Lyme Disease Basics for Providers
A Brief Primer by International Lyme and Associated Diseases Society
ILADS works to educate and support medical professionals in order to facilitate their provision of timely and effective care for patients with Lyme and other tick-borne diseases. Many Lyme patients see multiple providers over months or years before being accurately diagnosed. Further, many Lyme patients suffer from long term health problems – problems that might have been prevented with early and effective treatment.
This brief primer, written for healthcare providers, gives an overview of the epidemiology, transmission, diagnosis and treatment of Lyme and associated diseases. For more in-depth education and training in the treatment of Lyme, we strongly recommend our Lyme Fundamentals Course, Provider Training Program and Scientific Conferences.
Epidemiology of Lyme Disease
Lyme disease is a bacterial infection caused by several members of the Borrelia burgdorferi sensu lato complex and transmitted by the bite of an infected Ixodes (blacklegged) tick. It is the fastest growing vector-borne illness in the US.
In the last ten years, Ixodes ticks in the US (Ixodes scapularis in the northeast and upper midwest and Ixodes pacificus in the west) have significantly expanded their range. Forty-three states within the continental US have established or reported blacklegged tick populations. I. scapularis or I. pacificus ticks have been identified in nearly half of the counties within these states. Blacklegged ticks are also native to Europe, northern Asia, northern Africa and South America.
A patient's residence does not necessarily reflect his or her Lyme disease risk. People travel, pets travel, and ticks travel (migratory birds carry ticks over great distances). This creates a dynamic situation with many opportunities for exposure.
The CDC estimates that more than 300,000 people are diagnosed with Lyme disease each year in the US. Of these infections, an unknown number will result in a chronic, difficult-to-treat illness.
Lyme disease affects all age groups, with particularly high occurrences among children, especially ages 5-14, and adults 45-64. There is a slight male predominance in early infection.
Early Lyme disease is reported most commonly in the spring through fall, with the peak in June, July and August. Lyme cases are reported in each month of the year. In California and other similarly temperate areas, the “seasonality” of Lyme disease is less pronounced, with cases diagnosed throughout the year. Later manifestations of Lyme are diagnosed throughout the year as well.
Etiology of Lyme & Other Ixodes-Borne Illnesses
LYME DISEASE
Lyme disease is caused by members of the Borrelia burgdorferi sensu lato complex.
There are roughly two dozen species in the Borrelia burgdorferi sensu lato complex; not all are human pathogens. The geographic distribution of the species is not uniform. In the United States, almost all reported cases of Lyme disease appear to be the result of Borrelia burgdorferi sensu stricto (Bbss) infections. In Europe, 3 species - B. garinii, B. afzelii, and Bbss, are responsible for most cases of Lyme disease. The various species are further divided into strains and there are hundreds of strains worldwide. For the purposes of this document, any Borrelia burgdorferi sensu lato complex infection causing Lyme-like symptoms will be considered under the heading of Lyme disease.
Differences between genospecies of Borrelia produce variable clinical presentations, variable antibody responses and possibly a variable therapeutic response.
More recently identified black-legged tick transmitted pathogens Borrelia mayonii and the relapsing fever relative Borrelia miyamotoi have been documented to cause Lyme-like illnesses. Both seem to respond to the same treatments used for Lyme caused by B. burgdorferi.
Other blacklegged tick-borne pathogens are discussed as co-infections. A single tick bite can transmit multiple pathogens; tick bites occurring in succession may result in transmission of different pathogens at different times. It is not unusual for Lyme disease patients to be multiply infected.
CO-INFECTIONS
Black-legged ticks have been shown to transmit several other pathogens in addition to Borrelia burgdorferi.
It is important to consider co-infecting pathogens like Babesia, Anaplasma, Ehrlichia and Bartonella for patients who have risk factors for those illnesses and/or persistent symptoms after antibiotic treatment for Lyme disease.
