P o sttrea t men t Lyme Disease Syndrome John N. Aucott,

MD

KEYWORDS  Posttreatment Lyme disease syndrome  Persistent symptoms  Fatigue  Fibromyalgia  Musculoskeletal pain KEY POINTS  Overall, prognosis following appropriate antibiotic treatment of early or late Lyme disease is favorable but can be complicated by persistent symptoms of unknown cause.  Posttreatment Lyme disease syndrome (PTLDS) is characterized by fatigue, musculoskeletal pain, and cognitive complaints that persist for 6 months or longer after completion of antibiotic therapy.  PTLDS can vary markedly in disease severity from mild to severe symptoms with diminished health-related quality of life.  Two-tier serologic testing is neither sensitive nor specific for diagnosis of PTLDS because of variability in convalescent serologic responses after treatment of early Lyme disease.  Recommended treatment of PTLDS is largely symptom-based. There are currently no FDA-approved treatments for patients with PTLDS.

INTRODUCTION: NATURE OF THE PROBLEM

In general, the prognosis after treatment of uncomplicated infection with Borrelia burgdorferi, the causative agent of Lyme disease, is favorable. However, the clinical management of early or late-stage Lyme disease may in some cases be complicated by persistent fatigue, musculoskeletal, and cognitive symptoms after completion of standard antibiotic therapy. This documented constellation of patient-reported symptoms, which may be intermittent or constant,1 can be called posttreatment Lyme disease syndrome (PTLDS) when symptoms are prolonged for a period of 6 months or greater.2,3 Although objective findings, such as persistence of the erythema migrans rash (EM), cranial nerve palsy, meningitis, or radiculitis, may occasionally occur after treatment of early Lyme disease, these objective physical findings or laboratory manifestations more typical of untreated Lyme disease are not part of the clinical spectrum

Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Baltimore, MD 21224, USA E-mail address: [email protected] Infect Dis Clin N Am 29 (2015) 309–323 http://dx.doi.org/10.1016/j.idc.2015.02.012 0891-5520/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

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of PTLDS. Similarly, persistent joint synovitis may occur after repeated courses of antibiotic therapy for late Lyme arthritis and is also considered a distinct process, termed antibiotic-refractory late Lyme arthritis.4 Early investigators observed that patients with early or late-stage Lyme disease may have lingering symptoms after completion of antibiotic therapy, despite prompt administration of effective antibiotic therapy and resolution of the physical findings of infection.5–7 The frequency of PTLDS among such patients has been found to differ between 0% and 50% in published studies, and is likely related to variability of study design and enrollment criteria of the sample populations used.5,8 Reports of long-term follow-up in patients with early presentation and treatment of EM have generally shown excellent long-term outcomes.1 In the most recent treatment trials of EM conducted in North America, rates of PTLDS are approximately 10% to 20%.3 However, rates may be 50% in the community practice of medicine, where delayed diagnosis and treatment may be more common and classification of symptoms attributed to Lyme disease less certain.9,10 In addition, persistent symptoms may be more common among patients with sensory symptoms or frank neurologic involvement. In one series, patients who presented with facial palsy and were not treated for neuroborreliosis were more likely to have long-term symptoms and a diminished health-related quality of life on 10- to 20-year follow-up.11 In all stages of Lyme disease, clinical response to therapy may be delayed, with continued improvement over a period of weeks to months beyond the initial treatment duration. Minor lingering symptoms usually resolve spontaneously and do not necessarily indicate continued infection requiring further antibiotic therapy.12 Occasionally, however, patients may have an unsatisfactory response to initial therapy with the onset of new, worsening, or persistent symptoms, which may prompt a defined course of an alternative antibiotic.13 Occasionally, the coexistence of a second tick-borne pathogen, such as Babesia, may explain ongoing illness after treatment of Lyme disease.14 Biomarkers to identify patients at risk for PTLDS, or for distinguishing minor, resolving symptoms from an unsatisfactory response to initial therapy, are not currently available, but is an area of active research.15 Therefore, PTLDS remains a diagnosis of exclusion and should not be made when other, specific diagnoses can explain the patient’s symptoms and laboratory findings. These factors, in the context of an unknown cause and insensitive and nonspecific symptoms, laboratory studies, and other clinical tools, render the diagnosis and clinical management of PTLDS challenging for physicians. RISK FACTORS AND SEVERITY OF DISEASE

