46% IV). Of the 32 followed patients, 28/32 (88%) responded to antibiotics, whereas 4/32 (12%) remained symptomatic with median follow-up duration of 72 days. Four non-responsive cases included 1 ELD (radiculopathy) and 3 LLDs (meningitis, encephalopathy, and peripheral neuropathy). The rate of non-response to antibiotics was higher in late LD (4% of ELD vs. 60% of LLD; P = 0.008). There was no statistically significant difference between outcome groups when comparing age, treatment duration, history of anxiety/depression, and route of treatment (p > 0.05, respectively).ConclusionEncephalopathy, encephalitis, and peripheral neuropathy ascribed to LD were uncommon in this population and poorly responsive to antibiotics. This raises the question whether LD truly was causal or if irreversible damage occurs by late stage LD. Future studies are needed in this regard.DisclosuresAll authors: No reported disclosures.

Diagnosis and Treatment of Lyme Disease

Toward a more complete appreciation of the clinical spectrum of Borrelia burgdorferi infection: early lyme disease without erythema migrans

Lyme disease is the most common vector-borne disease in the United States. Recent environmental and socioecological changes have led to an increased incidence of Lyme and other tick-borne diseases, which enhances the urgency of identifying and mitigating adverse outcomes of Lyme disease exposure. Lyme disease during pregnancy, especially when untreated, may lead to adverse pregnancy and neonatal outcomes; however, long-term child outcomes following utero exposure to Lyme disease have not yet been systematically assessed. This concise review describes the current state of knowledge of Lyme disease as a congenital infection and the potential effects of in utero exposure to Lyme disease infection on the neurodevelopment of infants and children. We highlight the importance of distinguishing between acute Lyme disease and a chronic condition termed Post-Treatment Lyme Disease Syndrome, as the impacts of both conditions on the developing fetus and subsequent child development may differ. The importance of placental pathology for patients with acute or chronic symptoms of Lyme disease in pregnancy is explored. Future research aiming to understand and protect neurodevelopment after antenatal Lyme disease must carefully collect potentially confounding variables such as symptomatology and treatment, use clear and standard case definitions, and follow children into school-age and beyond.

Lyme disease: authentic imitator or wishful imitation?

Malaria and Lyme disease were the largest vector-borne epidemics in recent US history. Malaria, a mosquito-borne disease with intense transmission, had higher morbidity and mortality, whereas Lyme and other tick-borne diseases are more persistent in the environment. The responses to these two epidemics were markedly different. The anti-malaria campaign involved large-scale public works eradicating the disease within two decades. In contrast, Lyme disease control and prevention focused on the individual, advocating personal protection and backyard control, with the disease incidence steeply increasing since 1980s. Control of Lyme and other tick-borne diseases will require a paradigm shift emphasizing measures to reduce tick and host (deer) populations and a substantial R&D effort. These steps will require changing the political climate, perceptions and opinions to generate support among governmental levels and the general public. Such support is essential for providing a real solution to one of the most intractable contemporary public health problems.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of North American (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists, and dermatologists in North America. It is important to realize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); should not be considered inclusive of all proper treatments methods of care, or as a statement of the standard of care; do not mandate any particular course of medical care; and are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Whether and the extent to which to follow guidelines is voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. Although IDSA, AAN, and ACR make every effort to present accurate, complete, and reliable information, these guidelines are presented “as is” without any warranty, either express or implied. IDSA, AAN, and ACR (and their officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented. The guidelines represent the proprietary and copyrighted property of IDSA, AAN, and ACR. Copyright 2020 Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology. All rights reserved. No part of these guidelines may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of IDSA, AAN, or ACR. Permission is granted to physicians and healthcare providers solely to copy and use the guidelines in their professional practices and clinical decision-making. No license or permission is granted to any person or entity, and prior written authorization by IDSA, AAN, or ACR is required, to sell, distribute, or modify the guidelines, or to make derivative works of or incorporate the guidelines into any product, including but not limited to clinical decision support software or any other software product. Except for the permission granted above, any person or entity desiring to use the guidelines in any way must contact IDSA, AAN, or ACR for approval in accordance with the terms and conditions of third party use, in particular any use of the guidelines in any software product. Summarized below are the 2020 recommendations for the prevention, diagnosis, and treatment of Lyme disease. The panel followed a systematic process used in the development of other Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) (see Figure 1). