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The diagnosis and management of lyme disease is a controversial topic. With the recent revision of the Centers for Disease Control and Prevention (CDC) definition for Lyme disease in 2008, this article is intended to be a timely review of Lyme disease with particular emphasis on NC and the southeastern United States. This is an update for clinicians on the diagnosis and management, and is intended to elicit assistance in determining whether Lyme disease is an emerging infectious disease in the state.

Background
Lyme disease is a tickborne infection caused by the spirochete Borrelia burgdorferi (Bb) which was first discovered as a human pathogen in 1976. Named after the initial cluster that occurred in Lyme, Connecticut, the disease is now endemic in three major areas of the country and is the most common vectorborne disease reported in the U.S. with over 20,000 cases annually. Most cases are reported from the northeastern US, the northern Midwest and northern California. The vector of Bb in the eastern US is the black-legged tick Ixodes scapularis, and the preferred hosts and reservoir are the white-footed mouse and other small mammals, especially shrews. These mammals harbor Bb in their bloodstream, remain asymptomatic and are essential for the enzootic maintenance of Bb in the wild. Large mammals, especially deer, are also needed for maintenance as they are the preferred hosts for the adult tick. Incidental infections occur in humans and other mammals such as dogs.

In Lyme endemic areas such as the northeastern US, the two year lifecycle of I. scapularis ticks determines the transmission characteristics of Bb. After hatching from an egg in the early spring, an uninfected larval tick must feed on a Bb spirochetemic mammal to become infected. The fed larva, harboring Bb in its gut, drops off the host and morphs during the summer into the nymph stage carrying the spirochete with it (transstadial transmission). In the following late spring and early summer the nymph feeds again, commonly infecting a new reservoir host, sustaining the cycle. The nymph can also feed on an incidental host which explains why most human cases of Lyme disease are acquired between April and June. After feeding, the nymph morphs to the adult stage during the second summer. In the early fall it feeds one more time usually on deer. The adult tick feeding accounts for the second peak incidence in humans from September to November. The lifecycle ends with the adult ticks mating and the female laying eggs in the third spring. Thus for a human to become infected, the Bb lifecycle must be established and the human must be exposed to the habitats of this tick.

Ecology in the Southeast: Focus on North Carolina
While burgeoning human cases were reported from endemic areas such as the northeastern US in the past 25 years, surveillance reports from the southeastern US, including NC, remained sporadic. In NC, there are published studies that have demonstrated that both the vector (I. scapularis ticks) and Bb-infected reservoir host (small mammals) exist in the state. However, the studies have been small and there have been no systematic regional surveys done in NC. There have also been published reports that fail to identify the classic Bb transmission cycle in NC, or alternatively, show a transmission cycle involving small reptiles. Unlike small mammals, reptiles appear to be incompetent reservoir hosts for Bb resulting in low levels of enzootic transmission and less likely infection of humans. This natural phenomenon in the reptilian host seems to protect the incidental mammalian host from infection.

Further confounding the Lyme disease ecology in the southeast was the discovery of a clinical presentation of localized early infection (Stage 1, at right) in patients. Outbreaks (including NC) and sporadic cases were reported in people presenting with classic erythema migrans (EM) rash following tick bites from the common southern tick Amblyomma americanum (the "lone star" tick named for the identifying bright spot on the dorsum of adult females). However, in these southern cases, skin biopsies were negative for Bb and serology lacked Bb-specific antibody production. Because no microorganism has been conclusively identified in this syndrome, it currently is called the Southern Tick-Associated Rash Illness or STARI.

Pathogenesis and Clinical Manifestations of Human Disease
Lyme disease is best described as an infection with early and late manifestations categorized in three stages: early, early disseminated, and late (persistent) infection. Following the bite of an infected nymph or adult Ixodes tick, the tick must embed and feed for at least 24 hours for Bb inoculation to occur. This is why it is so important to perform tick inspections after exposure to tick habitats. Lyme disease can be completely avoided by prompt removal of ticks from the skin.