Box 1 shows a list of identified risk factors for PTLDS. A delay in diagnosis and subsequent treatment has been identified as the primary risk factor for PTLDS.9,16 Other reported risk factors include a larger number of symptoms and a greater symptom severity at the time of treatment.1,5 Fever, headache, photosensitivity, or neck stiffness during the acute illness have also been reported as risk factors for the persistent symptoms after initial antibiotic therapy.17 Initial treatment with antibiotics other than first-line agents, such as azithromycin, may be more likely to occur in the community setting where misdiagnosis rates are higher.10 Such situations may also be associated with a higher risk of PTLDS.6 A negative posttreatment serology was found to be more common in patients with posttreatment symptoms in one study,6 but baseline and convalescent serostatus was not associated with outcomes in another study.1 Early studies among patients diagnosed with acute Lyme disease found that duration of antibiotic therapy does not predict risk of PTLDS.18,19

Posttreatment Lyme Disease Syndrome

Box 1 Risk factors for PTLDS Probable  Delay in diagnosis  Overall severity of symptoms at treatment  Presence of neurologic symptoms at time of initial treatment Possible  Presence of fever, headache, photosensitivity, or neck stiffness during acute illness  Initial treatment with nonrecommended antibiotics  Lack of antibody seroconversion

PTLDS may also be more common after treatment of acute neuroborreliosis. The presence of sensory neurologic symptoms and frank neurologic involvement at the time of diagnosis and treatment may be another risk factor for the development of PTLDS. Patients treated for acute and subacute neuroborreliosis in Europe have reported rates of PTLDS ranging from 25% to 50%,20–22 generally higher than in North American studies of patients with EM. Some North American investigators have also suggested that facial palsy at initial presentation may be a risk factor for PTLDS.11 There is a large spectrum of illness severity in PTLDS, from minor symptoms to a more severe illness that has been characterized by declines in health-related quality of life and mild to moderate cognitive deficits in some patients.23–25 In antibiotic treatment trials of ideally diagnosed and treated early Lyme disease, only 10% of patients were found to have low health-related quality of life,26 which may be related to fatigue.27 However, in patients identified after treatment in the community setting, the impact of PTLDS on health-related quality of life was much higher.24 The more severe end of this illness spectrum has been described in population-based studies, where patients often had delayed treatment, initial misdiagnosis, or nonideal initial therapy.9,11,16 UNDERLYING MECHANISMS

Despite extensive study of Lyme disease, PTLDS remains an enigmatic condition, because the underlying pathogenesis of the syndrome is not understood. The clinical validity of PTLDS as the sequelae of an infectious disease continues to be debated. One explanation is that the apparent association of symptoms after treatment of Lyme disease represents anchoring bias, incorrectly linking common nonspecific symptoms to an antecedent episode of Lyme disease.28 However, there is precedent for postinfectious syndromes of persistent fatigue following other infectious diseases, such as Epstein-Barr virus, Q fever, and Ross River virus. In one large study from Australia, 12% of those infected with these agents had persistent symptoms at 6 months. The investigators found that the presence of fatigue was predicted by the severity of initial symptoms, and was not predicted by psychological factors.29 Although PTLDS-defining symptoms, such as fatigue and pain, are common in the general population, a meta-analysis of studies using non–Lyme infected control subjects has shown an increased prevalence of many symptoms in patients with PTDLS compared with control subjects.30 A subsequent prospective controlled clinical trial has provided additional evidence that symptoms are more severe after treatment of

