Lyme Arthritis an Update for Clinical Practice

CME REVIEW ARTICLE

Lyme Arthritis An Update for Clinical Practice

Katharine Christina Long, MD* and Keri Anne Cohn, MD, MPH, DTM&H†

significantly swollen left knee that is mildly warm to the touch. Abstract: Lyme disease is the most common vector-borne illness in He has discomfort with range of motion but is not exquisitely ten- North America, with the majority of cases occurring in the Northeast and der. He ambulates with a limp. He has a temperature of 100.8°F. upper Midwest. Lyme arthritis is the most prevalent manifestation of late- The remainder of his vital signs and physical examination stage Lyme disease. Lyme arthritis typically presents as a monoarthritis is normal. or oligoarthritis in large joints such as the knee. Accompanying positive How do you proceed in evaluating this patient? What diagnos- 2-tier Lyme serologies or polymerase chain reaction from synovial fluid/ tic tests are warranted? What diagnostic tests are useful? How do tissue is considered diagnostic for patients from an endemic area. The you acutely differentiate between Lyme arthritis and a septic joint? mainstay of initial treatment is a prolonged course of oral antibiotics. What is the best initial treatment? What anticipatory guidance do Key Words: Lyme arthritis, Lyme disease, pediatric arthritis you provide the family? (Pediatr Emer Care 2018;34: 588–593) INTRODUCTION Lyme arthritis was first described as an epidemic of TARGET AUDIENCE oligoarticular arthritis in the 1970s. Steere et al1 published a series This continuing medical education activity is targeted at any of cases describing the culture-negative, serologic-negative arthri- health care provider who may encounter and diagnose pediatric tis afflicting a small Connecticut coastal town called Lyme. In patients presenting with Lyme arthritis. General pediatricians, 1982, Dr Burgdorfer2 was the first to isolate the infectious agent nurse practitioners, physician assistants, and health care providers a spirochete, which he named Borrelia burgdorferi. Lyme disease who practice in emergency departments or urgent cares may find is now considered the most common vector-borne illness in North this content beneficial to their practice. America and Europe.3 The geographical distribution of Lyme disease has been consistently expanding over the last few years, now predom- LEARNING OBJECTIVES inately throughout the Northeast and Minnesota and Wisconsin in the Midwest. In 2015, 95% of confirmed cases of Lyme disease After completion of this CME activity, the reader should be originated from 14 states (Fig. 1). better able to: The primary vector is the Ixodes tick. It is believed that the majority of human Lyme disease cases are transmitted by ticks 1. Describe the epidemiology of Lyme disease. while they are in their small and difficult-to-detect nymph stage. 2. Identify the common manifestation of Lyme arthritis and differ- An infected nymph must feed for at least 72 hours in order to entiate it from other similar disease presentations. transmit the disease because the spirochetes live in the midgut of 3. List available diagnostic and treatment options. the tick and migrate to the salivary glands only after the gut has become engorged.3,4 The transmission rate at 72 hours or longer is 25%.3 n 8-year-old boy presents to your emergency department with There is a distinct seasonality to the disease, with two thirds A a chief complaint of left knee swelling that started 3 days ago. of cases of early Lyme occurring in June, July, or August, al- The family and patient deny any history of trauma. The patient has though peak incidence is largely dependent on temperature and had a low-grade fever. The patient reports that he feels like his moisture.5,6 Because Lyme arthritis is a late manifestation that oc- “ ” knee is going to pop from the pressure. He denies any other con- curs weeks or months after the initial infection, presentation can stitutional symptoms. Because you are an astute historian, you dis- occur during any season. Unsurprisingly, Lyme disease is more of- cover that the patient visited his grandparents in Connecticut over ten diagnosed in people who spend a large proportion of time out- the summer, approximately 4 months ago. On physical examina- doors in endemic areas. tion, you see an alert and interactive young man with a PRESENTATION *Academic Chief of Emergency Department Education, Valley Children's Classically, there are 3 described phases of Lyme disease: Hospital, Clovis; and Clinical Instructor (Affiliate) of Emergency