Lyme Disease

Justin LaPlante

Medical College of Virginia MSII

 

Lyme disease has afflicted children and adults in eastern Connecticut since at least 1972.  However, it wasn’t until 1976 that the disease was first described.  A cluster of fifty-one individuals near Lyme, Connecticut, presented with recurrent oligoarticular arthritis of the large joints.  The concomitant presentation of infections occurring in rural communities during late summer to early fall along with the presence of a characteristic rash termed erythema migrans lead physicians to suspect an arthropod borne disease.13,19  By 1978 epidemiological evidence correlated the prevalence of this disorder with Ixodes scapularis tick populations, which were suspected to be the vector for transmission.18,24  In 1982, Burgdorfer and coworkers at the Rocky Mountain Centers for Disease Control and Prevention identified a previously unknown bacterial spirochete termed Borrelia burgdorferi in the midguts of adult Ixodes scapularis ticks.5  After characterizing the pathogen, researchers discovered it in the blood, cerebrospinal fluid, and skin lesions of individuals with Lyme disease.3,20  Researchers were baffled as to how transmission of the spirochete occurred if the organism was only found in the midgut and hindgut of Ixodes.  Theories were proposed that either feces or regurgitation of the organism during feeding within the tick could transmit the spirochete. However, since both of these modes of transmission were inefficient, much research ensued.  Finally, in 1987, the spirochete was found in the saliva of the Ixodes tick and it became clear that as ticks took their blood meal from a host, they could transmit B. burgdorferi.16

 

Epidemiology

 

             Lyme disease is a systemic illness resulting from infection with the bacterial spirochete Borrelia burgdorferi transmitted by Ixodes ticks.  All Ixodes ticks associated with transmission of B. burgdorferi have three distinct lifecycle stages: larva, nymph, and adult.  During each of these stages the tick must obtain a blood meal at which time transmission may occur through the saliva of the infected tick.  Ixodes developmental stages generally occur in small mammals such as squirrels and mice.  The risk of transmission depends on variables that include tick densities, feeding habits, host animal infectivity, and duration of feeding.  Although white tailed deer do not act as a host for the development of Ixodes, they play an important indirect role in transmission of Lyme disease.  The white tailed deer is the preferred harbinger of the adult stage and may serve as a mechanism of spread for Ixodes as the deer wander throughout their large home range.

Ticks are unable to transmit Borrelia burgdorferi transovarially, and newly hatched ticks can only acquire the bacterium if they feed upon an infected host.  In addition, B. burgdorferi transmission between humans has not been documented. Therefore, in order to survive, the bacterium must either have a high prevalence within the host population, or survive long enough in a host, whether a rodent or human, for the newly emerging ticks (larva or nymph) to have an opportunity to feed on the infected individual.

B. burgdorferi employs a unique mechanism to evade the host immune system.  It alters one of the proteins on the surface of the organism, thereby altering its antigenic properties just enough to avoid the host immune system.  The bacterium is able to repeat this process many times, thereby staying within the body and serving as a potential reservoir for non-infected ticks to acquire the bacterium.  If treated with antibiotics, the organism can be completely cleared.

 

Prevalence

 

Lyme disease can be found throughout the United States and is now known to be the most common vector-borne infection in that country.  Most cases occur in the northeastern, mid-Atlantic, and north central states, and the largest number of cases are reported in persons aged 5-14 years and 50-59 years.  The Centers for Disease Control and Prevention (CDC) initiated systematic surveillance for Lyme disease in 1982 when 491 cases were reported from eleven states.17 Following development of a standardized case definition by the Council of State and Territorial Epidemiologists in 1990, Lyme disease became a nationally notifiable disease in 1991.  Since such designation the number of reported cases has increased from 9,896 in 1992 to 23,763 in 2002, the greatest number of infections reported from 47 states and the District of Columbia, an incidence of 8.2 cases per 100,000 persons.6

 

Clinical Manifestations

 

             Lyme disease develops in three separate and progressive stages, each of which has a variable time of onset, duration, and presentation. The symptoms present in any one individual vary widely.