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Lyme disease than in healthy matched control subjects, and are not primarily caused by pre-existing depression.25,26 In addition, evidence is emerging regarding the possible immune pathophysiology of PTLDS. Borrelia lipoprotein antigens are highly inflammatory, and retained antigens after killing of Borrelia has been shown in the mouse model and hypothesized in human illness.31,32 Evidence for specific immune response patterns and autoimmunity is also emerging as a potential mechanism for PTLDS.33 In one study of patients treated for EM in Europe, elevated interleukin-23 levels during acute disease were associated with the subsequent development of PTLDS.15 Antineural antibodies and certain antiborrelial antibodies have also been reported in PTLDS.34,35 Genetic predisposition to autoimmunity in Lyme disease is best described in late Lyme arthritis, where HLA-DR4 predisposes to the development of persistent inflammatory Lyme arthritis in a subset of patients that does not respond to further courses of antibiotic treatment.36 Patients who are HLA-DR4 positive and who have treatmentresistant Lyme arthritis have also been shown to have a strong immune response to an epitope on OspA that cross-reacts with human lymphocyte function antigen 1, which may serve as an autoantigen.37 In addition, a polymorphism in the TLRI gene (1805GG), which is present in 50% of whites, has been implicated in persistent autoimmune arthritis after antibiotic treatment.38 Certain genotypes of B burgdorferi in North America have been found to be more inflammatory and more likely to disseminate at the time of initial infection.39 These genotypes of B burgdorferi are associated with more symptomatic initial infection, which may be a risk factor for later PTLDS. Finally, recent animal studies have demonstrated residual organisms and the possibility of persistence of B burgdorferi DNA in mice and primates previously treated with antibiotics.40–42 Whether antibiotic-tolerant “persister” organisms play a role in human PTLDS remains unknown, although results from a small xenodiagnoses study report the identification of B burgdorferi DNA by polymerase chain reaction in a single patient with PTLDS.43 PATIENT HISTORY

The proposed case definition for PTLDS published in the 2006 practice guidelines of the Infectious Diseases Society of America is based on identifying individuals with persistent, otherwise unexplained symptoms after treatment of documented Lyme disease (Box 2).2 The central feature of this case definition is the presence of persistent or recurrent symptoms that began within the 6 months following completion of a regimen of currently recommended antibiotic therapy for physician-documented early or late Lyme disease (and subsequently persist for a period of 6 months or greater).2 A detailed past medical history and record review may be necessary to document a prior history of previously treated Lyme disease. The most commonly recognized symptoms reported by patients with PTLDS are fatigue, musculoskeletal pain, and cognitive complaints. However, a range of other symptoms have also been reported, such as sensory symptoms, sleep disruption, and emotional symptoms, as shown in Table 1.16,17,44,45 PHYSICAL EXAMINATION

Objective findings have been difficult to document in PLTDS. Unlike patients with persistent arthritis after treatment of late Lyme disease, patients with PTLDS have arthralgias and musculoskeletal pain, but rare evidence of joint synovitis.17 Objective neurologic signs have also been difficult to document.17 PTLDS is distinct from the residual, slowly resolving, or incomplete resolution of neurologic deficits that may occur

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Box 2 Proposed definition of post–Lyme disease syndrome Inclusion criteria An adult or child with a documented episode of early or late Lyme disease fulfilling the case definition of the Centers for Disease Control and Prevention.46 If based on erythema migrans, the diagnosis must be made and documented by an experienced health care practitioner. After treatment of the episode of Lyme disease with a generally accepted treatment regimen47 there is resolution or stabilization of the objective manifestations of Lyme disease. Onset of any of the following subjective symptoms within 6 months of the diagnosis of Lyme disease and persistence of continuous or relapsing symptoms for at least a 6-month period after completion of antibiotic therapy: fatigue, widespread musculoskeletal pain, complaints of cognitive difficulties. Subjective symptoms are of such severity that, when present, they result in substantial reduction in previous levels of occupational, educational, social, or personal activities. Exclusion criteria An active, untreated, well-documented coinfection, such as babesiosis. The presence of objective abnormalities on physical examination or on neuropsychologic testing that may explain the patient’s complaints. For example, a patient with antibioticrefractory Lyme arthritis would be excluded. A patient with late neuroborreliosis associated with encephalopathy, who has recurrent or refractory objective cognitive dysfunction, would be excluded. A diagnosis of fibromyalgia or chronic fatigue syndrome before the onset of Lyme disease. A prolonged history of undiagnosed or unexplained somatic complaints, such as musculoskeletal pains or fatigue, before the onset of Lyme disease. A diagnosis of an underlying disease or condition that might explain the patient’s symptoms (eg, morbid obesity, with a body mass index [calculated as weight in kilograms divided by the square of height in meters] 45; sleep apnea and narcolepsy; side effects of medications; autoimmune diseases; uncontrolled cardiopulmonary or endocrine disorders; malignant conditions within 2 years, except for uncomplicated skin cancer; known current liver disease; any past or current diagnosis of a major depressive disorder with psychotic or melancholic features; bipolar affective disorders; schizophrenia of any subtype; delusional disorders of any subtype; dementias of any subtype; anorexia nervosa or bulimia nervosa; and active drug abuse or alcoholism at present or within 2 years). Laboratory or imaging abnormalities that might suggest an undiagnosed process distinct from post–Lyme disease syndrome, such as a highly elevated erythrocyte sedimentation rate (150 mm/h); abnormal thyroid function; a hematologic abnormality; abnormal levels of serum albumin, total protein, globulin, calcium, phosphorus, glucose, urea nitrogen, electrolytes, or creatinine; significant abnormalities on urine analysis; elevated liver enzyme levels; or a test result suggestive of the presence of a collagen vascular disease. Although testing by either culture or polymerase chain reaction for evidence of Borrelia burgdorferi infection is not required, should such testing be done by reliable methods, a positive result would be an exclusion. From Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43(9):1089–134; with permission.

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Table 1 Symptoms found to be more common in PTLDS than control subjects Author

Symptoms

Shadick et al,16 1994

Arthralgia Numbness, tingling, burning pain Coordination difficulties Fatigue Concentration difficulties Emotional irritability

Shadick et al,17 1999

Joint pain Symptoms of memory impairment

Seltzer et al,44 2000

Joint or muscle pain Ability to formulate ideas

Va´zquez et al,45 2003

Neck pain Changes in behavior Joint or muscle pain Numbness or funny sensations in nerves Problems with memory

after treatment of acute or subacute neuroborreliosis meningitis, radiculitis, or cranial palsy.20 For instance, the resolution of pain after treatment of radiculopathy or neuropathy may be very gradual and with chronic involvement, this response may be incomplete. Some patients may develop chronic radicular pain, similar to patients with postherpetic neuroalgia. In one report, only one-half of patients who had late neurologic symptoms showed either resolution or sustained improvement after 6 months of follow-up after a 2-week course of ceftriaxone.48 Facial palsy itself resolves completely or almost completely in nearly all patients (121 of 122 patients in one series).49 In contrast to slowly or incompletely resolving neurologic signs, the syndrome of PTLDS is defined by patient-reported symptoms after treatment of neuroborreliosis. A complete neurologic examination with attention to evaluation of the peripheral nerves is indicated, and findings of decreased vibratory sensation may be most sensitive to damage from Lyme disease.16 Case reports of PTLDS have suggested that small fiber sensory neuropathy and autonomic neuropathy may play a role in these neurologic symptoms, and as a result they are difficult to document.50 Physical examination findings of orthostatic intolerance may be elicited on vital signs, because there is some evidence that postural orthostatic tachycardia syndrome is one possible mechanism for the symptoms of fatigue in PTLDS.51,52 IMAGING AND ADDITIONAL TESTING

Two-tier serologic testing at the time of clinical evaluation of PTLDS is alone neither sensitive nor specific to confirm prior treated Lyme disease nor to evaluate the clinical response to initial therapy because seroevolution after treatment of early Lyme disease is unpredictable in any given patient.53,54 Prior appropriate treatment is required to make the diagnosis of PTLDS; consequently, it would be predicted that patients with PTLDS may be seronegative or may have IgM or IgG antibodies on Western blot testing that are insufficient to meet diagnostic criteria, despite historical documentation of a definite case of Lyme disease.9,53–55 Similarly, declines in B burgdorferi C6 antibody titers do not correlate with recovery from PTLDS symptoms.56 Serologic testing is also limited by the persistence of antibodies decades after resolution of all clinical symptoms attributed to Lyme disease in many patients. In one study of