Depart- ment, Stanford University School of Medicine, Stanford, CA (Long); and early localized disease, early disseminated disease, and late dis- †Assistant Professor of Clinical Pediatrics, Perelman School of Medicine at ease. Although these entities are separated out for classification the University of Pennsylvania, Philadelphia, PA; and Director of Pediatric purposes, patients can present with overlapping symptoms. Early Emergency Medicine–Global Health Fellowship (Cohn), The Children's Hos- localized disease manifests as erythema migrans, a large singular pital of Philadelphia, Philadelphia, PA. The authors, faculty, and staff in a position to control the content of this CME annular skin rash that classically expands from the site of tick bite, activity and their spouses/life partners (if any) have disclosed that they have typically 3 to 30 days later. The rash is typically uniformly ery- no financial relationships with, or financial interest in, any commercial thematous or targetoid and can be associated with vesicular or ne- organizations pertaining to this educational activity. crotic areas in the center.4 Patients may or may not recall a tick bite Reprints: Katharine Christina Long, MD, Valley Children's Hospital, Madera, 1830 N Sanders, Clovis, CA 93619 (e-mail: [email protected]). on history. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Multiple erythema migrans skin lesions are associated with ISSN: 0749-5161 early disseminated Lyme disease, which appears 3 to 5 weeks after

588 www.pec-online.com Pediatric Emergency Care • Volume 34, Number 8, August 2018

FIGURE 1. Reported cases of Lyme disease 2001 compared with 2015. States in 2015 with reported Lyme disease: Connecticut, Delaware, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Vermont, Virginia, and Wisconsin, taken from https://www.cdc.gov/lyme/stats/index.html. exposure. Other manifestations of early disseminated disease in- propose predictor models that have not yet been externally vali- clude systemic symptoms such as fever, headache, myalgias, dated. In Lyme-endemic areas, arthrocentesis may be cautiously and fatigue. Occasionally, there are neurological manifestations deferred, pending serology results in children 2 years or older with at this stage such as facial nerve palsies or Lyme meningitis. Lyme unilateral knee swelling who do not have a history of fever, have carditis with associated prolonged PR interval or complete heart no pain with short arc motion, and have a C-reactive protein of block can also occur. Late disease is associated primarily with less than 4.0 mg/L or have an erythrocyte sedimentation rate of Lyme arthritis and occurs weeks to months after exposure. Enceph- less than 40 mm/h and an absolute neutrophil count of less than alopathy and encephalitis are also part of late-stage disease presen- 10 Â 103 cells/μL, as they are unlikely to have septic arthritis.15,16 tation; however, these entities are extremely rare. Lyme arthritis typically presents as a monoarthritis or oligoarthritis primarily involving the knee.1,7–10 The knee tends Serologic Testing to be very swollen with limited range of motion. It can be ery- The immune system takes several weeks to develop antibod- thematous and warm.11 Pain varies, although Lyme arthritis tends ies after exposure to B. burgdorferi. In early-stage Lyme disease, it not to be exquisitely painful as is seen with septic joints, and chil- is well known that one can be seronegative even after clinically dren can usually still ambulate with a limp. Lyme arthritis can also manifesting signs of Lyme such as erythema migrans.17 However, manifest as an asymmetric oligoarthritis. In oligoarthritis, the knee by the time patients develop Lyme arthritis (late disease), immuno- is involved along with other large joints such as the hip, shoulder, globulin G for B. burgdorferi is positive and is considered diagnostic ankle, elbow, temporomandibular joint, and wrist. Occasionally, in a patient from an endemic area who presents with monoarthritis or the arthritis is accompanied by constitutional symptoms such as oligoarthritis.18 Immunoglobulin M may start to wane and can be fever and fatigue.1,10 Overall, the incidence of Lyme arthritis is de- negative by 30 days and may or may not be positive at the time of creasing, secondary to early recognition and treatment of Lyme serologic testing. Initial serologic testing is performed using an disease in patients. However, approximately 50% to 60% of pa- enzyme-linked immunosorbent assay screening, followed by a con- tients who are not treated in the early