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text (http://onlinelibrary.wiley.com/doi/10.1002/acr.24495/abstract). A. Personal protective measures B. Repellents to prevent tick bites C. Removal of attached ticks A. Diagnostic tick testing B. Diagnostic testing of asymptomatic patients following tick bites Supplementary data. Supplementary materials (in addition to the full guideline) are available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24495/abstract. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Conflict of interest statement. See the Methodology section in the full guideline (on the Arthritis Care & Research website at http://online​library.wiley.com/doi/10.1002/acr.24495/abstract) for approach to conflict of interest (COI) by the IDSA/AAN/ACR COI review group. The following list is a reflection of what has been reported to the IDSA/AAN/ACR COI review group. To provide thorough transparency, the IDSA/AAN/ACR requires full disclosure of all relationships, regardless of relevancy to the guideline topic. The assessment of disclosed relationships for possible COI is based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. Dr. Lantos has received research funding from the National Cytomegalovirus Foundation and from the NIH and educational funding from Duke University; and has served as a consultant and reviewed trial protocol for Frederick O’Connor Medical Consultants, LLC. Dr. Bockenstedt has received research funding from the NIH and the Gordon and Llura Gund Foundation; has received remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research; and was awarded an endowed professorship as the Harold W. Jockers Professor of Medicine at Yale University. Dr. Falck-Ytter serves as director of the Evidence Foundation and the GRADE Network; conducts GRADE workshops with the Evidence Foundation; has served as the chair of the Guidelines Committee for the American Gastroenterological Association; and has received research funding from the Cleveland VA Medical Research and Education Foundation. Dr. Aguero-Rosenfeld serves as a council member for the New York City chapter of the American Society of Microbiology (ASM) and as a Board member of the American Lyme Disease Foundation; has provided legal testimony and consultation regarding Lyme disease and tick-borne diseases; and has received research grants from the NIH, BioFire, New York State Department of Health, and ViraMed. Dr. Auwaerter receives research funding from the Fisher Center for Environmental Infectious Diseases and the NIH; serves on the Board of Directors of the American Lyme Disease Foundation and as the Vice Chair of the Infectious Diseases Society of America (IDSA) Foundation; serves as a scientific advisor for DiaSorin, Adaptive Technologies, and Shionogi; provides legal expert opinion testimony regarding Lyme disease; had stock in Johnson & Johnson; has served as an editor for Johns Hopkins POC-IT ABX Guide, an advisor for the Food and Drug Administration (FDA), Genentech, Dynavax, Aradigm, Cempra, BioMérieux, Cerexa, and Medscape; has received research funding from Cerexa; has served on the FDA Advisory Board, the Medscape Advisory Board, and the IDSA Board of Directors; and his spouse has equity interest in venture capital–funded Capricor. Dr. Belani reviews non-continuing medical education (CME) lectures for and received honoraria and travel reimbursement from Horizon Therapeutics; and has received research funding from the NIH and the Children’s Hospitals and Clinics of Minnesota. Dr. Bowie has provided expert testimony to the Canadian Senate Subcommittee on Bill C-442: An Act Respecting a National Lyme Disease Strategy on behalf of the Association of Medical Microbiology and Infectious Disease Canada; and has received research funding from GlaxoSmithKline, Pfizer Canada, the Canadian Institutes of Health Research, and Vancouver Coastal Health Research Institute. Dr. Branda receives research funding from the Lyme Disease Biobank Foundation and Zeus Scientific; serves as a scientific advisor and consultant to DiaSorin, Inc.; has served as a scientific advisor and consultant for T2 Biosystems; has served on the scientific advisory board of Roche Diagnostics and AdvanDx; has received research funding from Karius, Inc., Alere, Inc., T2 Biosystems, BioMérieux, TBS Technologies, Immunetics, Inc., DiaSorin, Inc., Kephera Diagnostics, Inc., and the Bay Area Lyme Foundation; has participated in unfunded research collaborations with Karius Inc. and Kephera Diagnostics; was a member of the editorial board of the Journal of Clinical Microbiology; was a co-inventor on an application for a patent to protect intellectual property; and his spouse is an employee of Informed DNA. Dr. Clifford receives research funding from the NIH and the Alzheimer’s Association; serves as scientific consultant to Inhibikase and Excision BioTherapeutics; serves on Data and Safety Monitoring Boards (DSMB) for Biogen, Genzyme/Sanofi, Genentech, EMD Serono, Shire, Wave Life Sciences, Pfizer, Atara, Mitsubishi Tanabe, and IQVIA (formerly Quintiles); serves on Progressive Multifocal Leukoencephalopathy (PML) adjudication committees for Amgen, GlaxoSmithKline, EMD Serono, Bristol Myers Squibb, Roche, and the Takeda Oncology (formerly Millennium) Adjudication Committee–FDA, as well as Dr. Reddy’s Laboratories; has previously received research funding from the NIH; and his spouse formerly held stock in Johnson & Johnson. Dr. DiMario has received research funding from Novartis. Dr. Halperin serves as an Editorial Board Member of Neurology, and Vice Chair of the American Academy of Neurology (AAN) Guideline Subcommittee; has stock in Abbott Labs, AbbVie, Merck, and Johnson & Johnson; provides and has previously provided legal expert testimony defending physicians in medical malpractice cases on various neurologic issues, including Lyme disease; has received research funding from NIH, the Centers for Disease Control and Prevention (CDC); and has served as a section editor of neuroinfectious diseases in Neurology & Neuroscience