OVERVIEW: What every practitioner needs to know

Are you sure your patient has Lyme disease? What should you expect to find?

Lyme disease, which is caused by the spirochete Borrelia burdorferi, can be divided into three clinical stages.
Stage 1: The hallmark of stage 1 is erythema migrans, the characteristic circular, slowly expanding rash that begins as a flat or raised, erythematous lesion at the site of the causative tick bite. Flu-like symptoms of varying severity can be associated with this stage. Even without treatment, these symptoms resolve in 3-4 weeks. Completely asymptomatic infection occurs only rarely (<10%), however the rash may be overlooked or the systemic symptoms misattributed.
Stage 2: Dissemination of the spirochete from the site of initial inoculation can occur, especially after multiple bites from infected ticks. Symptoms of this stage may include secondary skin lesions that resemble the original tick bite, as well as malaise, fever, headache, and diffuse aches. Organ involvement after dissemination determines which symptoms predominate and most commonly may include palpitations (cardiac), facial palsy (peripheral nervous system) or aseptic meningitis (central nervous system [CNS]). Nervous system involvement is termed neuroborreliosis. Eye involvement with conjunctivitis or keratitis can also occur.
Stage 3: This is late infection, and can occur years after the initial infection. The classic symptom is monoarticular or oligoarticular arthritis, especially of the large joints of the leg. This is usually self-limiting, but chronic arthritis can occur in 10% of patients. Central and peripheral nervous system disease (late neuroborreliosis) is more rare but may include mood and sleep disturbances and memory loss, paresthesias and radicular pain.
The physical findings of Lyme disease are varied based on the stage of disease. There can be an erythematous papule or macule at the site of the initial tick bite. The hallmark of early infection (stage 1) is erythema migrans, a slowly expanding circular rash which classically has a ‘bullseye’ of central clearing, but need not always.
Stage 2 findings may include scattered secondary skin lesions as the spirochetes disseminate, diffuse muscle tenderness, fever, and then organ-specific findings: arrhythmias with carditis, neck stiffness or pain if aseptic meningitis is present, facial palsy or motor radiculopathy as peripheral nervous system manifestations, and conjunctivitis or keratitis with eye involvement.
Stage 3 findings are most commonly frank arthritis of the knee and other weight bearing large joints. Joint fluid is often present and is inflammatory (see laboratory findings section). Rarely, there can be a subacute encephalopathy (neuroborreliosis) with memory loss and mood changes. A very rare late skin finding is diffuse eosinophilic fasciitis, which can mimic scleroderma.
The term “chronic Lyme disease” has been given to a heterogeneous group of patients who continue to have nonspecific symptoms of weakness, fatigue, myalgias and neurocognitive complaints, even after adequate treatment for Lyme disease.There are no data that convincingly tie such complaints to ongoing infection, and prolonged or repeated courses of antibiotic therapy are emphatically not recommended.

How did the patient develop Lyme disease? What was the primary source from which the infection spread?

B. burgdorferi, the spirochete that causes Lyme disease, is spread by the bite of an infected Ixodes tick. The specific tick species varies geographically in the United States: I. scapularis in the Northeast and Midwest and I. pacificus on the West Coast. Infected mice and deer are the primary reservoirs.
Infection via tick bite occurs primarily in the summer and fall. Infected ticks must feed for 24-36 hours in order to transmit the spirochetes to humans, therefore removing an attached tick the same day as an exposure limits the risk of disease. However, young ticks (nymph form) are very small and may not be identified within 24 hours of attachment. The risk of transmission is also related to the likelihood that a tick itself harbors B. burdorferi – this differs by Ixodes species and is 15-65% for I. scapularis compared to only 2% for I. pacificus.
Disease prevalence has greatly increased as a consequence of the rising deer population near areas inhabited by humans. The primary reservoir in the Northeast is the white footed mouse. Voles and chipmunks can also harbor the organism. The small larval form ticks obtain spirochestes from these intermediate hosts and subsequently infect humans.
White tailed deer are primarily bitten by adult ticks, and after obtaining their blood meal the ticks detach and lay their eggs. The resulting larval forms then attach to rodents containing the spirochetes, allowing the infectious cycle to continue. Deer are responsible for maintaining the increasing large population of ticks capable of carrying the spirochete and infecting humans.