The frequency of tick-borne co-infections in Lyme disease patients from endemic areas ranges from 4 to 45%. When coinfections are left untreated, their continued presence increases morbidity and may prevent successful treatment of Lyme disease.
Laboratory evaluation for co-infecting pathogens can be challenging. Performance parameters of available tests are variable and do not always account for the different strains that may be responsible for illness.
Some of the most commonly encountered co-infections are:
Anaplasma: a white blood cell parasite that causes fever, headaches, generalized body aches and is associated with leukopenia (granulocytes), thrombocytopenia, and elevated transaminases.
Babesia: a malaria-like piroplasm that invades red blood cells causing fever, fatigue, chills, sweats, headaches, dyspnea, and may be associated with anemia and elevated transaminases.
Ehrlichia: a white blood cell parasite similar to Anaplasma and causing a similar clinical picture, the type of WBC invaded is species dependent; most commonly associated with Lonestar ticks, one type may be more associated with Ixodes ticks.
Bartonella: intracellular parasite that invades erythrocytes, endothelial and other cells; increasing but still inconclusive evidence for tick transmission; associated with fever, lymphadenopathy, eye disorders, myocarditis, endocarditis, encephalopathy, musculoskeletal involvement.
Powassan Virus: flavivirus with 2 lineages transmitted by different ixodes ticks. Lineage II also called deer tick virus; can cause severe neurologic symptoms; no known treatment; fatalities documented.
Tickborne Encephalitis Virus: prominent in Europe and Asia, a flavivirus that affects the central nervous system; no known treatment; a vaccine is available in some parts of Europe; limited use owing to adverse effects in children.
SELECTED OTHER TICK-RELATED DISEASES
STARI, another important tick-borne disease
Southern tick- associated rash illness (STARI), a Lyme-like illness, has been associated with bites from the Lonestar tick (Amblyomma americanum), not blacklegged ticks. The bacterial pathogen has not been clearly established. Limited evidence supports antibiotic treatment similar to that for Lyme disease. The Lonestar tick’s range continues to expand and in addition to its southern and central distribution now includes much of the northeastern US.
Alpha gal allergy
This IgE mediated allergic reaction to galactose alpha 1,3, galactose (alpha gal) a carbohydrate found in red meat, is associated with Amblyomma americanum tick bites. Treatment is centered around management of delayed hypersensitivity reaction and subsequent red meat avoidance.
Tick paralysis
This is an ascending paralysis resulting from a neurotoxin released by tick salivary glands during feeding. Many species of ticks have been implicated. Treatment is removal of the tick.
Symptoms and Signs of Lyme Disease
The medical literature documents the protean manifestations of Lyme disease, and familiarity with its varied presentations is key to recognizing both acute and disseminated disease.
Borrelia burgdorferi can infect any organ or tissue and thus, produce a wide range of symptoms.
Lyme should be considered in the differential diagnosis of rheumatologic and neurologic conditions, as well as chronic fatigue syndrome, fibromyalgia, somatization disorder and any difficult-to-diagnose multi-system illness.
Common Symptoms and Signs of Early Lyme Disease
Erythema Migrans rash (EM); see description below
Fatigue, malaise
Flu-like symptoms, including fever, headache, arthralgias, myalgias
Stiff neck
Dysesthesia
Lymphadenopathy
Facial nerve dysfunction leading to weakness or paralysis of facial muscles (often mislabeled as Bell's palsy)
Common Symptoms and Signs of Disseminated and Late Lyme Disease
Fatigue
Multiple red rashes (EM’s)
Severe headaches and neck stiffness
Joint swelling and/or pain
Neuropathic symptoms - nerve pain, numbness, hot/cold sensations, tingling
Cognitive dysfunction
Memory impairment
Unprovoked pain which may interfere with sleep
Palpitations or chest pain, shortness of breath
Lightheadedness, fainting
Gastrointestinal symptoms
Psychiatric symptoms- including depression, anxiety, and mood changes
Diagnosis of Lyme Disease
Because “classic” indicators of Lyme are not always apparent, and widely-available testing procedures are highly insensitive, diagnosis of Lyme disease must be made on a clinical basis. A provider must take into account patient’s medical history, symptoms, signs, and tick exposure risk.