Reports. Dr. Krause receives research funding from the Yale Emerging Infections Program; receives remuneration from Gold Standard Diagnostics for a collaborative research project; has stock in Gilead Sciences and First Trust NASDAQ Pharmaceuticals ETF; has received research funding from the NIH, the Centers for Disease Control and Prevention (CDC), the Gordon and Llura Gund Foundation, and L2 Diagnostics for NIH-sponsored research; has served as a scientific consultant and provided medical education and training for Oxford Immunotec, Inc.; has a patent pending (Enhanced Chemiluminescent enzyme-linked immunosorbent assay for detection of antibodies against Babesia microti), for which US Provisional Patent Application No. 62/580,588, was filed on November 2, 2017; serves on the Board of Directors for the American Lyme Disease Foundation and the Editorial Boards of Pathogens and Plos Neglected Tropical Diseases and the Editorial Advisory Board of Clinical Infectious Diseases; was on the Editorial Board of Journal of Clinical Microbiology, and will be on the Editorial Board of Clinical Microbiology Reviews starting January 2021. Dr. Liang has stock in Johnson & Johnson; received research funding from the Veterans Health Administration, the Arthritis Foundation, and the NIH; has served on the FDA Advisory Panel, Institute of Medicine panels; served as a scientific reviewer for the Research Grant Council of Hong Kong and the NIH; served on the Board of the Lupus Clinical Trials Consortium, Beacon Hill Villages, and Rx Foundation and advised the Institute for Clinical and Economic Review and the China Medical Board; previously had stock in Sequenom; and his spouse has stock in Johnson & Johnson. Dr. Meissner is a current member of the CDC Workgroups and serves as a volunteer consultant on the American Academy of Pediatrics Committee on Infectious Diseases and the NIH DSMB. Dr. Nigrovic receives research funding from the NIH, Department of Defense, and the NIH Center for Research Resources and for Advancing Translational Sciences (NCATS), Global Lyme Alliance, and Peabody Foundation; serves on the Editorial Board for Annals of Emergency Medicine; has served as scientific consultant for Adaptive Technologies; has received research funding from the NIH, Provider and Payer Quality Initiative (PPQI) Research Foundation, Harvard Catalyst, Hood Foundation, Bay Area Lyme Foundation, CDC, Emergency Medical Services for Children (EMSC), the National Patient-Centered Clinical Research Network (PCORNet), Milton Foundation, and Boston Children’s Hospital. Dr. Nocton receives research funding from Bristol Myers Squibb; serves as a member of the Subboard of Pediatric Rheumatology of the American Board of Pediatrics; and has received research funding from AbbVie, NIH, and the Arthritis Foundation. Dr. Pruitt has received research funding from Teva Pharmaceuticals and has served on the AAN Editorial Board of Neurology Clinical Practice. Ms Rips has received research funding from the Center for AIDS Research, Biogen Idec, Hoffmann-LaRoche, Sun Pharmaceutical Industries Ltd., Genzyme, the Alzheimer’s Association, and the American College of Radiology; and has served as a speaker for Teva Pharmaceuticals. Dr. Rosenfeld serves as a Council Member of the American College of Cardiology; has stock in Abbott, Proctor & Gamble, and General Electric; has received Fellowship Support from Boston Scientific, Medtronic, and Abbott Laboratories (formerly St. Jude Medical); has received research funding from Boehringer Ingelheim Pharmaceuticals, Inc.; and has served on the Program Committee and the Patient and Caregivers Committee of the Heart Rhythm Society. Dr. Savoy serves on the American Academy of Family Physicians (AAFP) Board of Directors, as an ex-officio Board member of Delaware Academy of Family Physicians (DAFP), as the Chair of the Centers for Medicare and Medicaid Services (CMS) Advisory Panel on Outreach and Education, and as Secretary of the Board of Directors of the Association of Departments of Family Medicine; receives honoraria from AAFP, DAFP, CMS, and Merck; has served on an Advisory Council for Highmark Health and as an advisor to the AAFP Adolescent Immunization Project; has received honoraria from AAFP; has served as the President of DAFP, as Editor of DelFamDoc, and as a member of AAFP Commissions. Dr. Sood has received research funding from the NIH; and has provided expert testimony for Danaher Lagnese, PC. Dr. Steere receives research funding from the NIH and the Mathers Foundation; has received research funding from the NIH, the American College of Rheumatology, the Mathers Foundation, the English-Bonter-Mitchell Foundation, Immunetics, Inc., Zeus Diagnostics, and the Ounsworth-Fitzgerald Foundation; and has served as a scientific advisor for Baxter Bioscience Institute of Systems Biology, Immunetics, Inc., Roche Diagnostics, and Viramed. Dr. Strle receives research funding from the Slovenian Research Agency; serves as the Head of Health Counsel of the Ministry of Health of the Republic of Slovenia and as a member of the Steering Committee for the European Society of Clinical Microbiology and Infectious Diseases Study Group for Lyme Borreliosis; serves on the Roche Diagnostics Advisory Board on Lyme Disease Diagnostics; and has received honoraria from Roche Diagnostics. Dr. Sundel receives research funding from the NIH and AbbVie, Inc.; serves as a content author and editor for UpToDate; provides expert testimony to Chin-Caplan, PC; has provided expert testimony for Conway Homer, PC; has served as an advisor for Paul Hastings, LLC; has served as a content editor for SimulConsult and as a Medical Education Resources lecturer for CME-granting educational courses; has received remuneration from SimulConsult as a co-investigator for an NIH-sponsored grant; and has received research funding from the NIH. Dr. Tsao receives research funding from the National Science Foundation, NIH, CDC, the