Lyme Disease RHEUMATOLOGY BOARD REVIEW MANUAL. Table of Contents. Introduction Early Lyme Disease Lyme Arthritis... 7

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1 RHEUMATOLOGY BOARD REVIEW MANUAL PUBLISHING STAFF PRESIDENT, PUBLISHER Bruce M. White EXECUTIVE EDITOR Debra Dreger SENIOR EDITOR Bobbie Lewis EDITOR Robert Litchkofski ASSISTANT EDITOR Melissa Frederick EDITORIAL ASSISTANTS Amanda Arkles Rita E. Gould SPECIAL PROGRAMS DIRECTOR Barbara T. White, MBA PRODUCTION DIRECTOR Suzanne S. Banish PRODUCTION ASSOCIATES Tish Berchtold Klus Christie Grams PRODUCTION ASSISTANT Mary Beth Cunney ADVERTISING/PROJECT MANAGER Patricia Payne Castle NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Internal Medicine. Endorsed by the Association for Hospital Medical Education The Association for Hospital Medical Education endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in medical education as they affect residency programs and clinical hospital practice. Lyme Disease Series Editor: Janet F. Burkholder, MD Assistant Professor of Medicine Associate Chief, Section of Rheumatology Temple University School of Medicine Philadelphia, PA Author: Judith A. O Donnell, MD Assistant Professor of Medicine and Public Health Division of Infectious Diseases Department of Medicine MCP Hahnemann University School of Medicine Philadelphia, PA Table of Contents Introduction Early Lyme Disease Lyme Arthritis Chronic Lyme Disease References Suggested Readings Cover Illustration by Christie Grams Copyright 2001, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA , All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, electronic, photocopying, recording or otherwise, without the prior written permission of Turner White Communications, Inc. The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White Communications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the authors and do not necessarily reflect those of Turner White Communications, Inc. Rheumatology Volume 5, Part 1 1

2 RHEUMATOLOGY BOARD REVIEW MANUAL Lyme Disease INTRODUCTION Lyme disease is currently the most common vectorborne disease in the United States. In 1998, more than 16,000 new cases were reported to the Centers for Disease Control and Prevention (CDC), and this figure likely underestimates the actual number of cases that occurred. Lyme disease is caused by 3 genospecies of the spirochete Borrelia: Borrelia burgdorferi, Borrelia garinii, and Borrelia afzelii. These are collectively referred to as Borrelia burgdorferi sensu lato. B. garinii and B. afzelii are the etiologic agents of Lyme disease in Europe, while B. burgdorferi causes Lyme disease in North America. Throughout this article, the term B. burgdorferi (Bb) will refer to the specific genospecies or to B. burgdorferi sensu lato. Lyme disease is a disease of protean manifestations. Its clinical stages are well described, but atypical presentations continue to appear in the published medical literature. This manual discusses the varied clinical presentations of Lyme disease, appropriate use of available diagnostic tests, and recommended treatment strategies. EARLY LYME DISEASE INITIAL PRESENTATION A 29-year-old woman presents to her primary care physician in June with a 5-day illness consisting of fevers, chills, and an erythematous, swollen thigh. HISTORY The patient explains that approximately 5 days ago she began feeling very tired, had a poor appetite, and experienced chills and myalgias. Three days ago, she developed intermittent fevers ranging from 100 to 101 F, occasional headaches, and worsened myalgias. Yesterday, she noticed a red swollen patch of skin on her left outer thigh that was pruritic and had a burning sensation. She denies any trauma to the area or any prior similar occurrences. The patient s past medical history is significant only for seasonal allergies and childhood asthma. She has no medication allergies, and her only medication is cetirizine. The patient is married, has no children, works as a retail store manager, and lives in Denver, Colorado. She has 2 cats and 1 dog. She denies tobacco use and illicit drug use, and drinks 2 to 4 glasses of wine weekly. She is sexually active solely with her husband and believes he is monogamous. Four weeks ago, she and her husband returned from a 10-day vacation in Rhode Island. PHYSICAL EXAMINATION Physical examination reveals a tired-appearing woman with an oral temperature of F, pulse of 100 bpm, and blood pressure of 112/74 mm Hg. She has no photophobia or mucosal lesions. Her neck is supple, and there is no palpable lymphadenopathy. Examination of the heart, lungs, and abdomen are unremarkable. Skin examination reveals a 7 12 cm, ill-defined, erythematous area involving her left lateral thigh extending from the hip to mid-thigh and from the groin laterally. The borders are not raised, and the area is very warm and mildly tender. Left calf tenderness, hip, ankle or knee joint abnormalities, or pretibial edema are not present. The rest of the skin examination is unremarkable. What is the differential diagnosis? Differential Diagnosis The skin involvement described in this patient is consistent with contact dermatitis, ringworm, cellulitis, or erythema migrans (EM). The patient should be queried about any exposures to new soaps, perfumes, clothing, or other environmental risks associated with a focal contact dermatitis and any exposures to children, 2 Hospital Physician Board Review Manual

