Tick-Borne Diseases

According to the Centers for Disease Control (CDC), the number of cases of tick-borne diseases more than doubled in the past decade. In this section, we review the main causes of tick-borne diseases in the United States:

• Lyme Disease

• Human Granulocytic Anaplasmosis

• Human Monocytic Ehrlichiosis

• Babesiosis

Lyme Disease

Lyme disease was first described in 1977 in what was initially thought to be an outbreak of juvenile rheumatoid arthritis in children living in Lyme, Connecticut.

In the United States, Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted by the Ixodes tick (black-legged (deer) tick). While Lyme disease has been reported in all U.S. states, it is predominately found in the Northeast and Midwest. However, typical geographic and seasonal patterns are changing due to climate change.

(Source: Lyme Disease. Centers for Disease Control 2011.)

Clinical Manifestations

• Localized erythema migrans (EM) is the most common clinical manifestation of Lyme disease and is seen in 80% of patients. EM occurs 1 to 2 weeks after the tick bite, and in 75% of cases, the rash is uniformly erythematous or has raised central erythema. The classic bull’s-eye rash is only seen in 30% of cases and may be associated with multiple EM lesions (see photographs below).

• Early disseminated disease can present within weeks to a few months after the tick bite. Symptoms include neurologic complications (facial palsy, meningitis, and radiculopathy) and cardiac complications (mainly heart block).

• Arthritis is a late manifestation that can occur more than 6 months after a bite from an infected tick.

Diagnosis

Diagnosis of Lyme disease should be considered in someone from an endemic area with outdoor exposures who presents with a rash consistent with EM. Serologic testing in patients with EM is of limited utility given its poor sensitivity (25%-40%).

• Individuals with one or more atypical rashes for EM should undergo antibody testing on an acute phase serum sample, followed by a convalescent phase serum sample in 2 to 3 weeks if the initial result is negative.

• Two-step serologic testing is recommended for disseminated forms of Lyme disease. The traditional method involves an enzyme immunoassay (EIA) to measure the concentration of antibodies to B. burgdorferi, and if positive or equivocal, a confirmatory Western blot. Newer methods that may be less labor-intensive include two sequential EIAs; however, they may not be available in all settings. The two-step approach has a sensitivity of 80%-100% in early disseminated neurologic and cardiac disease and 100% in later manifestations.

• Few nonserologic testing methods (e.g., nucleic acid amplification tests) have been studied. These tests are primarily thought to be beneficial when two-tiered serologic testing is positive (e.g., consideration of polymerase chain reaction [PCR] testing of synovial fluid in seropositive patients for whom diagnosis of Lyme arthritis is being considered but treatment decisions require more-definitive information).

Panel A shows a single erythema migrans lesion, Panel B shows vesicular erythema migrans, and Panel C shows multiple erythema migrans lesions. (Source: Lyme Disease. N Engl J Med 2014.)

Treatment

Doxycycline, amoxicillin, or cefuroxime axetil are used for the treatment of Lyme disease. Intravenous ceftriaxone is used to treat Lyme meningitis. More treatment details are provided in the table below.

Note that both amoxicillin and cefuroxime are not used for the treatment of anaplasmosis and ehrlichiosis, which can be transmitted by the Ixodes tick. In 15% of patients, a self-limiting Jarisch-Herxheimer reaction (fevers, arthralgias, and myalgias) can occur within the first 24 hours of treatment of anaplasmosis or ehrlichiosis with amoxicillin or cefuroxime.

(Source: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis 2021.)

Human Granulocytic Anaplasmosis

Anaplasmosis is caused by the obligate intracellular bacterium Anaplasma phagocytophilum. The vector is the same as for Lyme disease (the Ixodes tick). Cases of anaplasmosis are found in similar locations as cases of Lyme disease.

Clinical Manifestations

Symptoms of anaplasmosis occur 5 to 14 days after a bite from an infected tick.

• Patients have nonspecific symptoms including fever, myalgias, and arthralgias.

• Rash is seen in <10% of patients.

• Unlike patients with Lyme disease, patients with anaplasmosis often present with leukopenia, thrombocytopenia, and mild transaminitis.

Diagnosis

Diagnosis can be made by identification of morulae in a buffy coat smear, polymerase chain-reaction (PCR) test of blood, or serologies drawn 2 to 3 weeks after infectious symptoms.