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patients diagnosed 10 to 20 years earlier with early Lyme disease or late Lyme arthritis, the IgM remained positive in 10% of those initially diagnosed with early Lyme disease and 15% of those diagnosed with late Lyme arthritis. IgG western blots remained positive in 25% with remote early Lyme disease and 62% with remote late Lyme disease.55 This may lead to the misattribution of later nonspecific symptoms of a different cause to previous Lyme disease. Similarly, immunologic memory of other remote infections is common; therefore, extensive serologic testing for other bacterial infections is rarely helpful and likely to be confusing to patients and physicians unfamiliar with such limitations. There is very little evidence for the role of coinfection with other tick-borne pathogens in the risk for or pathophysiology of symptoms that represent PTLDS.57,58 MRI has not shown convincing evidence for specific focal brain abnormalities among patients with PTLDS.59 Central nervous system imaging with single-photon emission computed tomography scanning has been investigated in the context of PTLDS and posttreatment encephalopathy, and has been reported to show nonspecific white matter abnormalities.60 In patients with symptoms of abnormal or diminished sensation, nerve conduction studies or skin biopsy for small fiber nerve evaluation are important to document the presence of large or small fiber neuropathy, respectively. Patients with posttreatment symptoms may be difficult to separate clinically from patients with untreated late Lyme encephalopathy. The use of cognitive testing and lumbar puncture can be useful in these cases. In untreated late Lyme encephalopathy, subtle cerebrospinal fluid abnormalities including elevated protein or slightly elevated cell count are often but not universally present.61 In addition, neurocognitive testing in patients with late Lyme encephalopathy is abnormal, showing objective manifestations of cognitive dysfunction. Patients with prominent cognitive complaints caused by PTLDS are sometimes said to have posttreatment encephalopathy,27 a condition in which cognitive complaints and evidence of central nervous system inflammation are often difficult to quantify by current techniques, if they exist. DIFFERENTIAL DIAGNOSIS

The lack of specific biomarkers to establish the cause of nonspecific symptoms in many patients has led to the appearance of the term “chronic Lyme disease,” which is applied by some practitioners to describe a more heterogeneous, diverse group of patients. The diagnosis of chronic Lyme disease may mean different things to different patients and different medical practitioners.62 This may lead to confusion and suggests the need for a more precise taxonomy of the illnesses related to Lyme disease; those related to other tick-borne infections; and those that remain syndromic, such as fibromyalgia or chronic fatigue syndrome or idiopathic causes. Many patients who seek evaluation for chronic Lyme disease are not found to have past evidence of Lyme disease and do not meet the case definition of PTLDS or untreated late Lyme disease (Box 3).62,63 The frequency of PTLDS in referral settings seeing patients for evaluation of chronic Lyme disease ranges from less than 5% in nonendemic regions64 to 15% to 20% in endemic regions of the United States.65,66 Studies from tertiary referral clinics suggest that women may be more likely than men to be referred or self-referred for evaluation of long-standing symptoms thought to be caused by Lyme disease.63,66,67 The range of Lyme disease and non–Lyme disease related diagnoses present in this heterogeneous group of patients has been described by several investigators.63,65,67 Others seeking evaluation for chronic Lyme disease may not fit neatly into any specifically defined disease category,62,65 or meet criteria for fibromyalgia, chronic fatigue

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Box 3 Categories of chronic Lyme disease Category 1 Symptoms of unknown cause, with no evidence of Borrelia burgdorferi infection Category 2 A well-defined illness unrelated to B burgdorferi infection Category 3 Symptoms of unknown cause, with antibodies against B burgdorferi but no history of objective clinical findings that is consistent with Lyme disease Category 4 Post–Lyme disease syndrome From Feder HM Jr, Johnson BJ, O’Connell S, et al. A critical appraisal of chronic Lyme disease. N Engl J Med 2007;357(14):1422–30.

syndrome, or other medically unexplained syndromes of unknown cause.63,68–70 Close examination of referral populations show a group with well-documented Lyme disease who have onset of fibromyalgia after initial treatment of well documented Lyme disease. In this group of post–Lyme disease fibromyalgia, a sexbased difference is seen with woman outnumbering men by a ratio of 2:1.63,68 In those individuals diagnosed with fibromyalgia, the concept of central sensitization may be hypothesized as part of the pathophysiology of the continued pain.71 PTLDS is a diagnosis of exclusion and should not be made when other, specific diagnoses can explain symptoms and laboratory findings. Patients seeking evaluation for chronic Lyme disease are often found to have an alternative diagnosis, such as degenerative arthritis.67 Occasionally, Lyme disease may be associated with the development of a specific autoimmune illness, such as rheumatoid arthritis.67 The pathophysiologic relationship of neurologic diagnoses, such as Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis, to previous Lyme disease has been hypothesized, but is unproved.72 Most cases may be hypothesized to be coincidental or caused by autoimmunity or possibly other pathophysiologies triggered by infection.73 TREATMENT OF POSTTREATMENT LYME DISEASE SYNDROME