3 who may be infected with the dermatophytes (fungi) that cause ringworm. However, the presence of fever argues against these diagnoses. Cellulitis is an acute bacterial infection of the skin and subcutaneous tissue that presents with systemic signs of infection as well as diffuse erythema, edema, warmth, and tenderness of the involved area. Staphylococci and streptococci are the usual pathogens, barring specific epidemiologic exposures. The edges of the cellulitic lesion are not raised or indurated, and there can be lymphadenopathy involving regional nodes draining the infected area. Blood cultures are frequently negative. Cellulitis would be somewhat unusual in this young, nondiabetic patient without any antecedent trauma, history of eczema or chronic lymphedema, or epidemiologic exposure. Erythema migrans is the characteristic skin lesion seen in early localized Lyme disease (Figure 1A). EM begins as an erythematous macule or papule at the site of the tick bite. The most common sites of tick bites in adults are the groin, thigh, and axilla; children can often have EM lesions on their scalp. The lesion expands concentrically over several days, developing a final median diameter of 15 cm or more. Classically, EM lesions develop central clearing, producing the hallmark bull s- eye rash. However, there are numerous reports of no central clearing with EM, including one study of culture-proven early Lyme disease in which close to two-thirds of EM cases had no central clearing. 1 Additionally, EM lesions can be vesicular, become necrotic, or appear indurated. EM lesions feel hot on examination and may be painless or painful. Pruritus and dysesthesias are often reported by patients. It is thought that 25% or more of patients with Lyme disease may never develop an EM lesion. Almost all patients with EM also have some constitutional symptoms, including fever, headaches, malaise, arthralgias, and/or myalgias. This patient s presentation is compatible with early localized Lyme disease. HOSPITAL ADMISSION AND LABORATORY EVALUATION The physician makes a diagnosis of cellulitis and prescribes a 7-day course of oral cephalexin. The patient returns to the physician s office 5 days later with persistent fevers up to 102 F and spread of the erythema to her left buttock flank and medial thigh. The physician admits her to the hospital for intravenous (IV) antibiotic therapy with cefazolin and vancomycin and orders a complete blood count (CBC), blood chemistry and liver function tests, and blood cultures. The patient s hemoglobin and platelet count as well as chemistry and liver function tests are normal. White blood cell (WBC) count is 15,000/mm 3, with a differential of 72% segmented neutrophils, 2% band forms, 24% lymphocytes, and 2% monocytes. Over the next 2 days, fevers between 101 F and 102 F and a leukocytosis continue; blood cultures are reported as negative at 48 hours. The patient now has arthralgias in her hands and knees. An infectious diseases consultation is requested to evaluate non-healing cellulitis, and a rheumatology consultation is called to evaluate the fevers, arthralgias, and myalgias. Physical examination reveals additional concentric erythematous areas across the patient s back and no evidence of joint inflammation or diminished range of motion. The patient is observed to have drooping of the left side of her mouth, with ptosis and decreased sensation on the left side of her face. What is the most likely diagnosis at this time? Is this patient at risk for Lyme disease? Stages of Lyme Disease It is unlikely that this patient has cellulitis. Staphylococci and streptococci would be the most likely bacterial pathogens in this setting and should have been effectively treated by oral cephalexin and the current IV regimen. The progression of the erythema, persistence of fever, development of arthralgias, and new findings of concentric erythematous lesions and abnormal neurologic examination all point to the diagnosis of early Lyme disease. Several days after the initial EM lesion develops, multiple secondary EM lesions occur at distant sites from the tick bite, most often on the torso. These lesions represent spirochetemia and dissemination of infection with Bb and are considered one of several manifestations of early disseminated Lyme disease (Table 1). Bell s palsy (paralysis of the facial nerve) (Figure 2) occurs in approximately 10% of patients with Lyme disease, and in 25% of these patients it is bilateral. In the case patient, the presence of the EM lesions and neurologic abnormality makes a strong case for the diagnosis of Lyme disease. 2 Traditionally, Lyme disease was divided into 3 stages. The primary stage manifestation was erythema migrans, followed by neurologic or cardiac involvement in secondary stage Lyme, and finally arthritis or late neurologic manifestations were seen in tertiary Lyme. This classification system has more recently been modified to reflect the knowledge that Bb can disseminate early in the disease and that joint and central system involvement may occur at any time in the illness. Early Lyme disease is seen within 8 weeks of the tick bite and is divided into early localized or early disseminated, while late Lyme disease generally occurs more than 8 weeks after the tick bite. Rheumatology Volume 5, Part 1 3

4 Table 1. Lyme Disease Manifestations by Stage Stages of Disease* Early localized Early disseminated Late Clinical Manifestations Erythema migrans: a large red, flat lesion often with central clearing seen on thigh, groin, or axilla Fatigue, malaise, headache, and arthralgias Multiple EM lesions: represents spirochetemia and dissemination of infection Lyme carditis: presents as fluctuating degrees of atrioventricular heart block, rarely with myopericarditis; block resolves without therapy Aseptic meningitis: lymphocytic CSF pleocytosis Facial nerve palsy: occurs with or without other neurologic symptoms Acute radiculoneuritis: may occur alone or with other neurologic manifestations; can involve any dermatome; presents as severe radicular pain; muscle weakness and sensory loss occur days to weeks later Arthritis: may be migratory and oligoarticular, occurring intermittently; associated with an inflammatory synovial fluid with ,000 WBCs/mm 3 and neutrophil predominance Chronic Lyme arthritis: defined as 1 or more years of persistent joint inflammation; associated with certain HLA-DR subtypes, poor response to antibiotic therapy Subacute encephalopathy: presents as mood disturbance, personality change, sleep disturbances, memory loss, and other neurocognitive deficits; examination of CSF and neuropsychiatric testing should be performed Lyme radiculoneuropathy: chronic form is milder, mostly consisting of sensory loss without severe pain; responds to antibiotic therapy Acrodermatitis chronica atrophicans: red, violaceous lesions that become sclerotic; seen in Europe CSF = cerebrospinal fluid; EM = erythema migrans; HLA = human leukocyte antigen; WBC = white blood cell. *The incubation period from time of bite is 10 days to several weeks for early localized disease, 4 to 8 weeks for early disseminated disease, and several months to years for late disease. Risk Factors Before considering a diagnosis of Lyme disease, the clinician must first determine whether there has been any reasonable possibility of contact with the tick vector. This patient does not reside in an endemic area for Lyme disease, but she recently traveled to Rhode Island, an area known to be endemic for Lyme disease. In the United States, the majority of Lyme disease cases occur in the northeastern states from Maryland to Massachusetts, and in the north-central states of Wisconsin and Minnesota. There is a small pocket of endemic Lyme disease in northern California as well. Connecticut, Rhode Island, New York, New Jersey, Pennsylvania, and Wisconsin are the top 6 states reporting new cases of Lyme disease each year. In addition to time spent in an endemic area, the time of year also plays an important role in determining the probability of infection. The vector for Bb is the deer tick, Ixodes scapularis in the northeastern and northcentral states and Ixodes pacificus on the U.S. West Coast. Peak time for acquisition is late spring through early fall and is directly related to the tick s life cycle. The Ixodes spp. undergo 3 stages of development: larva, nymph, and adult. Larvae, which do not transmit Bb, molt into nymphs in early spring. Nymphs feed on small rodents and other mammals through spring into fall, when they molt into adults. Both nymphs and adults transmit infection, with the nymph being responsible for 90% of disease transmission. Outdoor activities in wooded areas or areas with tall grasses in regions with significant deer populations allow for human contact with I. scapularis. This patient did visit an area endemic for Lyme disease at peak season. ADDITIONAL HISTORY The patient and her husband traveled throughout Rhode Island, including Block Island and other shore points. They spent most of their time sightseeing, including many outdoor walks. The patient does not recall any tick bites during the vacation. 4 Hospital Physician Board Review Manual

5 A Figure 1. (A) Erythema chronicum migrans and (B) Ixodes scapularis. Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, Used by permission of the American College of Rheumatology. B Figure 2. Bell s palsy in Lyme disease. Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, Used by permission of the American College of Rheumatology. How helpful is the history of tick bite when considering a diagnosis of Lyme disease? Many patients with Lyme disease never recall having a tick bite. Ixodes spp. ticks are quite small the adult measures only 2 mm in width (Figure 1B). Many patients reporting tick bites often have been bitten by another insect (such as a spider) or the larger (and usually visible) dog tick. Due to the size of the Ixodes spp. tick, patients often never see the attached tick, which can allow for prolonged attachment and feeding. The duration of attachment of the tick is an important factor in Lyme disease transmission. Animal studies have shown that ticks must remain attached for 36 to 48 hours to transmit B. burgdorferi. A retrospective study looking at infected humans showed the risk of infection was significantly higher, between 18% to 25%, when ticks were attached for more than 72 hours. 3 In general, it is thought that 24 hours or more of attachment is necessary before a person should be considered at risk for Lyme disease. Thus, while it is important to inquire about tick bites in patients with possible Lyme disease, a positive or negative history should neither convince nor dissuade clinicians from further pursuit of the diagnosis. What further testing can aid in the diagnosis of Lyme disease? What factors must be considered when interpreting results of serologic tests for Lyme disease? Would cultures be helpful in this patient? Serologic Tests Lyme disease is a clinical diagnosis that can be supported by appropriate serologic test results; however, the diagnosis is never made with serology alone. Serology should never be used to screen patients for Lyme disease who are asymptomatic or who exhibit nonspecific constitutional symptoms. Additionally, there is no need to order serologic tests in patients who present with a classic EM lesion. The diagnosis of Lyme disease is made by the skin manifestations at this stage of infection. Serologic tests are often negative during early localized Lyme disease because the patient has not yet had time to mount a measurable immune response to Bb. Serology should be used in specific settings where the clinical presentation is consistent with early disseminated or late Lyme disease and the patient has a reasonable possibility of tick contact. The case patient was likely infected 4 to 5 weeks ago and has evidence of early disseminated Lyme disease. Serologies may be ordered to support the clinical diagnosis when the rash is not distinctive. Because of the multitude of Lyme antibody tests, lack of standardization of tests, inter- and intra-laboratory variability of results, and numerous problems with falsepositives, the Second National Conference on Serologic Diagnosis of Lyme Disease and the American College of Physicians began advocating a 2-step approach to serologic diagnosis of Lyme disease in the mid 1990s (Figure 3). This approach is now widely accepted; it consists of an initial enzyme immunoassay (EIA, such as enzyme-linked immunoabsorbent assay [ELISA]) or immunofluorescence assay (IFA) followed by Rheumatology Volume 5, Part 1 5