Evidence of potential exposure to B. burgdoferi includes a patient’s recall of an Ixodes bite but the incidence of this event varies. In Europe, 64% of Lyme disease cases were attributed to a known bite, but <30% of US patients with Lyme disease recall a tick bite.
The presence of erythema migrans (EM) rash is a “classic” indicator of Lyme disease, but the appearance of EM rashes is highly variable. Most EM rashes are solid colored, ranging from faint pink to a deep red. Less than 20% of all EMs have the classic “bull’s-eye” appearance. An EM may be missed if not specifically sought on exam, as they are typically asymptomatic and may be unnoticed or unrecognized by the patient.
An EM rash on a patient who has been exposed to an area where Lyme disease is endemic is considered pathognomonic of Lyme disease. Its presence should prompt immediate treatment with an appropriate course of antibiotic therapy.
Given that some patients present with flu-like symptoms without any rash or memory of one, doctors should take care to consider Lyme disease in areas where the infection is endemic, even when a patient presents without that hallmark sign.
Particularly for patients who have been exposed to both Ixodes and Amblyomma americanum ticks and who present with a rash, Lyme disease, STARI, and other tick-borne illnesses should be considered in the differential diagnosis.
Widely-used tests for Lyme are unreliable
The commonly recommended testing scheme for evaluating a person suspected of having Lyme disease calls for a first step using a highly sensitive ELISA, with subsequent performance of IgM and IgG Western blots only when the ELISA result is positive or equivocal. In this scheme, samples that are negative by ELISA are not investigated further.
Tests used in this strategy are subject to confounders of testing that affect accuracy and reliability, and because they are linked sequentially in the stated manner, those confounders are magnified, making the possibility of false negative test results much greater.
Performance characteristics are not only affected by the timing of testing but also by the particular disease manifestation being evaluated. In addition, seronegativity, even with serial measurement of antibodies, has been well documented to occur. (Engstrom, Dattwyler)
The interpretation criteria for IgM and IgG Western blots, adopted by CDC and ASTPHLD for standardization at the Dearborn conference in 1994 and used for surveillance purposes, were selected to have a specificity of 99%.
Primarily designed and intended to enhance specificity, this sequence necessarily results in reduced sensitivity. Thus, the two-step process recommended by the CDC fails to capture a significant number of infections.
Other Western blot interpretation criteria have been suggested that may enhance sensitivity.
The following individual antibody bands are thought to be significant with regard to providing evidence of Bbsl exposure: 23-25, 31, 34, 39, 83-93.
Emerging testing modalities, including a more promising method of culture, T-cell activation testing, antigen capture techniques, and proteomic methods present new opportunities for addressing the challenges faced in laboratory evaluation of Lyme disease. As in all testing, interpretation of positives and negatives depends upon the clinical setting.
Stated simply, laboratory results can support the diagnosis but cannot, in isolation, make or rule out the diagnosis of Lyme disease.
Comprehensive evaluation is required
Lyme disease has been called the “great imitator.” and its symptoms can mimic those of rheumatologic and neurologic conditions, chronic fatigue syndrome, fibromyalgia, and many difficult-to-diagnose multi-system illnesses. However, in some patients, symptoms attributed to Lyme disease may actually be the result of other illnesses.
Chronically ill Lyme patients may also have non-tick related infections such as EBV, CMV, HHV6, Mycoplasma, Chlamydia pneumoniae, parvovirus, candida and more.
The interaction of Lyme and other tick-borne illnesses with these opportunistic infections is not well understood.