Which individuals are of greater risk of developing Lyme disease?

Individuals who live in areas of the United States with Ixodes ticks that harbor B. burgdorferi are at risk. These regions broadly are the Northeast, Midwest and Mid-Atlantic states as well as the West Coast.
Individuals that spend time outdoors in the spring and summer for work or recreation are at increased risk.
Those individuals who do not identify and remove a feeding tick within 24 hours of attachment are at greater risk.

Beware: there are other diseases that can mimic Lyme disease:

The differential diagnosis of erythema migrans include: staphylococcal and streptococcal skin infections, spider bites and medication-related rash.
Lyme arthritis must be distinguished from bacterial arthritis and non-infectious inflammatory arthritis.
Lyme eosinophilic fasciitis, a late skin manifestation, can resemble scleroderma.
Lyme encephalopathy must be distinguished from other causes, such as other infections, toxins, auto-immune conditions, or metabolic diseases.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

Complete blood count (CBC) may show a mild leukocytosis, but usually is normal.
The erythrocyte sedimentation rate (ESR) is elevated in about half of cases (>20-30mm/hr).
Mildly elevated liver function tests may be present.
Joint arthrocentesis is moderately inflammatory with white blood cell (WBC) count of 25,000/µL. Routine cultures are negative.

Results that confirm the diagnosis

Diagnosis is based on both clinical and laboratory findings. It requires a patient to have a tick exposure and either erythema migrans identified by a clinician OR a late manifestation of disease, PLUS laboratory confirmation as detailed below.
There are some laboratories which offer tests which should never be used for diagnosis as they are unreliable – these include Lyme urinary antigen and polymerase chain reaction (PCR) of inappropriate specimens such as blood and urine. The two-stage serologic testing model below is the recommended testing algorithm.
Laboratory confirmation of Lyme disease requires serologic testing for antibodies specific to B. burgdorferi. Enzyme-linked immunosorbent assay (ELISA) is the preferred test method, as it is more sensitive and specific than indirect immunofluorescence assays (IFA).
A two test method is recommended, with all positive ELISA specimens then tested by western blot, since false positive ELISA tests have been documented in patients with coexisting conditions including rheumatoid arthritis, lupus, syphilis, relapsing fever, viral illnesses and leptospirosis.
Serology may be negative in early infection and in this case, acute and convalescent sera should be tested by ELISA and western blot to assess for a four-fold increase in titer.
Late CNS manifestations are almost always associated with positive two-stage testing for antibodies as described above.
The Cerebrospinal Fluid (CSF) may show pleocytosis and increased protein. In difficult cases, a positive CSF polymerase chain reaction (PCR) may help establish the diagnosis. A negative PCR result does not rule out disease
Culture is not routinely available in clinical labs. A punch biopsy of the erythema migrans lesion is the highest yield.
PCR of biopsy specimens when available has greater sensitivity than culture, especially in chronic disease. A negative PCR result does not rule out disease.

What imaging studies will be helpful in making or excluding the diagnosis of Lyme disease?

Brain imaging with MRI can be useful in neuroborreliosis to exclude other causes of mild encephalopathy
MRI = $$$-$$$$ ($ = 60-125, $$ 125-500, $$$ 500-1,000, $$$$ > 1,000)

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has Lyme disease, what therapies should you initiate immediately?

Remember that the diagnosis is based on a combination of clinical and laboratory data. The exception is early Lyme disease (exposure to Ixodes ticks and erythema migrans on exam). Early Lyme disease is a clinical diagnosis and may be treated without further laboratory testing.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

For Lyme disease, a clinical diagnosis (for early Lyme disease) or a combination of clinical and laboratory diagnosis (for all other stages) is necessary prior to treatment. There is no significant role for empiric therapy.