 

Stage 1 (Localized Infection)

 

After an incubation period of 3 to 30 days, 70 to 80 percent of infected individuals present with a red macular (flat) or papular (raised) rash. The rash, termed erythema migrans (EM) typically begins at the site of the tick bite.  It forms a large annular lesion up to 12 inches in diameter over the course of several days. As the rash develops, the center of the lesion can turn blue before clearing, remain an even red color, become necrotic or vesicular, or have several rings of red within an outer ring.  The most characteristic form develops central clearing, and is known as a target or bulls eye lesion.  The lesion may be warm to the touch, but is generally not painful.  Up to 20 percent of infected individuals do not present with a rash.  Other common symptoms include a flu-like illness, chills, fever, muscle and joint aches, and swollen lymph nodes.

 

Stage 2 (Disseminated Infection)

 

After several days to weeks, the bacteria can spread hematogenously to other sites.  During the dissemination phase, subsequent multiple rashes, either similar or dissimilar to the initial rash, may present elsewhere on the body.  In addition, other symptoms such as fatigue, headaches, sore throat, stiff neck, and migratory muscle, bone or joint pain afflicting single or multiple areas of the body at the same time can occur.  More severe signs of disseminated disease include splenomegaly, hepatitis, iritis, meningitis, cerebellar ataxia, and facial palsy, although the latter three occur in only about 15 percent of untreated patients. Disseminated disease can also result in myocarditis, which typically produces heart block of varying severity.

 

Stage 3 (Chronic Manifestation)

 

About 60 percent of individuals receiving no treatment ultimately develop frank arthritis months after the initial infection.  The oligoarticular arthritis generally afflicts the larger joints such as knees and elbows and episodes last up to several months.  During early onset, small joints may also be affected.  A small subset of patients with a specific major histocompatibility complex gene can develop chronic arthritis of the large joints leading to destruction of bone and cartilage, even after the spirochetes are eradicated.  The most severe cases can also display neurological impairment resulting in altered memory, mood, or sleep functions.9

 

Chronic Lyme Disease (Post-Lyme Syndrome)

 

At present no uniform definition or description for the chronic manifestations of Lyme disease has been accepted, but interest in this topic has surged.  Chronic Lyme disease (CLD) only afflicts a small proportion of those initially treated for Lyme Disease and is more likely to affect those that were either untreated or delayed treatment initially.8  Most common symptoms include fatigue, arthralgia, myalgia, headaches, memory or concentration impairment, and neuropathic discomfort.25  Symptoms may be manifest several months to years after treatment or diagnosis.  Treatments for CLD are being evaluated and at present no consensus exists.  Two recent randomized double blind placebo controlled studies found that parenteral Ceftriaxone administration alone for twenty-eight days or administered for thirty days followed by sixty days of Doxycycline had no significant affect on the quality of life or cognitive function, and only minor benefits for fatigue associated with CLD.10,12 

 

Coinfection

 

Coinfection of individuals with Lyme disease and Babesiosis, Ehrlichiosis, or both is not uncommon.  Testing should be considered in any individual diagnosed with Lyme disease that presents with a persistent and irremediable flu-like illness following antiborrelial treatment.  Babesia microtia and B. divergens are protozoal organisms transmitted through Ixodes scapularis ticks, the same vector that harbors Borrelia burgdorferi.  Babesia is an intraerythocytic parasite that forms a ring structure similar to that of Plasmodium falciparum, although no hematoidin pigment is formed.  This infection can be diagnosed with a routine peripheral blood smear, and may be confirmed by PCR or serological testing.1

The most common coinfecting ehrlichiosis is human granulocytic ehrlichiosis (HGE) caused by Anaplasma phagocytophilum.  Anaplasma is also transmitted by the Ixodes scapularis tick and is more prominent in the Northeastern and Midwestern United States.  Anaplasma is an obligate intracellular bacterium that typically is harbored by granulocytes.  Intracellular microcolonies, or morulae, in a peripheral blood smear are diagnostic, but the diagnosis may be confirmed by culture, PCR, or serology.1 

Historically, treatment for babesiosis has been clindamycin and quinine for 7 to 10 days, however this regimen often produced unwanted side effects such as gastrointestinal upset, tinnitus, and vertigo.  A recent prospective randomized trial comparing a seven-day cycle of clindamycin and quinine with atovaquone and azithromycin found that the later combination was just as effective.  Therefore, a 7-day course of atovaquone and azithromycin should be considered for individuals with babesiosis.11  Doxycycline is the drug of choice for treatment of HGE, although tetracycline has proven successful as well.  Doxycycline is a first line antibiotic for the treatment of Lyme disease as well.15,22