6 Patient with signs and/or symptoms possibly consistent with early disseminated or late Lyme disease Initial test: B. burgdorferi enzyme immunoassay or immunofluorescence assay Negative No serologic evidence of Lyme disease Negative False-positive initial test No serologic evidence of Lyme disease Positive or equivocal Supplementary test: B. burgdorferi Western blot Positive Serologic evidence of past or present infection with B. burgdorferi Figure 3. Algorithm for use of Lyme serologies in individuals suspected of having Lyme disease. supplementary immunoblotting when appropriate. The first-step tests are referred to as initial and not screening because they do not have appropriate specificity to be used as a true screening tool. The second-step tests are referred to as supplemental rather than confirmatory because they evaluate for similar antigens and have limited specificity. If the first test performed is positive or equivocal, then the second-step test, a Western blot, should be ordered. If the Western blot is negative, then the patient does not have serologic evidence of Lyme disease and should be considered to have a falsepositive first-step test. If the Western blot is positive, then the patient has serologic evidence of infection with Bb. This result does not necessarily imply that the patient has active Lyme disease at the time of serologic testing, only that the patient has evidence of either past or present infection. The ultimate interpretation of the test results can be done only within the clinical context of the patient s presentation. The 2-step approach provides better sensitivity and specificity than use of either test alone. The sensitivity is approximately 70% in early disease and 100% in late disease; the specificity approaches 90%. Interpretation of Tests First, while either an EIA/ELISA or an IFA is suggested as an appropriate first-step test, the EIA/ELISA is probably the preferred test because the IFA is more difficult for laboratory technicians to interpret and may be more likely to be read as falsely positive by a technician unfamiliar with the test. Second, the Western blot is an immunoblot that separates the specific IgM and IgG antibodies to Bb into distinct bands based on mass. Many laboratories automatically report both IgM and IgG antibody Western blot results. After the first 4 weeks of infection, a positive IgM Western blot is not useful and should not be used to support a diagnosis of Lyme disease. Additionally, the IgM antibodies may be falsely positive, and a positive IgM Western blot with a negative IgG Western blot should never be interpreted as a positive second-step test. Third, all of the serologic tests for Lyme disease are qualitative tests. The absolute number that may be reported by the laboratory for the B. burgdorferi ELISA test should be interpreted as positive or negative based on that particular test s defined cut-off point. The absolute number should never be used to assess disease activity. Finally, once a patient is found to have serologic evidence of Lyme disease, there is no reason for repeat Lyme serologic tests. These tests are not useful for assessing treatment success or for following disease activity over time. Patients may remain seropositive for Lyme disease for years after infection and treatment. Repeating these tests only adds to the confusion around them and usually leads to inappropriate re-treatment. Cultures Bb can be successfully cultured only in specific settings. In patients with EM, the culture of an aspirate of the leading edge of the lesion has yielded a positive result in 70% of patients in one series. 4 Blood cultures are rarely positive, except during early disseminated disease. Cultures are not routinely recommended in suspected cases of Lyme disease, and need not be performed in this patient. DIAGNOSIS The consulting infectious diseases specialist and the rheumatologist concur that the patient most likely has early disseminated Lyme disease. Lyme disease ELISA and Western blot are ordered, and the IV antibiotics are discontinued. Oral amoxicillin 500 mg 3 times daily is prescribed for a total of 21 days. The fevers resolve within 36 hours of initiation of amoxicillin therapy and the patient is discharged to home. The ELISA and Western blot (both IgM and IgG) are reported as positive 1 week later. At initial presentation, this patient had early localized 6 Hospital Physician Board Review Manual

7 Lyme disease with the EM lesion; without proper therapy she has progressed to the next stage of Lyme disease, early disseminated Lyme disease. What is appropriate therapy for early Lyme disease? Antibiotic Therapy Oral therapy is the preferred treatment for early localized Lyme disease and for those patients with early disseminated Lyme disease without carditis or aseptic meningitis (Table 2). Doxycycline and amoxicillin are felt to be equally efficacious. Patients should be advised that their associated constitutional symptoms may resolve slowly, potentially persisting for a few weeks after completion of therapy. They should also understand that additional courses of antibiotics do not alleviate these symptoms. PATIENT FOLLOW-UP The patient returns to her primary physician s office 10 days after discharge. She reports some residual myalgias but no arthralgias. The primary EM lesion and the lesions across her back are faded, and the primary lesion is only 6 cm in diameter. She notes that she has not had her menses for 8 weeks. The patient explains that her menstrual cycle is irregular, and she often goes as long as 6 to 7 weeks between menses. A urine human chorionic gonadotropin test performed in the office is positive. Will the diagnosis and treatment of Lyme disease impact on her fetus? Like syphilis, the Bb spirochete has the potential for transmission across the placenta. In contrast to syphilis, a definitive congenital Lyme disease syndrome has not been identified in children born to mothers infected with Bb during pregnancy. Therefore, women such as this patient with Lyme disease during pregnancy should not be counseled to terminate their pregnancies. This patient should continue her 21-day course of amoxicillin as originally prescribed and should be reassured that the fetus will not be harmed. The tetracycline class of antibiotics is contraindicated in pregnancy. LYME ARTHRITIS INITIAL PRESENTATION A 16-year-old male without any past medical history presents in December with his mother to her rheumatologist s office complaining of right knee pain, swelling, and erythema. HISTORY The patient says that the pain began approximately 3 weeks ago. Soon after, he began to note swelling of the right