stages of Lyme disease will firmatory Western blot test. Lyme arthritis generates a robust immu- go on to develop Lyme arthritis.9 For patients with a diagnosis of nological response that subsequently seems to provide a protective Lyme arthritis, it is important to evaluate for the possibility of con- advantage to reinfection.19 It is important to note that patients current Lyme carditis or neurologic involvement with a thorough can remain seropositive for years and that seroreactivity alone is physical examination and electrocardiogram, as it may alter treat- not an indication for retreatment.20 ment course. Lyme carditis occurs in approximately 1–2% of patients with Lyme borreliosis, and can be asymptomatic. Because Lyme carditis is a severe complication of late stage Lyme disease Synovial Fluid Testing and consider performing an electrocardiogram on all patients with Synovial fluid testing is typically performed on children present- presumed Lyme arthritis.12,13 Patients with prolonged headache or ing with acute arthritis in order to rule out patients with septic arthritis the presence of meningismus may have Lyme meningitis, and a who require immediate parenteral antibiotics and surgical consult. lumbar puncture would be indicated.14 However, there is some evidence for deferral of arthrocentesis Lyme arthritis can be difficult to distinguish from septic ar- in well-appearing children with a low concern for septic arthritis, thritis or noninfectious arthritis such as oligoarticular juvenile reassuring physical examination and low-risk laboratory evaluation, rheumatoid arthritis or transient synovitis. Recent studies have who live in a Lyme-endemic region. The criterion standard in syno- attempted to identify distinguishing trends in clinical presentation vial fluid analysis includes cell count, Gram stain, and culture. It is and laboratory evaluation. Overall, patients with Lyme arthritis important but challenging to acutely distinguish Lyme arthritis from tend to have elevated white blood cell (WBC) counts, erythrocyte septic arthritis because serologic testing often takes days to result. sedimentation rate values, and C-reactive protein values when On average, Lyme arthritis elicits a synovial WBC count that ranges compared with patients with transient synovitis. When compared from 10,000 to 50,000 cells per microliter, whereas pyogenic arthri- with patients with septic arthritis, patients with Lyme arthritis tis tends to have a synovial WBC count of greater than 50,000 cells are more likely to have knee involvement and are less likely to re- per microliter.21,22 Table 1 provides a proposed guideline for syno- port a history of fever. Both Deanehan et al15 and Baldwin et al16 vial fluid interpretation.23 Importantly, if there is concern for septic

Disease Society of America suggests that “clinicians should con- TABLE 1. Proposed Guidelines for Synovial Fluid Interpretation sider waiting several months before initiating retreatment because of anticipated slow resolution of inflammation after treatment.”30 • Positive WBC count >50,000 Treat as pyogenic arthritis Patients may benefit from nonsteroidal anti-inflammatory cells per microliter or agents to assist with pain control. Therapeutic arthrocentesis is a Gram stain positive – • reasonable option for short-term symptomatic relief. Physical Equivocal WBC 25,000 50,000 Consider clinical parameters therapy has also been shown to benefit patients with prolonged • Lyme 30 • Gonorrhea symptoms. Systemic corticosteroids are not recommended. • Intra-articular corticosteroids have been used, although some re- Tuberculosis 19 • Alternative diagnoses search suggests it may prolong symptoms. Complications of Negative WBC <25,000 • Toxic synovitis Lyme arthritis can include popliteal cysts, which are at risk of rup- • Alternative diagnoses turing and should be aspirated. Rarely patients can go on to develop persistent synovitis or 26 Adapted from Arson et al. “antibiotic-refractory Lyme arthritis.” Persistent synovitis is defined as Lyme-associated arthritis that persists for more than 3 months despite ongoing treatment with oral antibiotics, 1 month of parental arthritis, a positive Gram stain is highly suggestive, but a negative antibiotics, or a combination of the two.31,32 This is a postinfectious Gram stain does not exclude the diagnosis of septic joint. inflammatory process, and Lyme PCR from the synovial fluid is Polymerase chain reaction (PCR) testing of the synovial fluid negative. Arthrocentesis for Lyme PCR can be done if this diagno- is often positive (40%–96%) prior