Stage 1: Early Infection (Localized)
After inoculation into the dermis, Bb begins to replicate and elicit an immune response. As many as 30 days following the bite, the classic early manifestation of Lyme disease, the target or bull's eye rash of EM, appears. Most people do not remember the tick bite because of the small size of Ixodes nymphs. The rash is at least 5 cm across and expands, with or without central clearing, from the point of inoculation. Primary EM lesions associated with tick bites are single or multiple, erythematous or violaceous, macular or papular, often pruritic and occasionally burning or painful. In about 20% of early Lyme cases, no EM rash is documented. This may mean that the rash did not occur or was not seen (e.g. as can happen on the scalp).

The early signs and symptoms of Lyme disease may spontaneously resolve within a week with clearance of Bb from the body by the immune response. Only 20% of persons will have positive serologic tests during the acute illness, but this increases to 50% to 80% in the convalescent phase after antibiotic therapy. Antibiotics for a suspected clinical case should not be withheld pending test results because of the poor sensitivity of available serologic tests in early Lyme disease. Detection by culture of Bb from a skin biopsy of an EM lesion has a sensitivity as high as 75%; however skin biopsy is not practical in most clinical settings.

Stage 2: Early Disseminated Infection
In untreated cases weeks to months following the acute phase, hematogenous dissemination occurs with the subsequent development of systemic manifestations of Lyme disease. There may be a period of well-being after resolution of the acute phase and some patients may not recall any acute symptoms. Disseminated disease may also overlap with the acute phase resulting in EM on physical exam along with systemic manifestations of fever, headache, malaise and fatigue, generalized achiness and regional lymphadenopathy. Early Lyme disease in this phase is difficult to differentiate from the other common tickborne infections seen in NC: Rocky Mountain spotted fever (RMSF) and Ehrlichiosis, particularly in patients without documented primary EM.

The target organs of early disseminated Bb include the skin, heart, nervous system, joints and eyes. Disseminated skin lesions differ from primary EM. They tend to be multiple evanescent salmon-colored macules of varying sizes and might be missed on physical exam because of their transience and subtle coloring, particularly on dark skinned people. They are not associated with tick bites. Both EM and secondary lesions usually fade within a month.

In about 15% of untreated patients, frank neurologic disease develops. In early disseminated infection, the hallmark neurological lesion is a motor or sensory radiculopathy, classically unilateral or bilateral 7th cranial nerve (Bell's) palsy. Meningoencephalitis presents with the typical features of aseptic meningitis: fever, headache, meningismus, and mental status changes. Cerebrospinal fluid analysis shows a lymphocytic pleocytosis with a total WBC count about 100 cells/mm3, elevated protein and a normal glucose. Gram stain and routine cultures are negative. Other manifestations include mononeuritis multiplex, cerebellar ataxia, and myelitis.

Five percent of untreated patients develop cardiac involvement with focal lesions in the conduction system resulting in varying degrees of atrioventricular (AV) heart block; sometimes requiring temporary pacing. Some patients have evidence of more diffuse disease compatible with acute myopericarditis (mild left ventricular dysfunction but rarely cardiomegaly). Heart murmurs do not occur. Heart involvement presents with palpitations, lightheadedness or syncope; chest pain and shortness of breath are uncommon. Cardiac disease is brief, lasting from three days to six weeks.

In this stage, migratory musculoskeletal pain is common in joints, tendons, bursae, muscle and bones. Conjunctivitis is the most common eye abnormality but there are case reports of iritis, panophthalmitis, choroiditis with retinal detachments, or interstitial keratitis.