knee, which has increased over the past 2 weeks. Over the past few days, the knee has become somewhat red, and the patient has had difficulty ambulating due to the pain. He also notes feeling hot and cold but has not measured his temperature. He denies any trauma to the joint and has no other complaints. The patient lives in Philadelphia, Pennsylvania, with his parents and 2 siblings. He attends high school, where he is active on the basketball and baseball teams. He has been unable to practice with the basketball team for the past 2 weeks due to his knee symptoms. His family history is significant for his mother s diagnosis of rheumatoid arthritis 1 year ago. He denies tobacco and illicit drug use. Upon questioning without his mother in the room, he admits to drinking beer at weekend parties. He initially denies all sexual activity, but with specific questioning regarding sexual practices, admits to receiving oral sex from a former girlfriend 2 months ago. There are no pets in the home. He is currently not working but had been a counselor at a day camp in a city park during the previous summer. His travel history is significant for 3 weekend trips to the New Jersey shore. PHYSICAL EXAMINATION Vital signs are within normal limits except for an oral temperature of F. The right knee is obviously swollen, red, and warm to touch and has a large effusion. Range of motion is moderately limited, and pain is elicited during range-of-motion testing. A genitourinary examination is normal and reveals no urethral discharge. The rest of the examination is unremarkable. What is the differential diagnosis? Differential Diagnosis The differential diagnosis in a patient with fever and an acute inflammatory monarthritis of his knee includes septic arthritis, early rheumatoid arthritis, spondyloarthropathy, trauma, gout, or pseudogout. The absence of systemic features such as rash, back pain, diarrhea, or adenopathy makes psoriatic arthritis and inflammatory bowel disease less likely in this patient. Gout and pseudogout are rare in this age group and are easily diagnosed by synovial fluid analysis. Early rheumatoid arthritis can Rheumatology Volume 5, Part 1 7

8 Table 2. Recommended Treatment for Lyme Disease by Stage in Adults Stages First-Line Therapies Alternative Therapies Comments Early Localized Erythema migrans Early Disseminated Doxycycline 100 mg po bid days OR amoxicillin 500 mg po tid days Cefuroxime axetil 500 mg po bid 21 days OR clarithromycin 500 mg po bid days Doxycycline preferred if concomitant ehrlichiosis is suspected Carditis Ceftriaxone 2 g IV daily OR cefotaxime 2 g IV q8h OR penicillin 3 4 million units q4h (all regimens for days) Doxycycline 100 mg po bid OR amoxicillin 500 mg po tid (both regimens for 21 days) Oral regimens should be used only if first-degree block with PR interval < 0.3 seconds is present. Can change to oral regimen once clinical response maintained Facial palsy Doxycycline 100 mg po bid days OR amoxicillin 500 mg po tid days Ceftriaxone 2 g IV daily for days Some experts suggest lumbar puncture to rule out CSF abnormality prior to giving oral regimen Meningitis Late Lyme Disease Ceftriaxone 2 g IV daily OR cefotaxime 2 g IV q8h (both for 21 days) Penicillin million units daily for 21 days Should complete therapy with IV agents Arthritis Doxycycline 100 mg po bid for 28 days OR amoxicillin 500 mg po tid for 28 days Ceftriaxone 2 g IV daily for days IV therapy only for recurrent arthritis or oral treatment failures Neurologic Ceftriaxone 2 g IV daily for days OR cefotaxime 2 g IV q8h for days Penicillin million units daily for days Treatment for longer than 28 days has not been shown to improve outcome bid = twice a day; CSF = cerebrospinal fluid; IV= intravenous; po = orally; q = every; tid = three times per day. present with an acute arthritis of 1 joint. Reiter s syndrome may present with arthritis alone and is a consideration. The most important diagnosis to consider in this setting is septic arthritis because it is rapidly destructive; it can be successfully treated with early initiation of antibiotic therapy and joint destruction averted. The patient s clinical findings may be compatible with septic arthritis. The most likely bacterial pathogens are Staphylococcus aureus, Group A and B streptococci, and Neisseria gonorrhoeae (the most common cause of septic monoarticular arthritis in adults under the age of 30 years). Obtaining a thorough sexual history by asking specific questions about various sexual practices in a nonjudgmental manner is of paramount importance in this clinical scenario. While female-to-male, oral-to-genital transmission of the gonococcus is less common than with vaginal intercourse, N. gonorrhoeae must still be considered in this adolescent male. Synovial fluid, blood, and urethral swabs should be collected and sent for culture or DNA testing for gonococcus. Finally, this patient s clinical presentation and epidemiologic risk factors make Lyme arthritis due to infection with Bb a diagnostic possibility. HOSPITAL ADMISSION AND LABORATORY TESTING Arthrocentesis performed in the office yields 30 ml of purulent fluid. The patient is admitted to the hospital for further management and IV antibiotics. Blood cultures, a urethral swab for N. gonorrhoeae and Chlamydia trachomatis, a CBC, blood chemistry and rheumatoid factor tests, and erythrocyte sedimentation (ESR) rate measurement are ordered. Preliminary synovial fluid results include a WBC count of 29,720/mm 3, with 60% segmented neutrophils, 28% lymphocytes, and 10% monocytes and a red blood cell count of 2400/mm 3. Evaluation for crystals is negative. Gram stain shows many neutrophils and no organisms. Cultures are pending. 8 Hospital Physician Board Review Manual