to antibiotic therapy23–26 but sis is being considered. Persistent synovitis has been associated may not add any additional clinical value, given the high specific- with a strong HLA-type autoimmune response.21 In consultation ity and sensitivity of serologic testing in late Lyme disease. How- with a rheumatologist, patients with persistent symptoms have been ever, synovial PCR could be very helpful in certain clinical treated with disease-modifying antirheumatic drugs such as metho- scenarios as an adjunctive test to further support the diagnosis.24 trexate or hydroxychloroquine.19,30 Additional antibiotic courses For patients with persistent synovitis or “antibiotic-refractory are not recommended. Rarely, patients with medically refractory arthritis,” a negative PCR has been proposed as a way to evaluate cases have required arthroscopic synovectomy. for treatment-resistant arthritis (a postinfectious inflammatory process), but has not been validated for widespread clinical use.23,25 Culture or immunologic studies of synovial fluid are low yield SUMMARY and not recommended for the diagnosis of Lyme arthritis. Lyme arthritis is the most prevalent late-stage manifestation of Lyme disease. Positive serologic testing is considered diagnostic in those from endemic areas, but often the results are unavail- MANAGEMENT able at the time of clinical presentation. Differential diagnosis If untreated, Lyme arthritis may eventually resolve, although includes septic arthritis, and therefore it is reasonable for patients patients can remain symptomatic for years.1 Antibiotic treatment to undergo arthrocentesis for synovial fluid evaluation. For pa- can prevent long-term joint damage and hastens resolution of tients with a possible diagnosis of Lyme arthritis, it is important symptoms and is therefore indicated upon diagnosis.27,28 However, symptoms often do not immediately resolve upon the initiation of antibiotics, and a waxing-and-waning course is not unusual. This clinical course should be shared with patients and their families to guide expectations. Ninety percent of patients will ultimately re- spond completely to an initial treatment with oral antibiotics alone within approximately 3 months.27 Importantly, antibiotic treatment of Lyme arthritis does not prevent progression to neuroborreliosis at a later date, which can occasionally occur. Oral antibiotics with amoxicillin, cefuroxime, or doxycycline for a complete 28-day course represent first-line treatment for Lyme arthritis without concurrent cardiac or neurologic manifestations (Fig. 2). Doxycycline at this time is recommended only for children 8 years or older because of concerns for dental and bone deposition. Recent literature suggests, however, that the de- gree of dental staining is minimal based on a study in children younger than 8 years treated with doxycycline for Rocky Mountain spotted fever.29 Macrolides are known to be less effective for early Lyme disease and are generally not recommended for late disseminated disease, including Lyme arthritis. Because of the increased risks associated with prolonged parenteral therapy, intravenous antibiotics are generally not given first line for isolated Lyme arthritis. If a patient reports only moderate improvement in his/her symptoms despite oral antibiotic treatment, a second 28-day course of oral antibiotics is indicated.30 Parental regimens (eg, ceftriaxone) for 14 to 28 days should be considered if symptoms are worsening despite an appropriate course of oral antibiotics. Alternative parenteral regimens include cefotaxime or penicillin G. The Infectious FIGURE 2. Treatment guidelines for Lyme arthritis.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Pediatric Emergency Care • Volume 34, Number 8, August 2018 Lyme Arthritis to evaluate for the possibility of concurrent Lyme carditis or neu- 17. Shrestha M, Grodzicki RL, Steere AC. Diagnosing early Lyme disease. rologic involvement as it may alter treatment course. The majority Am J Med. 1985;78:235–240. of patients improve within a few months after a 28-day course 18. Craft JE, Grodzicki RL, Steere AC. Antibody response in Lyme disease: of oral antibiotics. Rarely, patients experience an antibiotic- evaluation of diagnostic tests. JInfectDis. 1984;149:789–795. refractory “persistent synovitis,” which may benefit from referral 19. Steere AC, Angelis SM. Therapy for Lyme arthritis: strategies for the to a rheumatologist. treatment of antibiotic-refractory arthritis. Arthritis Rheum.2006;54: 3079–3086. REFERENCES 20. Kalish RA, McHugh G, Granquist J, et al. Persistence of immunoglobulin 1. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. M or immunoglobulin G antibody responses to Borrelia burgdorferi 10–20 – Ann Intern Med. 1987;107:725 731. years after active Lyme disease. Clin Infect Dis. 2001;33:780–785. — 2. Burgdorfer W, Barbour AG, Hayes SF, et al. Lyme disease a tick-borne 21. Thompson A, Mannix R, Bachur R. Acute pediatric monoarticular arthritis: – spirochetosis? Science. 1982;216:1317 1319. distinguishing Lyme arthritis from other etiologies. Pediatrics. 2009;123: 3. Dennis DT, Hayes EB. Epidemiology of Lyme borreliosis. In: Kahl O, Gray 959–965. JS, Lane RS, et al, eds. Lyme Borreliosis: Biology, Epidemiology and 22. Puius YA, Kalish RA. Lyme arthritis: pathogenesis, clinical presentation, Control. Oxford: CABI Publishing; 2002:251. and management. Infect Dis Clin North Am. 2008;22:289–300. 4. Murray TS, Shapiro ED. Lyme Disease. Clin Lab Med. 2010;30:311–328. 23. Li X, McHugh GA, Damle N, et al. Burden and viability of Borrelia 5. Barbour AG, Fish D. The biological and social phenomenon of Lyme burgdorferi in skin and joints of patients with erythema migrans or Lyme disease. Science. 1993;260:1610–1616. arthritis. Arthritis Rheum. 2011;63:2238–2247. 6. Moore SM, Eisen RJ, Monaghan A, et al. Meteorological influences on the 24. Arvikar SL, Steere AC. Diagnosis and treatment of Lyme arthritis. Infect seasonality of Lyme disease in the United States. Am J Trop Med Hyg. Dis Clin North Am. 2015;29:269–280. 2014;90:486–496. 25. Nocton JJ, Dressler F, Rutledge BJ, et al. Detection of Borrelia burgdorferi 7. Cristofaro RL, Appel MH, Gelb RI, et al. Musculoskeletal manifestations DNA by polymerase chain reaction in synovial fluid from patients with – of Lyme disease in children. J Pediatr Orthop. 1987;7:527 530. Lyme arthritis. NEnglJMed. 1994;330:229–234. 8. Eichenfield AH, Goldsmith DP,Benach JL, et al. Childhood Lyme arthritis: 26. Arson P, Posner J, Dooley RN, Coffin S, Jacobstein C, Lavelle J. The – experience in an endemic area. J Pediatr. 1986;109:753 758. Children's Hospital of Philadelphia, Clinical Practice Guideline on 9. Gerber MA, Zemel LS, Shapiro ED. Lyme arthritis in children: clinical Suspected Septic Arthritis. Last updated February 2017. Available at: http:// epidemiology and long-term outcomes. Pediatrics. 1998;102(4 pt 1): www.chop.edu/clinical-pathway/septic-arthritis-suspected-clinical- 905–908. pathway. Accessed February 2017. 10. Willis AA, Widmann RF,Flynn JM, et al. Lyme arthritis presenting as acute 27. Dattwyler RJ, Wormser GP,Rush TJ, et al. A comparison of two treatment septic arthritis in children. J Pediatr Orthop. 2003;23:114–118. regimens of ceftriaxone in late Lyme disease. Wien Klin Wochenschr.2005; – 11. Culp RW, Eichenfield AH, Davidson RS, et al. Lyme arthritis in children: 117:393 397. an orthopaedic perspective. J Bone Joint Surg Am.1987;69:96–99. 28. Steere AC, Levin RE, Molloy PJ, et al. Treatment of Lyme arthritis. 12. Forrester JD, Meiman J, Mullins J, et al. Notes from the field: update on Arthritis Rheum. 1994;37:878. Lyme carditis, groups at high risk, and frequency of associated sudden 29. Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in cardiac death—United States. MMWR. 2014;63:982–983. children treated with doxycycline for suspected Rocky Mountain spotted 13. Applegren ND, Kraus CK. Lyme disease: emergency department fever. J Pediatr. 2015;166:1246–1251. considerations. JEmergMed. 2017;52:815–824. 30. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, 14. Cohn KA, Thompson AD, Shah SS, et al. Validation of a clinical prediction treatment, and prevention of Lyme disease, human granulocytic rule to distinguish Lyme meningitis from aseptic meningitis. Pediatrics. anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious 2012;129:e46–e53. Diseases Society of America. Clin Infect Dis. 2006;43:1089–1134. 15. Deanehan JK, Kimia AA, Tan Tanny SP, et al. Distinguishing Lyme from 31. Akin E, Aversa J, Steere AC. Expression of adhesion molecules in synovia septic knee monoarthritis in Lyme disease–endemic areas. Pediatrics. of patients with treatment-resistant Lyme arthritis. Infect Immun.2001;69: 2013;131:e695–e701. 1774–1780. 16. Baldwin KD, Brusalis CM, Nduaguba AM, et al. Predictive factors for 32. Steere AC, Duray PH, Butcher EC. Spirochetal antigens and lymphoid cell differentiating between septic arthritis and Lyme disease of the knee in surface markers in Lyme synovitis: comparison with rheumatoid synovium children. J Bone Joint Surg Am. 2016;98:721–728. and tonsillar lymphoid tissue. Arthritis Rheum. 1988;31:487–495.