Diagnosis of Chronic Lyme Disease
For many patients, Lyme disease is strictly an acute infection but for others, the infection is chronic. Common symptoms include:
Fatigue
Cognitive dysfunction
Headaches
Sleep disturbances
Migratory myalgia and arthralgia
Numbness and tingling
Neuropathic pain
Depression and anxiety
Musculoskeletal problems
The diagnostic issues discussed above also apply to patients with chronic Lyme disease. As a result, patients can exhibit significant symptoms of Lyme disease for years and even decades that are misattributed to other entities. Although symptoms of chronic Lyme disease overlap with the symptoms of other illnesses, a well-conducted meta-analysis demonstrated that persistent Lyme disease symptoms were a distinct set of symptoms that differed from those of fibromyalgia, depression and chronic fatigue. Additionally, in comparing the cerebrospinal fluid of patients with chronic, post-treatment manifestations of Lyme disease to that of patients with chronic fatigue syndrome, researchers found that the two groups could be distinguished from each other based on the presence of unique proteins.
As in early disease, a comprehensive evaluation is required.
Prophylaxis and Treatment
Evidence indicates that 20 days of prophylactic antibiotic treatment may be highly effective for preventing the onset of Lyme disease after known Ixodes tick bite. Patients with early Lyme disease may be best served by receiving 4-6 weeks of antibiotic therapy. Cases of chronic B. burgdorferi infection require individualized treatment plans.
Black-legged Tick Bite
If administered promptly after an Ixodes tick bite, 20 days of doxycycline may prevent the patient from contracting Lyme disease. Recent mouse studies demonstrate that the effectiveness of this strategy falls off dramatically if administration begins > 48 hours post tick removal.
Patients should be cautioned to watch for Lyme disease symptoms.
Patients should be educated about tick bite prevention.
Lyme Disease
Many patients with early Lyme have been treated with short courses of antibiotics (< 20 days) and recovered. However, both in practice and in the scientific literature, it has been observed that a significant number of patients do not return to their pre-Lyme health with short courses of antibiotics. The ILADS guidelines working group reviewed the available research and developed recommendations based upon the best-available evidence, clinical expertise, and patient-centered values.
Given the relatively low success rates in trials using 20 or fewer days for the treatment of EM rashes, ILADS recommends that EM patients receive 4-6 weeks of doxycycline, amoxicillin or cefuroxime as initial therapy. A minimum of 21 days of azithromycin is also acceptable and has been shown to be especially effective against European strains of Borrelia.
Further treatment is guided by the clinical course and response to treatment. Ten to twenty percent of patients who have been treated for early Lyme disease remain ill following antibiotic therapy.
Although the guidelines do not discuss the treatment of non-EM early Lyme disease or disseminated disease, these topics are reviewed in the Fundamentals Course. For non-EM early disease, initial treatment is similar to that for EM. Patients with disseminated disease may need longer courses of antibiotics and antibiotic combinations.
Follow-up is a mainstay of care for patients with Lyme disease and other tick-borne infections. If symptoms have not resolved, if they return after treatment is stopped, or if new symptoms develop, it is important to consider persistent infection as a possible cause of the illness. The bacteria that cause Lyme disease have been shown in the lab as well as in animal and human studies to be able to survive despite antibiotic treatment.
Currently available testing cannot demonstrate B. burgdorferi eradication.
Consideration of co-infections is important in patients who remain symptomatic.
When necessary, antibiotic therapy should be extended, as the consequences of untreated persistent Lyme infection may outweigh the potential consequences of long-term antibiotic therapy.
Long-term antibiotic therapy is not without risks. Although there are ways to reduce those risks, providers should discuss with their patients the antibiotic options available, the risks and benefits of treatment, and the risks of untreated chronic or persistent Lyme infection.
Patients can be repeatedly infected with Lyme disease. Both relapse and re-infection must be considered when symptoms recur after treatment.
ILADS emphasizes patient-centered, person specific care, and the importance of careful assessment and re-assessment of the full clinical picture to guide treatment decisions, initially and if symptoms persist or return.