9 How do the synovial fluid findings affect the differential diagnosis? The high number of WBCs with neutrophil predominance is consistent with early septic arthritis or an inflammatory arthropathy. The absence of organisms on Gram stain does not rule out the diagnosis of bacterial arthritis because two-thirds of patients with septic arthritis will not have organisms identified on synovial fluid Gram stain. However, Lyme arthritis can also present with similar synovial fluid parameters and should remain high on the differential diagnosis list. If the patient has Lyme arthritis, it is late stage Lyme disease, which is manifested as either arthritis or neurologic disease (Table 1). Joint involvement may be polyarticular during the early disseminated stage, but as the disease progresses the attacks are limited to 1 or 2 joints. The knee is involved in 90% of late Lyme arthritis cases. The involved joint is swollen, painful, and stiff, with the swelling and stiffness often appearing worse than the degree of pain experienced by the patient. The synovial fluid will contain large numbers of WBCs, with a majority being neutrophils. Untreated Lyme arthritis may result in chronic arthritis and destruction of the joint space. What tests should be done to determine whether the patient has Lyme arthritis? Serologic tests would be helpful in supporting the diagnosis in this setting. Both ELISA and Western blot for Bb should be ordered using the 2-step testing approach. PCR Assay Joint fluid culture for Bb is of minimal value and should not be performed. Polymerase chain reaction (PCR) assays are available for identification of Bb in various clinical specimens, including blood, skin, synovial fluid, cerebrospinal fluid, and urine. PCR testing of synovial fluid is the most helpful application of this technology in the diagnosis of Lyme disease. In a study involving synovial fluid samples from 88 patients with Lyme arthritis, PCR assay was found to have a sensitivity of 85% and a specificity of 100%. 5 PCR testing of synovial fluid can confirm the clinical diagnosis and identify potential treatment failures and thus should be strongly considered in patients with possible Lyme arthritis, such as this young man. PCR assay should also be performed when patients with known Lyme arthritis exhibit recurrent disease after antibiotic treatment; a positive test indicates need for a second treatment. DIAGNOSIS The patient is empirically treated with nafcillin and ceftriaxone to provide appropriate coverage for the most likely pathogens (ie, S. aureus, the β-hemolytic streptococci, N. gonorrhoeae, and Lyme disease). At 72 hours, the patient s fevers are diminished somewhat. The blood and synovial fluid cultures, gonorrhea and chlamydia testing, and rheumatoid factor test are negative. The ESR is 89 mm/hr. Both the Bb ELISA and IgG Western blot are reported as positive. The anti-staphylococcal antibiotic is discontinued and ceftriaxone is maintained. How should this patient s antibiotic therapy be managed? Lyme arthritis can be treated successfully with either oral or IV antibiotics. Both doxycycline and amoxicillin given for a 28-day treatment course are currently accepted as appropriate regimens. Ceftriaxone 2 g daily has also been effective and can be given for a total of 14 to 28 days. Large prospective studies comparing oral and IV regimens in the treatment of Lyme arthritis have never been done. Most experts recommend an oral regimen as firstline therapy for Lyme arthritis, reserving IV ceftriaxone for patients with recurrent Lyme arthritis. Intravenous ceftriaxone is considered alternative therapy for first-episode Lyme arthritis (Table 1) due to its cost and the need for prolonged IV access with its known potential complications. Once management of the effusion is better controlled, the patient can be changed to an oral antibiotic regimen and treated for a total of 28 days. FOLLOW-UP At 5 days, the patient s fevers have completely resolved. He is discharged on the seventh hospital day on oral doxycycline for a total course of 28 days. His mother wants to know the likelihood of a complete functional recovery. What is the natural history of untreated and treated Lyme arthritis? Lyme Arthritis In patients with untreated early Lyme disease, Lyme arthritis usually begins several months after infection. Approximately 60% of these individuals experience attacks of intermittent joint swelling, usually of the knee. In young children, these attacks last an average of 1 month; in adolescents and adults, bouts of arthritis can last for 1 to 5 months before remitting. Without treatment, patients can develop recurrent arthritis; the Rheumatology Volume 5, Part 1 9

10 proportion of patients developing these recurrences decreases by 10% to 20% yearly. 6 Between attacks, joints appear relatively normal. Histopathologically, the involved synovium will have synovial cell hyperplasia and mononuclear cell infiltrates, consistent with a chronic inflammatory arthritis. Chronic Lyme arthritis is defined as continuous joint inflammation for at least 1 year s duration; it occurs in a small minority of untreated patients. The overwhelming majority of patients with acute and chronic Lyme arthritis will respond to antibiotic therapy. In the subset of patients who do not have resolution of arthritis after antibiotic therapy, synovial fluid PCR assay for Bb should be performed. If positive, the patients should be treated again with IV ceftriaxone therapy for 1 month. Patients in whom inflammation persists after a second course of antibiotic therapy are often labeled treatment-resistant. Additional courses of antibiotic therapy or prolonged courses of ceftriaxone have not proved beneficial in these individuals. Chronic Lyme arthritis after successful eradication of Bb from the joint space is thought to be secondary to an autoinflammatory/autoimmune response in certain genetically predisposed individuals. Infrequently, patients with successfully treated arthritis may present years later with neuroborreliosis, the other manifestation of late Lyme disease. The case patient and his mother should be informed of his overwhelming chances for complete recovery but should understand that any recurrence of arthritis should be evaluated by a physician. CHRONIC LYME DISEASE INITIAL PRESENTATION A 38-year-old woman presents as a new patient to a rheumatologist s office in St. Louis, Missouri, complaining of low-grade fevers, diffuse myalgias and arthralgias, and extreme fatigue. She states, I think my Lyme disease is acting up again, and I need more antibiotics. HISTORY Upon questioning, the patient presents