There is no Food and Drug Administration–approved treatment of PTLDS. Previous controlled clinical trials with intravenous antibiotics have failed to provide convincing evidence that antibiotics provide sustained improvement in fatigue or other symptoms, although design and interpretation of these studies have been debated.23,24,70,74 Current Infectious Diseases Society of America guidelines recommend against intravenous or prolonged oral antibiotic therapy for cases of PTLDS without objective evidence for active B burgdorferi infection.2 Patients with PTLDS who also meet diagnostic criteria for fibromyalgia could be candidates for treatment with agents, such as pregabalin and milnacipran, which have been shown to provide symptomatic improvement. In some cases PTLDS may be associated with postural orthostatic tachycardia syndrome in which treatment of orthostatic intolerance may improve symptoms of fatigue.51 Pharmacologic treatment tailored toward symptoms of pain, sleep disruption, attention-deficit disorder, and

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fatigue may be considered, but has never been subject to controlled trials to test effectiveness in the PTLDS population. Although there is a lack of consensus in the literature for identifying and treating possible physiologic causes for persisting symptoms, there are clinical care options for targeting symptom management and reducing the impact of symptoms on daily life functioning. There are validated behavioral symptoms management interventions for pain,75–77 symptoms of cognitive decline,78,79 and fatigue80–82 to facilitate maximal participation in life activities. Other nonpharmacologic modalities to consider include low-impact exercise and sleep hygiene interventions. All of these interventions are currently available, and individuals who are suffering with symptoms of PTLDS can be referred for appropriate interventions based on individual symptom presentation. The treatment of antibiotic-refractory late Lyme arthritis, based on the initial “adequate” therapy of B burgdorferi infection and including up to two to three defined courses of antibiotics,83 may be one model for further investigation. Experience suggests that this management approach results in few if any cases of residual infection, as measured by B burgdorferi polymerase chain reaction of synovectomy samples in those who remain symptomatic.84,85 In those who remain symptomatic, the mechanism of persistent synovitis has been extensively investigated and includes evidence for autoimmune arthritis.86,87 Primary treatment of this autoimmune phase has been with disease-modifying anti-inflammatory drugs, such as hydroxychloroquine and methotrexate.88 Future research into the role of other anti-inflammatory agents includes oral antibiotics with anti-inflammatory properties.89,90 Doxycycline has shown benefit in other illness, such as rosacea, thought to be inflammatory in origin.91,92 If persistent infection is found to contribute to the pathogenesis of PTLDS, new antibiotic regimens will need to be developed that are directed toward the latent and persisting stage of the organism.93 Further research to elucidate the mechanisms underlying persistent symptoms after Lyme disease and controlled trials of new approaches to the treatment and management of these patients are needed.3 SUMMARY

Overall, prognosis following appropriate antibiotic treatment of early or late Lyme disease is favorable but can be complicated by persistent symptoms of unknown cause. PTLDS is characterized by fatigue, musculoskeletal pain, and cognitive complaints that persist for 6 months or longer after completion of antibiotic therapy. PTLDS can vary markedly in disease severity from mild to severe symptoms with diminished health-related quality of life. The pathophysiology and mechanisms of persistent illness in PTLDS are not understood and there are little data on the effectiveness of nonantibiotic interventions. Risk factors for PTLDS include delayed diagnosis, increased severity of symptoms, and presence of neurologic symptoms at time of initial treatment. Two-tier serologic testing is neither sensitive nor specific for diagnosis of PTLDS because of variability in convalescent serologic responses after treatment of early Lyme disease. Recommended treatment of PTLDS is largely symptom-based because there are currently no Food and Drug Administration– approved treatments for patients with PTLDS. REFERENCES

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