A peripheral-blood smear (Wright-Giemsa stain) shows intracytoplasmic inclusions in neutrophils (arrow). Classic Anaplasma phagocytophilum morulae are stippled and resemble mulberries, but many other appearances are possible. As shown here, characteristic features include basophilic staining of the bacteria that is distinct in color from the nuclear material, as well as localization of the bacteria in a vacuole. (Source: Case 16-2018: A 45-Year-Old Man with Fever, Thrombocytopenia, and Elevated Aminotransferase Levels. N Engl J Med 2018.)

Treatment

Most cases of anaplasmosis are self-limiting, but severe illness can occur. The reported case fatality rate is <1%. Treatment is with doxycycline for 10 days. Reponses are typically prompt (within 48 hours). Lack of improvement during this time frame should raise concern for another coinfected tick-borne illness or alternative diagnosis.

Human Monocytic Ehrlichiosis

Ehrlichiosis is caused by infection of monocytes and tissue macrophages with the intracellular bacteria Ehrlichia chaffeensis, E. ewingii, or E. muris eauclairensis. Most cases are caused by E. chaffeensis, which is carried by the Lone Star tick (Amblyomma americanum). This tick is found predominantly in the Southeastern states and extends into the Midwest and New England states.

(Source: Tickborne Diseases of the United States. Centers for Disease Control 2022.)

Symptoms

Symptoms of E. chaffeensis are similar to those of anaplasmosis (nonspecific symptoms including fever, myalgias, and arthralgias), with the addition of gastrointestinal symptoms and a higher rate of rash (33%). The mortality rate associated with ehrlichiosis is also higher, with a case fatality rate of 3% in patients presenting with severe disease.

Treatment

Treatment is with doxycycline, and a prompt response is expected.

Babesiosis

Babesiosis is caused by intraerythrocytic protozoa. It was first discovered by microbiologist Victor Babes in 1888 as a cause of hemolytic disease in cattle. As with Lyme disease and anaplasmosis, the Ixodes tick is the vector of transmission. The predominating species is Babesia microti in the United States and Babesia divergens in Europe. The natural reservoir is the white-footed mouse. During a blood feed of a tick, sporozoites within the salivary gland enter human blood. The sporozoites attach to erythrocytes, replicate, and eventually rupture the erythrocytes to infect other cells.

Clinical Manifestations

The presentation of babesiosis can range from asymptomatic disease to death. The time to onset after a bite from an infected Ixodes tick is 1 to 4 weeks. Symptoms include fevers/chills, headache, and arthralgias. Lab findings show mild-to-moderate hemolytic anemia, supported by elevated lactate dehydrogenase and low haptoglobin levels. Thrombocytopenia is common. Severe babesiosis can develop in immunosuppressed patients, particularly those who are asplenic, transplant recipients, or undergoing treatment with rituximab.

Diagnosis

The definitive diagnosis of babesiosis is made with a Giemsa- or Wright-stained blood smear that shows trophozoites in the shape of rings within erythrocytes (see figure below). Although rare, tetrads of merozoites resembling a Maltese cross can be seen. If no forms are visible, smears can be repeated every 12 to 24 hours. If blood smears remain negative despite high pretest probability, PCR blood tests can be ordered.

(Source: Babesiosis. N Engl J Med 2008.)

The following algorithm can be used to guide diagnostic laboratory testing for babesiosis:

(Source: Human Babesiosis. N Engl J Med 2012.)

Treatment

The preferred treatment choice is a combination of atovaquone and azithromycin for 7 to 10 days for immunocompetent hosts; treatment duration is often extended for immunocompromised patients. Removal of parasites by red-cell-exchange transfusion should be considered in patients with high levels of parasitemia (>10%); significant anemia; or renal, hepatic, or pulmonary compromise. The duration of antiparasitic therapy is 6 weeks, with potentially longer therapy required if the parasitemia has not resolved.

For immunocompetent patients, the recommendation is to monitor Babesia parasitemia during treatment of acute illness with peripheral-blood smears, but experts recommend against testing for parasitemia once symptoms have resolved. For immunocompromised patients, the recommendation is to monitor parasitemia using blood smears, even after patients are asymptomatic, until the blood smears are negative.

(Source: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA): 2020 Guideline on Diagnosis and Management of Babesiosis. Clin Infect Dis 2021.)