a large binder with detailed notes regarding her recent medical history. Her past medical history is significant for irritable bowel syndrome and migraines. She and her family moved from Long Island, New York, to St. Louis 6 months ago. Approximately 3 years ago, she was bitten by a tick in her backyard and 24 to 36 hours afterwards developed a red, swollen lump the size of a quarter at the site of the bite. She was seen by her primary care physician and given a 2-week course of oral doxycycline. Three months later, she developed headaches, myalgias, and arthralgias and went back to the doctor s office. Her medical records show that she had no photophobia, neck stiffness, or frank joint abnormalities at that time. She had serologic testing for Lyme disease: Bb ELISA and the IgM Western blot were positive, and the IgG Western blot was negative. She received a 1-month course of doxycycline at that time for secondary Lyme disease. Her symptoms resolved but recurred 6 months later, and she began experiencing severe fatigue, such that she could not care for her children and had to leave her part-time job. She sought out a Lyme disease specialist who performed repeat Lyme serologies and found that her Bb ELISA was positive at a higher number than previously and that both the IgM and IgG Western blots were negative. He prescribed a 1-month course of IV ceftriaxone. Her symptoms improved on IV therapy but had not completely resolved by the end of the month; the ceftriaxone was ultimately continued for 3 months. The patient did well off antibiotics for 8 months and then had a relapse. The Lyme disease specialist then treated her again with a 3-month course of IV ceftriaxone. This therapy was completed 1 year prior to her current presentation. In the past 12 months, the patient has had 2 bouts of fatigue with myalgias and arthralgias, each lasting a month and each treated with oral azithromycin. She moved to St. Louis while completing the most recent course of antibiotics. The current symptoms began approximately 6 weeks ago. She describes diffuse arthralgias involving hands, feet, ankles, elbows, and shoulders. She notes muscle pain in upper and lower extremities, as well as across her lower back. She is always most stiff in the mornings, but has residual stiffness throughout the day. At the present time, her fatigue is worst in the morning. PHYSICAL EXAMINATION Physical examination reveals an anxious woman. The general medical examination is unremarkable. No skin abnormalities are noted. A careful musculoskeletal examination reveals normal range of motion in all joints other than mild hyperlaxity of the metacarpophalangeal joints. No swelling, erythema, or warmth is detected. Multiple (16/18) tender trigger points are noted. What are the important points in this patient s history, and how should they be interpreted? 10 Hospital Physician Board Review Manual

11 The Tick Bite The patient describes a local reaction to a tick or other insect bite and not an EM lesion. The small size, timing of the appearance, and her description of a raised lump all argue against an EM lesion. Use of antibiotic prophylaxis after a tick bite is not routinely recommended. Even in Lyme-endemic areas, the incidence of infection with B. burgdorferi after a deer tick bite is low, usually estimated to be between 1% and 3%. The efficacy of prophylactic antibiotics in this setting remains unproved. One cost-effectiveness analysis of empiric antibiotics after tick bite suggested that 2 weeks of doxycycline may be warranted and cost-effective when the probability of infection was or more. 7 This study is a theoretical one, and its findings have never been validated in a prospective clinical trial. In a meta-analysis of 3 prospective randomized blinded trials evaluating the risks and benefits of antibiotic prophylaxis after deer tick bites, it was estimated that 1 case of Lyme disease would be prevented for every 83 patients treated with antibiotics. 8 Moreover, if penicillin or amoxicillin were the prophylactic antibiotic prescribed, then a 10% incidence of drug-induced rash would be expected. Currently, there is no definitive recommendation regarding the management of deer tick bites. Since the majority of tick bites do not result in disease transmission, and since early stage Lyme disease is easily and effectively treated with antibiotics, most experts counsel watchful waiting in patients with a history of recent tick bite. Serologic testing should never be utilized in this setting. While expert opinion suggests that routine use of antimicrobial therapy for tick bites is unwarranted, exceptions in specific patient subpopulations may exist. For example, patient identification of an engorged tick suggests prolonged attachment (36 to 48 hours), and in this setting the likelihood of infection increases. Such individuals may benefit from antibiotic prophylaxis. Amoxicillin and doxycycline, both administered for 10 days, have been studied as prophylactic regimens. In this particular patient, antibiotic prophylaxis was most likely unnecessary. Nonspecific Illness and Interpretation of Lyme Serologies The patient describes a nonspecific illness of headaches, myalgias, and arthralgias. She did not have objective signs or symptoms consistent with early disseminated Lyme disease such as carditis, aseptic meningitis, a facial nerve palsy, or disseminated EM lesions. As discussed earlier, serologic testing is neither sensitive nor specific enough to make a diagnosis of Lyme disease without clinical correlation. Lyme serologies should only be ordered in a patient with specific signs and symptoms consistent with 1 of the stages of Lyme disease. This patient s pretest probability of having Lyme disease given her nonspecific symptoms was low, and testing was not warranted. In fact, her test results are consistent with a false-positive ELISA, as the Western blot IgM should never be used alone to interpret the second-step test as positive. Antibiotic Treatment for Nonspecific Illness This woman describes a story that is remarkably similar to that of many patients seeking an explanation for their fatigue and nonspecific symptoms. There is a misconception common among the public that Lyme disease can cause a chronic fatigue-like illness. This has never been proved in the published medical literature. As in this case, patients often believe their symptoms resolve while on antibiotic therapy. Many patients will seek out medical care with physicians who will treat them with prolonged courses of antibiotic therapy. The use of either an oral or an IV antibiotic for more than 1 month in the treatment of any stage of Lyme disease has never been shown to be beneficial. In fact, prolonged courses of antimicrobials may actually be harmful. Prolonged courses of ceftriaxone in the management of Lyme disease have been associated with biliary complications requiring cholecystectomy. 