Table I provides treatment regimens for Lyme disease.

Table I.n

Recommended Treatment for Lyme Disease

2. Next list other key therapeutic modalities.

Patients being treated for Lyme disease should also be evaluated for coinfection with Babesia microti and Ehrlichia chaffeensis, which are also transmitted via Ixodes ticks in much the same geographic distribution.
Coinfection may cause an atypical presentation for any of these diseases.
Coinfection should be considered if patients remain febrile after 48 hours after starting appropriate therapy for Lyme disease or if they have a marked diffuse rash or anemia, leucopenia or thrombocytopenia, all of which are uncommon in Lyme disease but can be seen in babesiosis and erlichiosis.
Patients who, following appropriate treatment for Lyme disease, present with nonspecific complaints including weakness, fatigue, myalgias and neurocognitive dysfunction may request treatment for “chronic Lyme disease”, with prolonged or repeated courses of antibiotics. There are no data to suggest that this is helpful, and antibiotics should not be given.

What complications could arise as a consequence of Lyme disease?

What should you tell the family about the patient’s prognosis?

Most patients recover fully within 3-4 weeks after appropriate treatment. Even patients who present with 3rd degree atrioventricular (AV) block do not usually require temporary cardiac pacing.
For CNS Lyme disease (neuroborreliosis), 75% are expected to have a full recovery, and of the remaining 25% only 10-12% will have chronic neurologic deficits that affect their daily lives.

Add what-if scenarios here:

If a patient has had appropriate treatment for Lyme disease, but then presents with nonspecific complaints including weakness, fatigue, myalgias, and neurocognitive dysfunction, which he or she attributes to “chronic Lyme disease”, it is important to discuss the lack of evidence that prolonged or repeated courses of antibiotics are helpful. There have been case control studies that have shown that these types of complaints are no more likely in patients post-Lyme disease than in age-matched controls without a history of Lyme disease.

What pathogens are responsible for this disease?

In Europe and Asia, Lyme disease is caused by B. garinii and B. afzelii and the vector is Ixodes ricinus and Ixodes persulcatus, respectively.

B. garinii has been associated with a more severe encephalomyelitis with spastic paraparesis, marked cognitive dysfunction, ataxia and bladder dysfunction. B. afzelii is associated with acrodermatitis chronicum atrophicans in Europe, which is atrophic lesions of the distal extremities that can resemble scleroderma.

How do these pathogens cause Lyme disease?

B. burgdorferi cycles two types of hosts between it – ticks and mammals. It cannot live freely in the environment. It does not produce large numbers of proteins, and has a relatively small genome. It does produce a large number of lipoproteins that may help it evade the mammalian immune system.

The ways in which B. burgdorferi cause disease and evade the immune system are complex and not yet fully understood.

A protein called outer surface protein A (OspA) assists in binding the bacterium to the tick midgut. When the tick bites a mammalian host, ospA is down-regulated and outer surface protein C (OspC) is up-regulated, which assists with tissue invasion. B. burgdorferi that do not express OspC cannot effectively infect mammals.

However, OspC is a potent target for IgM antibiodies, and is soon down-regulated after initial infection. The organisms utilize host proteins to move through tissue (it does not secrete its own proteases but binds host plasmin for this function). Other virulence factors include P66 which binds integrin receptors on platelets and can facilitate bacteremia and complement regulator acquiring surface proteins (CRASPs) that bind complement Factor H, which blocks the complement from killing the organism.

How can Lyme disease be prevented?

There was previously a FDA-licensed human vaccine for Lyme disease, based on OspA. However, there were concerns that vaccination could be associated with vaccine-induced Lyme arthritis and although there were no data to support these claims on review of the available clinical trial data, the manufacturer due to poor sales chose to remove the vaccine from market. There is currently no approved vaccine.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Epidemiology

Diuk-Wasser, MA, Hoen, AG, Cislo, P, Brinkerhoff, R, Hamer, SA, Rowland, M, Cortinas, R, Vourc’h, G, Melton, F, Hickling, GJ, Tsao, JI, Bunikis, J, Barbour, AG, Kitron, U, Piesman, J, Fish, D. “Human risk of infection with Borrelia burgdorferi, the Lyme disease agent, in eastern United States”. Am J Trop Med Hyg. vol. 86. 2012. pp. 320-7. (Modeling exercise to help estimate risk based on extrapolating maps of known infected ticks in this area.)

Microbiology and pathophysiology

Radolf, JD, Caimano, MJ, Stevenson, B, Hu, LT. “Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes”. Nat Rev Microbiol. vol. 10. 2012. pp. 87-99. (A thorough review of what is currently known about B. burgdorferi life cycle and host pathophysiology.)

Clinical Management

Lantos, PM, Charini, WA, Medoff, G, Moro, MH, Mushatt, DM, Parsonnet, J, Sanders, JW, Baker, CJ. “Final report of the Lyme disease review panel of the Infectious Diseases Society of America”. Clin Infect Dis. vol. 51. 2010. pp. 1-5. (Includes full discussion of patients presenting with complaints of chronic Lyme disease, reinforces recommendations to not treat with prolonged antibiotics.)

O’Connell, S. “Lyme borreliosis: current issues in diagnosis and management”. Curr Opin Infect Dis. vol. 23. 2010. pp. 231-5. (Overall review of clinical features of Lyme disease.)

Halperin, JJ. “Nervous system Lyme disease: diagnosis and treatment”. Rev Neurol Dis. vol. 6. 2009. pp. 4-12. (Review of clinical aspects of neuroborreliosis.)

Other references:

Erol, I, Kiliçarslan, B, Saygi, S, Demir, S, Alehan, F. “Acute transverse myelitis in a child with Lyme disease and a review of literature”. Pediatr Neurol.. vol. 48. 2013 Apr. pp. 325-8.

Berghoff, W. “Chronic Lyme Disease and Co-infections: Differential Diagnosis”. Open Neurol J.. vol. 6. 2012. pp. 158-78.

Leibler, JH, Zakhour, CM, Gadhoke, P, Gaeta, JM. “Zoonotic and Vector-Borne Infections Among Urban Homeless and Marginalized People in the United States and Europe, 1990-2014”. Vector Borne Zoonotic Dis.. vol. 16. 2016 Jul. pp. 435-44.

Butler, AD, Carlson, ML, Nelson, CA. “Use of a tick-borne disease manual increases accuracy of tick identification among primary care providers in Lyme disease endemic areas”. Ticks Tick Borne Dis.. 2016 Nov 23. pp. S1877-959X(16)30235-7

Wormser, GP, Strle, F, Shapiro, ED, Dattwyler, RJ, Auwaerter, PG. “A critical appraisal of the mild axonal peripheral neuropathy of late neurologic Lyme disease”. Diagn Microbiol Infect Dis.. 2016 Nov 12. pp. S0732-8893(16)30374-1

Curcio, SR, Tria, LP, Gucwa, AL. “Seroprevalence of Babesia microti in Individuals with Lyme Disease”. Vector Borne Zoonotic Dis.. vol. 16. 2016 Dec. pp. 737-743.

Miraglia, CM. “A Review of the Centers for Disease Control and Prevention’s Guidelines for the Clinical Laboratory Diagnosis of Lyme Disease”. J Chiropr Med.. vol. 15. 2016 Dec. pp. 272-280.

Clinckaert, C, Bidgoli, S, Verbeet, T, Attou, R, Gottignies, P, Massaut, J, Reper, P. “Peroperative cardiogenic shock suggesting acute coronary syndrome as initial manifestation of Lyme carditis”. J Clin Anesth.. vol. 35. 2016 Dec. pp. 430-433.

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Borrelia burgdorferi including Lyme disease