 

Diagnosis

 

Diagnosis can be based on a patient’s symptoms, the clinical findings, and residence in an area where Lyme disease is endemic.  If more testing is necessary, the CDC recommends a two step approach.  Step 1 entails evaluating the patient’s blood for the target antibody or antigen by enzyme linked immunosorbant assay (ELISA).  Following a positive or indeterminate result, Western blot can be used to confirm the initial results by identifying specific antibody to the infective spirochete.  If the tick is retained, some state or local health departments can identify the tick and test for the presence of Borrelia burgdorferi. 4,6

 

Treatment

 

            Common orally administered treatments for early stage disease include a 2 to 4 week course of amoxicillin for children less than 12 years old and doxycycline for older individuals.  Adult treatments include either doxycycline, amoxicillin, cefuroxime or erythromycin if allergic to penicillin.  For late or chronic disease that manifests with neurological or cardiovascular symptoms intravenous ceftriaxone or penicillin is typically administered.  Intravenous treatment can be replaced with oral administration of antibiotics once cardiovascular signs are no longer evident.  Late stage disease may require several rounds of treatment to completely eliminate the spirochete.4,6     

 

Prevention

 

Lyme Disease can be prevented by is avoiding places where ticks may be present, such as woodlands, shrubbery, and open fields. Contact with ticks can be reduced by wearing long sleeve shirts and long pants, and tucking pant bottoms into socks. Light colored clothing allows ticks to be visualized more easily. 

Applying an insect repellant containing N,N-diethyl-3-methylbenzamide (DEET), minimizes exposure.  Although it is almost 100 percent effective for mosquitoes, DEET is only about 85 percent effective against ticks. It is also effective for chiggers and fleas, and to a limited extent for biting flies and gnats.23  In a recent comparison study of mosquito repellents, products containing DEET provided much longer complete protection times.  Polymerized and microencapsulated DEET preparations persist longer and decrease absorption through the skin.7 Sunscreens containing DEET should be avoided because the need for frequent application for proper sun protection unnecessarily increases DEET exposure. 

Aversion to DEET is common. Although adverse affects such as bullous eruptions, urticaria, ataxia, respiratory distress, seizures, and death have been reported, they have only followed inappropriate application. CDC currently states that DEET does not pose a health hazard if label directions are followed.  Preparations containing 30 percent DEET or less are considered safe for infants over 2 months of age, and in children, adults, and pregnant women when applied as directed by the manufacturer.21,23

            Permethrin is a highly effective insecticide, not a repellant, that should be applied to clothing, not to skin. Most available preparations are sprays. Clothing that has been heavily sprayed usually retains its insecticide properties through three washings. The combination of DEET on skin and Permethrin on clothing is currently the best available barrier to mosquitoes and ticks.

Any dog that spends time outdoors, especially in tall grass, shrubs, or woodlands should be considered a potential source for ticks.  Just as humans are afflicted with the symptoms of Lyme disease, so too are dogs, and dogs in endemic areas should vaccinated for Lyme disease.

            Daily examination of the skin for ticks is an essential element in Lyme disease prevention. However, Ixodes ticks, particularly in the nymph stage, are so small they may not be recognized. If a tick has attached to the skin, prompt removal minimizes the probability of infection as the tick must be attached for 24 hours or longer in order to transmit the bacterium.  Ticks should be removed with fine-tipped tweezers by grabbing it at the skin surface and pulling with steady, even pressure.  To avoid breaking the mouthparts of the tick off in the skin, the tweezers should not be twisted. If mouthparts do become lodged within the skin only limited attempts to remove them should be made. Once the head has been removed from the body, the tick can no longer transmit the bacterium.  Following removal, the bite site should be treated with a disinfectant.

 

References

 

1)      Aguero-Rosenfeld ME: Laboratory Aspects of Tick-Borne Diseases: Lyme, Human Granulocytic Ehrlichiosis and Babesiosis. Mt Sinai J Med. 2003; 70(3):197-206.