9 Many of these patients also develop line-related bacteremias secondary to their permanent intravenous access. What is the significance of the patient s Lyme ELISA being higher on one occasion? Did this patient ever have Lyme disease? The Bb ELISA is a qualitative test, even though the laboratory performing the test will report an absolute number. The Bb ELISA numerical value is interpreted based on the test manufacturer s cut-off points for negative, positive, and equivocal. For example, if a positive ELISA is interpreted as 1.0 or greater, a patient with a measurement of 1.1 and another with a measurement of 5.0 both have a positive ELISA; however, the patient with the 1.1 measurement is not less positive and the patient with the 5.0 is not highly positive. In the case patient, the different numerical values for the ELISA between tests do not imply more or uncontrolled disease activity or suggest treatment failure. Given the above history and available test results, this patient never had Lyme disease. The normal joint examination excludes the chronic arthritides (eg, rheumatoid arthritis and the spondyloarthropathies). It is important to exclude rheumatoid arthritis because Rheumatology Volume 5, Part 1 11

12 patients with high titers of autoantibodies (eg, rheumatoid factor, antinuclear antibody [ANA]) are more likely to have a false-positive Lyme titer. The presence of trigger points is suggestive of fibromyalgia and mandates a search for both mimics of fibromyalgia and secondary causes. Before a diagnosis is made, therefore, tests for hypothyroidism and systemic lupus erythematosus should be performed. Major causes of sleep disturbance such as obstructive sleep apnea, chronic depression, and pain should be evaluated by history. FURTHER TESTING Important findings include an elevated thyroidstimulating hormone level (23.9 µu/ml) and an ANA titer of 1:40. DIAGNOSIS AND TREATMENT The patient is diagnosed with hypothyroidism and is started on hormone replacement therapy. Because she has been diagnosed and treated for Lyme disease by several clinicians, she is initially reluctant to believe the diagnosis. She is referred to a clinical social worker who specializes in cognitive behavior therapy. Over the next several months she gradually feels better. At her most recent follow-up visit with her rheumatologist, the patient s trigger points have resolved, and she feels like she has gotten her life back. REFERENCES 1. Nadelman RB, Nowakowski J, Forester G, et al. The clinical spectrum of early Lyme borreliosis in patients with culture-proven erythema migrans. Am J Med 1996; 100: Jackson CG, von Doersten PG. The facial nerve. Current trends in diagnosis, treatment, and rehabilitation. Med Clin North Am 1999;83: Sood SK, Slazman MB, Johnson BJ, et al. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis 1997;175: Berger BW, Johnson RC, Kodner C, et al. Cultivation of Borrelia burgdorferi from erythema migrans lesions and perilesional skin. J Clin Microbiol 1992;30: Nocton JJ, Dressler F, Rutledge BJ, et al. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med 1994;330: Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med 1987;107: Magid D, Schwartz B, Craft J, and Schwartz JS. Prevention of Lyme disease after tick bites. N Engl J Med 1992; 327: Warshafsky S, Nowakowski J, Nadelman RB, et al. Efficacy of antibiotic prophylaxis for prevention of Lyme disease: a meta-analysis. J Gen Intern Med 1996;11: Ettestad PJ, Campbell GL, Welbel SF, et al. Biliary complications in the treatment of Lyme disease. J Infect Dis 1995;171: SUGGESTED READINGS Brown SL, Hansen SL, Langone JJ. Role of serology in the diagnosis of Lyme disease. JAMA 1999;282:62 6. Burlington DB. FDA Public Health Advisory: assays for antibodies to Borrelia burgdorferi: limitations, use and interpretation for supporting a clinical diagnosis of Lyme disease. Washington (DC): U.S. Govt. Printing Office; 1997 July. Publication No Dennis DT. Epidemiology, ecology, and prevention of Lyme disease. In: Rahn D, Evans J, editors. Lyme disease. Philadelphia: American College of Physicians; 1998:7 34. Dennis DT, Meltzer MI. Antibiotic prophylaxis after tick bites. Lancet 1997;350: Dinerman H, Steere AC. Lyme disease associated with fibromyalgia. Ann Intern Med 1992;117: Eckman MH, Steere AC, Kalish RA, Pauker SG. Cost effectiveness of oral as compared with intravenous antibiotic therapy for patients with early Lyme disease or Lyme arthritis. N Engl J Med 1997;337: Guidelines for laboratory evaluation in the diagnosis of Lyme disease. American College of Physicians. Ann Intern Med 1997;127: Lyme disease Unites States, MMWR Morb Mortal Wkly Rep 1997;46: Nichol G, Dennis DT, Steere AC, et al. Test-treatment strategies for patients suspected of having Lyme disease: a costeffectiveness analysis. Ann Intern Med 1998;128: Schmidt BL. PCR in laboratory diagnosis of human Borrelia burgdorferi infections. Clin Microbiol Rev 1997;10: Shapiro ED, Gerber MA, Holabird NB, et al. A controlled trial of antimicrobial prophylaxis for Lyme disease after deer-tick bites. N Engl J Med 1992;327: Sigal LH. Musculoskeletal manifestations of Lyme arthritis. Rheum Dis Clin North Am 1998;24: Steere AC, Levin RE, Molloy PJ, et al. Treatment of Lyme arthritis. Arthritis Rheum 1994;37: Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med 1987;107: Copyright 2001 by Turner White Communications Inc., Wayne, PA. All rights reserved. 12 Hospital Physician Board Review Manual