Stage 3: Late (Persistent) Infection
Months after the primary infection in the context of robust cellular and humoral immune responses, about 60% of untreated patients experience attacks of joint swelling and pain. It was this presentation in Lyme, Connecticut in 1976 in a cluster of children mistakenly diagnosed with juvenile rheumatoid arthritis that lead to the discovery of Bb. Large joints, especially the knees, are affected. Attacks last from weeks to months with periods of complete remission. Arthrocentesis fluid is typical of an acute inflammatory infectious arthritis with a neutrophilic leukocytosis, but with negative gram stain and routine cultures. In untreated cases, arthritis attacks last longer in the second and third year of illness; however, the total number of patients who continue to have attacks diminishes by 10% to 20% each year. Even in untreated cases, chronic or intermittent arthritis resolves within several years except in about 10% of patients who will have persistent arthritis that resists antibiotic treatment. Chronic, antibiotic-treatment resistant Lyme arthritis is associated with specific host factors including human leukocyte antigen (HLA) haplotypes DRB1*0401, DRB1*0101 and related alleles.

In about 5% of untreated patients, chronic neurologic disease develops months to years after initial infection, sometimes following long periods without symptoms (i.e. latency). Syndromes include axonal polyneuropathy (spinal radicular pain or distal paresthesias) and Lyme encephalopathy (subtle cognitive disturbances). In the former, electrophysiologic studies often demonstrate an axonal neuropathy affecting proximal and distal nerve segments. In the latter, the cerebrospinal fluid (CSF) is normal but intrathecal antibody production to Bb can be present. Neuropsychological tests and brain scans may be abnormal but are non-specific.

Laboratory Criteria for Diagnosis
Diagnosis is usually based on the clinical picture, exposure to a tick habitat in a Lyme-endemic area, and positive antibody production to Bb. In Stage 1, skin biopsy of EM for culture of Bb is the most sensitive and specific lab test but requires an invasive procedure and rapid transport into specialized medium making this test impractical. Because of poor sensitivity (20% to 30% IgM positive), serologic testing of serum in Stage 1 infection is not recommended in favor of treatment in the setting of EM. IgM antibody detection improves to 50% to 80% in the convalescent phase (two to four weeks) even in treated EM cases; however, serologic testing is much more valuable in Stage 2 and 3 infections. After a month, >95% of patients with active infection have positive IgG antibody responses, and a positive IgM alone likely represents a false positive and should not be relied upon.

For serologic testing, the CDC recommends a two-test approach with samples first tested using an enzyme-linked immunoabsorbant assay (ELISA) with equivocal or positive results followed by Western blotting. For IgM, two of three bands (23, 39, and 41 kDa) and for IgG, five of ten bands (18, 23, 28, 30, 39, 41, 45, 58, 66, and 93 kDa) must be present for a positive result.

In suspected cases of neuroborreliosis (Stage 2 meningitis or Stage 3 neuropathy or encephalopathy), intrathecal measurement of IgG antibody is recommended. Encephalomyelitis must be confirmed by demonstration of antibody production against Bb in the CSF, evidenced by a higher titer of antibody in CSF than in serum. Detection of Bb DNA using polymerase chain reaction is superior to culture in joint fluid but has been only positive in small numbers of CSF samples. The Lyme urine antigen test has been unreliable and is not recommended.

Prevention and Treatment
Primary prevention involves avoiding tick infested areas, and when not possible, preventing tick bites by wearing protective clothing pre-treated with permethrin or application of DEET-containing repellant to the skin and/or clothing. For people living in endemic areas or those who have daily tick exposure, secondary prevention involves performing frequent. careful tick checks, especially on the legs, groin and axillae. Lyme disease is prevented if ticks are removed within 24 hours and before engorgement, though it may not always be possible to find all embedded ticks due to their small size. For tertiary prevention, in endemic areas, a single 200 mg dose of doxycycline was shown to prevent Lyme disease if given within 72 hours of finding an engorged nymphal I. scapularis tick.

Evidence-based treatment regimens are derived from controlled clinical trials primarily performed in Lyme-endemic regions. For early infection (Stage 1 and 2) in adults, a 14-21 day course of oral doxycycline (100 mg bid) is preferred even in cases of meningitis. When an acute presentation is less clear (e.g. absence of EM), this regimen will also cover the other major tick borne infections common in NC, RMSF, STARI and Ehrlichiosis. Alternative regimens for early Lyme disease include amoxicillin (500 mg tid), cefuroxime axetil (500 mg bid), or erythromycin (250 mg qid). In children 8 or younger, choices include amoxicillin (250 mg tid or 20 mg/kg/day in divided doses), cefuroxime axetil (125 mg bid), or erythromycin (250 mg tid or 30 mg/kg/day in divided doses).