 

2)      Belongia EA: Epidemiology and Impact of Coinfections Acquired from Ixodes Ticks. Vector Borne Zoonotic Dis. 2002; 2(4): 265-273

 

3)          Benach JL. et al.: Spirochetes Isolated From the Blood of Two Patients with Lyme Disease.  NEJM 1983; 308(13):740-742.       

 

4)          Bratton RL, Corey GR: Tick-Borne Disease.  Am Fam Physician. 2005 Jun 15; 71(12):2323-2330.                

 

5)          Burgdorfer W., Barbour AG:  et al.: Lyme disease-a tick-borne spirochetosis?  Science. 1982 Jun 18; 216(4552):1317-1319.           

 

6)      Centers for Disease Control and Prevention.  Lyme Disease- United States, 2001-2002.  MMWR Morb Mortal Wkly Rep 2004; 53(17): 365-369.

 

7)      Fradin MS, Day JF: Comparative Efficacy of Insect Repellents against Mosquito Bites. NEJM 2002; 347(1):13-18.

 

8)      Kalish RA, Kaplan RF, Taylor E, et al.: Evaluation of study patients with Lyme disease, 10–20-year follow-up. JID 2001, 183:453–460.

 

9)      Kasper, et al:  Harrison’s Principles of Internal Medicine, 16th Edition, 2005; 995-999.

 

10)  Klempner M, Hu L, Evans J, et al.: Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. NEJM 2001; 345: 85–92.

 

11)  Krause PJ, Lepore T, Sikand VJ, et al. Atovaquone and azithromycin for the treatment of human babesiosis. NEJM 2000; 343: 1454-1458.

 

12)  Krupp LB, et al.: Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003 Jun 24;60(12):1923-1930.

 

13)  Mast WE, Burrows WM: Erythema Chronicum Migrans and "Lyme Arthritis".
JAMA. 1976 Nov 22; 236(21):2392.

 

14)  McGready R, et al.: Safety of the insect repellent N,N-diethyl-m-toluamide (DEET) in pregnancy. Am J Trop Med Hyg 2001; 65:285-289.

 

15)  Moss WJ, Dumler JS: Simultaneous infection with Borrelia burgdorferi and human granulocytic ehrlichiosis. Pediatr Infect Dis J 2003; 22(1):91-92.

 

16)  Ribeiro JMC, Mather TN, Piesman J, Spielman A:  Dissemination and salivary delivery of Lyme disease spirochetes in vector ticks (Acari: Ixodidae). J Med Entomol 1987; 24:201-205.

 

17)  Schmid GP, Horsley R, Steere AC, et al.: Surveillance of Lyme disease in the United States, 1982. J Infect Dis 1985; 151:1144-1149.

 

18)  Steere AC, Broderick TF, Malawista SE: Erythema Chronicum Migrans and Lyme Arthritis: Epidemiological Evidence for a Tick Vector. Am. J. Epidemiol. 1978; 108:312-321.      

 

19)  Steere AC, et al.:  Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities.  Arthritis Rheum. 1977 Jan-Feb;20(1):7-17.      

 

20)  Steere AC, et al.: The Spirochetal Etiology of Lyme Disease. NEJM 1983; 308(13):740-742.

 

21)  Sudakin DL, Trevathan WR: DEET: a review and update of safety and risk in the general population. J Toxicol Clin Toxicol. 2003; 41(6):831-839.

 

22)  Thompson C, Spielman A, Krause PJ: Coinfecting Deer-Associated Zoonoses: Lyme Disease, Babesiosis, and Ehrlicbiosis. Clin Infect Dis. 2001; 33(5):676-685.

 

23)  United States Environmental Protection Agency. OPPTS. Reregistration Eligibility Decision (RED): DEET. 1998, EPA738-R-98-010: 1-118. http://www.epa. gov/oppsrrd1/REDs/0002red.pdf.

 

24)  Wallis RC, Brown SE, Kloter KO, Main AJ Jr.: Erythema Migrans and Lyme Arthritis: Field Study of Ticks.  Am. J. Epidemiol. 1978; 108:322-327.          

 

25)  Weinstein A, Britchkov M: Lyme arthritis and post-Lyme disease syndrome. Curr Opin Rheumatol. 2002 Jul;14(4):466-474.

 

 

The contents of this article represent the opinions and assertions of the author and do not purport to reflect the position of the Medical College of Virginia nor Virginia Commonwealth University.