Michigan Lyme Disease Association, and the Michigan Department of Health and Human Services; serves as a Scientific Council Advisor Member for the Canadian Lyme Disease Research Network and as a scientific advisor for the American Lyme Disease Association; has received research funding from Michigan State University; has served as an Associate Editor for Ticks and Tick-Borne Diseases and on the Tick Vectors, Surveillance, and Prevention Subcommittee of the US Department of Health and Human Services Tick-Borne Disease Working Group; and has received remuneration for providing educational seminars for Boehringer Ingelheim (formerly Merial). Dr. Wormser receives research funding from Immunetics, Inc., Rarecyte, Inc., Institute for Systems Biology, and Quidel Corporation; serves on the Board of the American Lyme Disease Foundation; provides and has previously provided expert testimony in malpractice cases; has stock in AbbVie, Inc. and Abbott Laboratories; has received research funding from the CDC, NIH, BioMérieux, Bio-Rad Laboratories, and DiaSorin, Inc; has served as a scientific research advisor for Baxter International and as a Lyme disease advisor and expert for the Missouri Board of Registration for the Healing Arts; has a patent approved (US patent no. 10,669,567 B2) for High Sensitivity Method for Early Lyme Disease Detection; filed 2 patent applications related to early Lyme disease detection (application no: 62/277,252) and Lyme arthritis and post-treatment Lyme disease syndrome (application no: 62/725,745); and has served on the Editorial Boards for Clinical Infectious Diseases, Vector-Borne and Zoonotic Diseases, and Ticks and Tick-Borne Diseases. Dr. Zemel has served as an advisor for Novartis Promotional Speakers Bureau. No other disclosures relevant to this article were reported. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. The expert panel expresses its gratitude for thoughtful reviews of an earlier version to the external reviewers. The panel thanks the IDSA, AAN, and ACR for supporting the guideline development process. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Lantos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of North American (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists, and dermatologists in North America. It is important to realize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is developed and when it is published or read); should not be considered inclusive of all proper treatments methods of care, or as a statement of the standard of care; do not mandate any particular course of medical care; and are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Whether and the extent to which to follow guidelines is voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. Although IDSA, AAN, and ACR make every effort to present accurate, complete, and reliable information, these guidelines are presented “as is” without any warranty, either express or implied. IDSA, AAN, and ACR (and their officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented. The guidelines represent the proprietary and copyrighted property of IDSA, AAN, and ACR. Copyright 2020 Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology. All rights reserved. No part of these guidelines may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of IDSA, AAN, or ACR. Permission is granted to physicians and healthcare providers solely to copy and use the guidelines in their professional practices and clinical decision-making. No license or permission is granted to any person or entity, and prior written authorization by IDSA, AAN, or ACR is required, to sell, distribute, or modify the guidelines, or to make derivative works of or incorporate the guidelines into any product, including but not limited to clinical decision support software or any other software product. Except for the permission granted above, any person or entity desiring to use the guidelines in any way must contact IDSA, AAN, or ACR for approval in accordance with the terms and conditions of third party use, in particular any use of the guidelines in any software product. Summarized below are the 2020 recommendations for the prevention, diagnosis, and treatment of Lyme disease. The panel followed a systematic process used in the development of other Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR) clinical practice guidelines, which included a standardized methodology for rating the certainty of the evidence and strength of recommendation using the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) (see Figure 1). A detailed description of background, methods, evidence summary and rationale that support each recommendation, and knowledge gaps can be found online in the full text (http://onlinelibrary.wiley.com/doi/10.1002/acr.24495/abstract). A. Personal protective measures B. Repellents to prevent tick bites C. Removal of attached ticks A. Diagnostic tick testing B. Diagnostic testing of asymptomatic patients following tick bites Supplementary data. Supplementary materials (in addition to the full guideline) are available on the Arthritis Care & Research website at http://onlinelibrary.wiley.com/doi/10.1002/acr.24495/abstract. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Conflict of interest statement. See the Methodology section in the full guideline (on the Arthritis Care & Research website at http://online​library.wiley.com/doi/10.1002/acr.24495/abstract) for approach to conflict of interest (COI) by the IDSA/AAN/ACR COI review group. The following list is a reflection of what has been reported to the IDSA/AAN/ACR COI review group. To provide thorough transparency, the IDSA/AAN/ACR requires full disclosure of all relationships, regardless of relevancy to the guideline topic. The assessment of disclosed relationships for possible COI is based on the relative weight of the financial relationship (i.e., monetary amount) and the relevance of the relationship (i.e., the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. Dr. Lantos has received research funding from the National Cytomegalovirus Foundation and from the NIH and educational funding from Duke University; and has served as a consultant and reviewed trial protocol for Frederick O’Connor Medical Consultants, LLC. Dr. Bockenstedt has received research funding from the NIH and the Gordon and Llura Gund Foundation; has received remuneration from L2 Diagnostics for investigator-initiated NIH-sponsored research; and was awarded an endowed professorship as the Harold W. Jockers Professor of Medicine at Yale University. Dr. Falck-Ytter serves as director of the Evidence Foundation and the GRADE Network; conducts GRADE workshops with the Evidence Foundation; has served as the chair of the Guidelines Committee for the American Gastroenterological Association; and has received research funding from the Cleveland VA Medical Research and Education Foundation. Dr. Aguero-Rosenfeld serves as a council member for the New York City chapter of the American Society of Microbiology (ASM) and as a Board member of the American Lyme Disease Foundation; has provided legal testimony and consultation regarding Lyme disease and tick-borne diseases; and has received research grants from the NIH, BioFire, New York State Department of Health, and ViraMed. Dr. Auwaerter receives research funding from the Fisher Center for Environmental Infectious Diseases and the NIH; serves on the Board of Directors of the American Lyme Disease Foundation and as the Vice Chair of the Infectious Diseases Society of America (IDSA) Foundation; serves as a scientific advisor for DiaSorin, Adaptive Technologies, and Shionogi; provides legal expert opinion testimony regarding Lyme disease; had stock in Johnson & Johnson; has served as an editor for Johns Hopkins POC-IT ABX Guide, an advisor for the Food and Drug Administration (FDA), Genentech, Dynavax, Aradigm, Cempra, BioMérieux, Cerexa, and Medscape; has received research funding from Cerexa; has served on the FDA Advisory Board, the Medscape Advisory Board, and the IDSA Board of Directors; and his spouse has equity interest in venture capital–funded Capricor. Dr. Belani reviews non-continuing medical education (CME) lectures for and received honoraria and travel reimbursement from Horizon Therapeutics; and has received research funding from the NIH and the Children’s Hospitals and Clinics of Minnesota. Dr. Bowie has provided expert testimony to the Canadian Senate Subcommittee on Bill C-442: An Act Respecting a National Lyme Disease Strategy on behalf of the Association of Medical Microbiology and Infectious Disease Canada; and has received research funding from GlaxoSmithKline, Pfizer Canada, the Canadian Institutes of Health Research, and Vancouver Coastal Health Research Institute. Dr. Branda receives research funding from the Lyme Disease Biobank Foundation and Zeus Scientific; serves as a scientific advisor and consultant to DiaSorin, Inc.; has served as a scientific advisor and consultant for T2 Biosystems; has served on the scientific advisory board of Roche Diagnostics and AdvanDx; has received research funding from Karius, Inc., Alere, Inc., T2 Biosystems, BioMérieux, TBS Technologies, Immunetics, Inc., DiaSorin, Inc., Kephera Diagnostics, Inc., and the Bay Area Lyme Foundation; has participated in unfunded research collaborations with Karius Inc. and Kephera Diagnostics; was a member of the editorial board of the Journal of Clinical Microbiology; was a co-inventor on an application for a patent to protect intellectual property; and his spouse is an employee of Informed DNA. Dr. Clifford receives research funding from the NIH and the Alzheimer’s Association; serves as scientific consultant to Inhibikase and Excision BioTherapeutics; serves on Data and Safety Monitoring Boards (DSMB) for Biogen, Genzyme/Sanofi, Genentech, EMD Serono, Shire, Wave Life Sciences, Pfizer, Atara, Mitsubishi Tanabe, and IQVIA (formerly Quintiles); serves on Progressive Multifocal Leukoencephalopathy (PML) adjudication committees for Amgen, GlaxoSmithKline, EMD Serono, Bristol Myers Squibb, Roche, and the Takeda Oncology (formerly Millennium) Adjudication Committee–FDA, as well as Dr. Reddy’s Laboratories; has previously received research funding from the NIH; and his spouse formerly held stock in Johnson & Johnson. Dr. DiMario has received research funding from Novartis. Dr. Halperin serves as an Editorial Board Member of Neurology, and Vice Chair of the American Academy of Neurology (AAN) Guideline Subcommittee; has stock in Abbott Labs, AbbVie, Merck, and Johnson & Johnson; provides and has previously provided legal expert testimony defending physicians in medical malpractice cases on various neurologic issues, including Lyme disease; has received research funding from NIH, the Centers for Disease Control and Prevention (CDC); and has served as a section editor of neuroinfectious diseases in Neurology & Neuroscience Reports. Dr. Krause receives research funding from the Yale Emerging Infections Program; receives remuneration from Gold Standard Diagnostics for a collaborative research project; has stock in Gilead Sciences and First Trust NASDAQ Pharmaceuticals ETF; has received research funding from the NIH, the Centers for Disease Control and Prevention (CDC), the Gordon and Llura Gund Foundation, and L2 Diagnostics for NIH-sponsored research; has served as a scientific consultant and provided medical education and training for Oxford Immunotec, Inc.; has a patent pending (Enhanced Chemiluminescent enzyme-linked immunosorbent assay for detection of antibodies against Babesia microti), for which US Provisional Patent Application No. 62/580,588, was filed on November 2, 2017; serves on the Board of Directors for the American Lyme Disease Foundation and the Editorial Boards of Pathogens and Plos Neglected Tropical Diseases and the Editorial Advisory Board of Clinical Infectious Diseases; was on the Editorial Board of Journal of Clinical Microbiology, and will be on the Editorial Board of Clinical Microbiology Reviews starting January 2021. Dr. Liang has stock in Johnson & Johnson; received research funding from the Veterans Health Administration, the Arthritis Foundation, and the NIH; has served on the FDA Advisory Panel, Institute of Medicine panels; served as a scientific reviewer for the Research Grant Council of Hong Kong and the NIH; served on the Board of the Lupus Clinical Trials Consortium, Beacon Hill Villages, and Rx Foundation and advised the Institute for Clinical and Economic Review and the China Medical Board; previously had stock in Sequenom; and his spouse has stock in Johnson & Johnson. Dr. Meissner is a current member of the CDC Workgroups and serves as a volunteer consultant on the American Academy of Pediatrics Committee on Infectious Diseases and the NIH DSMB. Dr. Nigrovic receives research funding from the NIH, Department of Defense, and the NIH Center for Research Resources and for Advancing Translational Sciences (NCATS), Global Lyme Alliance, and Peabody Foundation; serves on the Editorial Board for Annals of Emergency Medicine; has served as scientific consultant for Adaptive Technologies; has received research funding from the NIH, Provider and Payer Quality Initiative (PPQI) Research Foundation, Harvard Catalyst, Hood Foundation, Bay Area Lyme Foundation, CDC, Emergency Medical Services for Children (EMSC), the National Patient-Centered Clinical Research Network (PCORNet), Milton Foundation, and Boston Children’s Hospital. Dr. Nocton receives research funding from Bristol Myers Squibb; serves as a member of the Subboard of Pediatric Rheumatology of the American Board of Pediatrics; and has received research funding from AbbVie, NIH, and the Arthritis Foundation. Dr. Pruitt has received research funding from Teva Pharmaceuticals and has served on the AAN Editorial Board of Neurology Clinical Practice. Ms Rips has received research funding from the Center for AIDS Research, Biogen Idec, Hoffmann-LaRoche, Sun Pharmaceutical Industries Ltd., Genzyme, the Alzheimer’s Association, and the American College of Radiology; and has served as a speaker for Teva Pharmaceuticals. Dr. Rosenfeld serves as a Council Member of the American College of Cardiology; has stock in Abbott, Proctor & Gamble, and General Electric; has received Fellowship Support from Boston Scientific, Medtronic, and Abbott Laboratories (formerly St. Jude Medical); has received research funding from Boehringer Ingelheim Pharmaceuticals, Inc.; and has served on the Program Committee and the Patient and Caregivers Committee of the Heart Rhythm Society. Dr. Savoy serves on the American Academy of Family Physicians (AAFP) Board of Directors, as an ex-officio Board member of Delaware Academy of Family Physicians (DAFP), as the Chair of the Centers for Medicare and Medicaid Services (CMS) Advisory Panel on Outreach and Education, and as Secretary of the Board of Directors of the Association of Departments of Family Medicine; receives honoraria from AAFP, DAFP, CMS, and Merck; has served on an Advisory Council for Highmark Health and as an advisor to the AAFP Adolescent Immunization Project; has received honoraria from AAFP; has served as the President of DAFP, as Editor of DelFamDoc, and as a member of AAFP Commissions. Dr. Sood has received research funding from the NIH; and has provided expert testimony for Danaher Lagnese, PC. Dr. Steere receives research funding from the NIH and the Mathers Foundation; has received research funding from the NIH, the American College of Rheumatology, the Mathers Foundation, the English-Bonter-Mitchell Foundation, Immunetics, Inc., Zeus Diagnostics, and the Ounsworth-Fitzgerald Foundation; and has served as a scientific advisor for Baxter Bioscience Institute of Systems Biology, Immunetics, Inc., Roche Diagnostics, and Viramed. Dr. Strle receives research funding from the Slovenian Research Agency; serves as the Head of Health Counsel of the Ministry of Health of the Republic of Slovenia and as a member of the Steering Committee for the European Society of Clinical Microbiology and Infectious Diseases Study Group for Lyme Borreliosis; serves on the Roche Diagnostics Advisory Board on Lyme Disease Diagnostics; and has received honoraria from Roche Diagnostics. Dr. Sundel receives research funding from the NIH and AbbVie, Inc.; serves as a content author and editor for UpToDate; provides expert testimony to Chin-Caplan, PC; has provided expert testimony for Conway Homer, PC; has served as an advisor for Paul Hastings, LLC; has served as a content editor for SimulConsult and as a Medical Education Resources lecturer for CME-granting educational courses; has received remuneration from SimulConsult as a co-investigator for an NIH-sponsored grant; and has received research funding from the NIH. Dr. Tsao receives research funding from the National Science Foundation, NIH, CDC, the Michigan Lyme Disease Association, and the Michigan Department of Health and Human Services; serves as a Scientific Council Advisor Member for the Canadian Lyme Disease Research Network and as a scientific advisor for the American Lyme Disease Association; has received research funding from Michigan State University; has served as an Associate Editor for Ticks and Tick-Borne Diseases and on the Tick Vectors, Surveillance, and Prevention Subcommittee of the US Department of Health and Human Services Tick-Borne Disease Working Group; and has received remuneration for providing educational seminars for Boehringer Ingelheim (formerly Merial). Dr. Wormser receives research funding from Immunetics, Inc., Rarecyte, Inc., Institute for Systems Biology, and Quidel Corporation; serves on the Board of the American Lyme Disease Foundation; provides and has previously provided expert testimony in malpractice cases; has stock in AbbVie, Inc. and Abbott Laboratories; has received research funding from the CDC, NIH, BioMérieux, Bio-Rad Laboratories, and DiaSorin, Inc; has served as a scientific research advisor for Baxter International and as a Lyme disease advisor and expert for the Missouri Board of Registration for the Healing Arts; has a patent approved (US patent no. 10,669,567 B2) for High Sensitivity Method for Early Lyme Disease Detection; filed 2 patent applications related to early Lyme disease detection (application no: 62/277,252) and Lyme arthritis and post-treatment Lyme disease syndrome (application no: 62/725,745); and has served on the Editorial Boards for Clinical Infectious Diseases, Vector-Borne and Zoonotic Diseases, and Ticks and Tick-Borne Diseases. Dr. Zemel has served as an advisor for Novartis Promotional Speakers Bureau. No other disclosures relevant to this article were reported. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. The expert panel expresses its gratitude for thoughtful reviews of an earlier version to the external reviewers. The panel thanks the IDSA, AAN, and ACR for supporting the guideline development process. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Lantos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Lantos, Rumbaugh, Bockenstedt, Falck-Ytter, Aguero-Rosenfeld, Auwaerter, Baldwin, Bannuru, Belani, Bowie, Branda, Clifford, DiMario, Halperin, Krause, Lavergne, Liang, Meissner, Nigrovic, Nocton, Osani, Pruitt, Rips, Rosenfeld, Savoy, Sood, Steere, Strle, Sundel, Tsao, Vaysbrot, Wormser, Zemel. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Phillip Baker has taken “Lyme denialism” to new depths (1). According to the Institute of Medicine, there are at least 116 million people living with acute and chronic pain in the United States. According to Baker, not one of those individuals suffers from chronic Lyme disease as a result of persistent infection with the Lyme spirochete, Borrelia burgdorferi. What is the basis for his opinion? Baker claims that “there is no evidence to indicate that chronic Lyme disease is due to a persistent infection” or that “extended antibiotic therapy is beneficial and safe”. This denialist statement about a disease that causes pain and suffering equivalent to that of diabetes or congestive heart failure ignores a growing body of evidence from the peer-reviewed medical literature that contradicts his opinion (2–5). Baker starts by attacking “Lyme-literate” physicians who use a “Lyme disease specialty laboratory” to diagnose tick-borne disease in a manner that is inconsistent with the surveillance case definition established by the Centers for Disease Control and Prevention (CDC). What Baker fails to tell us is that the CDC admits that its surveillance case definition “was developed for national reporting of Lyme disease” and was “not intended to be used in clinical diagnosis” (6). Thus, the diagnostic approach that Baker endorses is inappropriate for diagnosis of Lyme disease. Furthermore, the 46 patented commercial laboratory tests that Baker recommends for Lyme disease diagnosis have a sensitivity of only 46% and appear to yield results that are biased against women (7–9). Consequently, these commercial tests miss more than one-half of the patients with chronic Lyme disease in the United States. In contrast, the maligned “Lyme disease specialty laboratory” uses diagnostic criteria based on evidence from the peerreviewed medical literature (10, 11), and its “genderneutral” testing has a sensitivity and specificity of 90% (12). Clearly, this testing is preferable for the diagnosis of Lyme disease. As for Baker’s pat statement that “there is no evidence to indicate that chronic Lyme disease is due to a persistent infection,” numerous reports of veterinary cases and animal models confirm persistent infection with the Lyme spirochete in gerbils, hamsters, mice, dogs, monkeys, birds, and horses (13– 15). Among these cases, persistent pathology was seen in mice, dogs, and horses after the animals failed short-course treatment for their infection. Furthermore, there are at least 27 reports of persistent symptoms and failure to eradicate B. burgdorferi infection in humans treated with short-course antibiotic therapy for their tick-borne disease (5). Why does Baker deny these reports? He does so because they do not fit his limited view of Lyme disease. Baker also attacks the safety and efficacy of prolonged antibiotic therapy for chronic Lyme disease, stating that “all of the evidence obtained thus far...indicates no significant benefit as well as serious safety problems” with extended antibiotic therapy for these patients. What Baker fails to tell us is that the number of patients in controlled trials of Lyme disease treatment totals a mere 221 highly selected subjects who do not represent the vast majority of patients with chronic Lyme disease (3–5). Further analysis of these studies reveals that they were “of questionable quality”, lacked the power to detect potentially positive treatment effects, and failed to report predefined endpoints (16). Even so, in two of the four controlled trials, a significant benefit was seen in fatigue and cognition with the limited antibiotic regimen that was used, and safety problems were minimal (17, 18). In larger studies of extended antibiotic therapy, the safety of this treatment was shown to be acceptable, and the benefit of extended therapy was significant in terms of cognition, fatigue, and myalgic pain, although it took 6 –12 months of i.v. therapy to achieve this benefit (19, 20). In summary, Baker’s denialist view of the Lyme disease epidemic ignores significant evidence from the peer-reviewed medical literature that contradicts his opinion. It follows that practitioners who subscribe to his narrow view are abandoning the multitude of patients with acute and chronic pain who would benefit from treatment for their persistent spirochetal infection.

Background:Finland conducts public health surveillance for Lyme borreliosis (LB) based on clinically diagnosed and laboratory-confirmed cases. We used data from seroprevalence studies to determine the extent to which LB cases were underascertained by public health surveillance.Methods:The numbers of incident symptomatic LB cases in 2011 in six regions in Finland were estimated using (1) data from Borrelia burgdorferi sensu lato seroprevalence studies, (2) estimates of the proportion of LB infections that are asymptomatic, and (3) estimates of the duration of LB antibody detection. The numbers of estimated incident symptomatic LB cases were compared with the numbers of surveillance-reported LB cases to estimate regional underascertainment multipliers. Underascertainment multipliers were applied to the numbers of surveillance-reported LB cases in each region in 2021 and summed to estimate the number of symptomatic LB cases in Finland among adults in 2021. A sensitivity analysis evaluated the impact of different durations of antibody detection.Results:Using an asymptomatic proportion of 50% and a 10-year duration of antibody detection, the estimated regional underascertainment multipliers in Finland ranged from 1.0 to 12.2. Applying the regional underascertainment multipliers to surveillance-reported LB cases in each region and summing nationally, there were 19,653 symptomatic LB cases in Finland among adults in 2021 (526/100,000 per year). With 7,346 surveillance-reported LB cases in Finland among adults in 2021, the estimated number of symptomatic LB cases indicate that there were 2.7 symptomatic LB cases for every surveillance-reported LB case among adults. With a 5- or 20-year duration of antibody detection, there were an estimated 36,824 or 11,609 symptomatic LB cases among adults in 2021, respectively.Discussion:Finland has robust public health surveillance for LB, but cases are underascertained. This framework for estimating LB underascertainment can be used in other countries that conduct LB surveillance and have conducted representative LB seroprevalence studies.

Support for deer herd reduction on offshore Islands of Maine, U.S.A

Research on patients with persistent symptoms despite prior treatment for Lyme disease can be challenging to interpret given the diversity of criteria selected to characterize Lyme disease and to define the syndrome of those with persistent symptoms. Because most research studies only include patients with well-documented prior Lyme disease, the generalizability of the study results is limited, excluding the larger group of patients often seen in community practice who do not meet these stringent enrollment criteria. Researchers at the Lyme and other Tick-borne Diseases Clinical Trials Network (LTD-CTN) recognized early on that a research classification system was needed to facilitate the design of studies that are more inclusive. This paper presents a proposed research classification system. Criteria used in published clinical research on previously treated Lyme disease were reviewed. Clinical expertise was provided by principal investigators in the LTD-CTN. Further input was obtained from a diverse panel of stakeholders in the field, including clinicians, academic researchers, and patient advocates. This classification system was developed based on feedback collected from all these sources. The new research classification system proposes criteria for Lyme disease at different levels of diagnostic certainty: well-defined, probable, possible, and uncertain. Criteria for ascertainment for each classification level and additional factors to be considered in patient selection for research are described. The proposed research classification system should improve the quality and generalizability of clinical research by providing clear case definitions for enrollment of a more diverse group of patients with sequelae from Lyme disease.

Background Lyme borreliosis (LB), the most common tickborne disease in Europe, is endemic in Germany. Nine German states (with 42% of the German population) conduct LB surveillance with mandatory notification by clinicians and laboratories but an analysis of outpatient claims estimated that only one of every six LB cases in these states were reported. We estimated the LB incidence after adjusting for under-ascertainment of public health surveillance. Methods Nationally representative studies estimated the prevalence of antibodies against Borrelia burgdorferi sensu lato in adults and children in Germany. Published estimates of the asymptomatic proportion and the duration of antibody detection were used to estimate the number of LB cases from seroprevalence data in states that conduct LB surveillance. The number of estimated LB cases were compared to the number of surveillance-reported cases to derive under-ascertainment multipliers for adults and children. The derived multipliers were applied to the number of reported cases in 2021 to estimate the number and incidence of LB cases in the states that conducted surveillance in 2021. A sensitivity analysis evaluated the impact of different antibody durations. Results Using a 50% asymptomatic proportion and 10-year antibody duration, the estimated number (population-based incidence) of LB cases in states that conducted surveillance was 128,870 (408/100,000) in 2021. Since there were 11,051 reported cases in these states, these data indicate there were 12 LB cases in 2021 for every reported case in these states. Using 20-year or 5-year antibody duration, the estimated number (incidence) of LB cases in the states that conducted surveillance was 64,935 – 259,740 (204 - 816/100,000) in 2021, respectively. Conclusion Incidence of LB in states that conduct surveillance in Germany is higher than reported. Under-ascertainment of LB cases in states that conduct surveillance is even greater than that estimated in a claims data analysis of medically-attended LB cases. Enhancements of LB surveillance, including expanding nationwide, would facilitate further elucidation of the true LB disease burden in Germany. Disease prevention efforts, including availability of an efficacious vaccine, are needed to address this important public health problem. Disclosures Julia Olsen, BS, Pfizer: Employee Gordon Brestrich, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Andreas Pilz, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds|Pfizer: Stocks/Bonds Kate Halsby, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Patrick Kelly, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Claudius Malerczyk, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds Frederick Angulo, DVM PhD, Pfizer: Employee|Pfizer: Stocks/Bonds James H. Stark, PhD, Pfizer: Employee|Pfizer: Stocks/Bonds.