For Lyme arthritis, longer courses of 30 to 60 days are recommended using doxycycline (100 mg bid) or amoxicillin (500 mg qid); or 14-28 day parenteral regimens including ceftriaxone (2 g daily) or penicillin G (20 million units in four divided doses daily). Parenteral regimens are most commonly used in neuroborreliosis; or in high degree AV block until the patient is stabilized when the course can be completed with oral regimens. Oral regimens for early infection are recommended for first-degree AV block (P-R interval >0.3 seconds) and facial palsy alone. Approximately 15% of patients experience a Jarisch-Herxheimer-like reaction within the first 24 hours of treatment of a disseminated infection.

Public Health Surveillance in North Carolina
In 2008, in consultation with the Council of State and Territorial Epidemiologists, the CDC updated its surveillance case definition for Lyme disease. Case definitions are broadly based on clinical, epidemiological and laboratory criteria.

Prior to 2008, stage 1 (EM) Lyme disease was based on an exposure to an endemic area and the EM rash. In 2008, an endemic region or county was further defined as one with an established population of a tick vector (I. scapularis) infected with Bb, or two or more people with laboratory confirmed Lyme disease (Stage 1: EM with positive culture or IgM serology; Stage 2 or 3, clinically compatible syndrome with positive IgG serology).

However, the new CDC case definition may still lead to misclassification of cases in NC and the southeastern US. Established populations of I. scapularis infected with Bb have been found here, especially in the eastern part of the state, but because larvae and nymphs feed preferentially on reptiles, mammalian and human infections may not occur frequently. Since STARI is a common clinical presentation in NC, counting these cases as Lyme disease may result in over-estimation of Lyme disease incidence and prevalence.

Therefore, beginning with the 2009 tick season, the NC Division of Public Health (DPH) is seeking to better understand Lyme disease incidence in NC. The most accurate method to accomplish this surveillance is using Stage 1 disease; thus, for patients presenting with EM, the division's staff is requesting primary care providers to report EM cases to their local health departments, elicit a travel history within the past 30 days, and obtain a blood serological IgM test (ELISA and reflex Western blot if ELISA equivocal or positive).

EM patients should still be treated with standard regimens for Stage 1 Lyme disease. Treated patients who are IgM negative or in whom acute specimens were not obtained will be asked to give a convalescent specimen within two to four weeks. NC counties (the county where the person was most likely exposed) with two or more laboratory confirmed EM cases will be declared endemic for Lyme disease. Lyme disease testing is available at most clinical reference labs and at no cost if the specimen is routed to the CDC via the NC public health courier system. The CDC turn-around time is approximately six weeks; however, as stated above, awaiting an IgM lab result should not influence a treatment decision.

This enhanced surveillance will assist public health agencies in improving important tick bite prevention messages to the public and in informing clinicians on estimating the probability of Lyme disease in their patients presenting with EM or later manifestations. This surveillance will also help to determine incidence and trend of Lyme disease in NC and the southeastern US.

Selected References

• Apperson CS, et al. Relative utilization of reptiles and rodents as hosts by immature Ixodes scapularis (Acari: Ixodidae) in the coastal plain of North Carolina, USA. Experimental & Applied Acarology 1993;17:719.


• Kirkland KB, et al. Erythema migrans-like rash illness at a camp in North Carolina: a new tick-borne disease? Archives of Internal Medicine 1997;157:2635.


• Steere AC. Borrelia burgdorferi (Lyme disease, Lyme borreliosis). In: Mandell GL, et al, eds. Principles and Practice of Infectious Diseases, 6th Ed. Elsevier; 2005:2798.


• 2008 Lyme disease CDC case definition, accessed March 17, 2009 at: www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm