Tickborne Illnesses

EXECUTIVE SUMMARY

• Although Lyme disease is the most common tickborne infectious disease, all tickborne diseases are increasing, and the geographic area of infected ticks is expanding.
• Lyme disease is transmitted by tick bites, but the tick must be attached for about 36 hours in general to transmit the disease. The rash erythema migrans is the first symptom.
• Doxycycline is the first-line treatment for many tickborne diseases for both adults and children. Staining of the teeth is not seen in children.
• In general, treatment of acute tickborne disease should be started when the disease is suspected, and should not be withheld pending confirmation by laboratory testing.

Introduction

Tickborne illnesses are a large and growing group of diseases that all providers will see in clinical practice regardless of geographic location. Blood-feeding ticks can transmit a wide variety of pathogens to people, which can result in significant infection and morbidity. During the past 10 years, the incidence of these diseases has increased rapidly, and the geographical regions where they occur has expanded. Recognizing symptoms that often are nonspecific and initiating appropriate treatment are critical to patient outcomes.

This article will cover the identification of the vectors of transmission, presentation for the diseases that are transmitted, and the appropriate treatment. Important diseases transmitted by ticks include Lyme disease, anaplasmosis, ehrlichiosis, and Rocky Mountain spotted fever (RMSF). Less prevalent tickborne diseases are babesiosis, tularemia, and Powassan virus.

Epidemiology

The most recent data collected by the Centers for Disease Control and Prevention (CDC) show that the reported yearly number of tickborne diseases doubled from 2004 to 2016.¹ Lyme disease accounts for 82% of the reported tickborne diseases. The incidences of anaplasmosis, ehrlichiosis, and babesiosis also have been on the rise. In 2016, 22 cases of Powassan virus were reported, a significant increase from previous years.¹

There are many different types of ticks, but only a few carry the pathogens that infect humans. Ixodes scapularis is by far the largest culprit of disease transmission. (See Figure 1.) This tick is widely distributed across the eastern United States and transmits the pathogens that cause Lyme disease, anaplasmosis, ehrlichiosis, babesiosis, and Powassan virus disease. It is identifiable by its black legs and dark, round scutum (central body) and is commonly known as the deer tick. Amblyomma americanum (the Lone Star tick) is widely distributed in the eastern United States, but is more common in the South. (See Figure 2.) It is identified by a light center dot located on its body. This tick can transmit ehrlichiosis, tularemia, and southern tick associated rash illness (STARI). Dermacentor variabilis (American dog tick) is found to the east of the Rocky Mountains and in areas along the Pacific coast. (See Figure 3.) It transmits tularemia and RMSF. (See Table 1.)

The life cycle of a tick occurs over a two-year period. The I. scapularis tick begins as a six-legged larva and hatches in the early summer.² In the late summer, the tick has its first blood meal, usually from mice or other small mammals. This is when the tick acquires the infection. Then the tick will molt and reemerge the next spring as a nymph. The infected nymph can spread the organism to a second host to carry on the disease cycle. The nymphs are small and hard to detect, making this stage the most likely time when infection is transmitted to humans. Once the tick feeds, it drops off the host and molts to become an adult in the autumn. Adult ticks seek a blood meal that autumn and into the next early spring, then will lay eggs and complete the cycle.

Transmission of the disease occurs during the tick bite. The disease invades the salivary glands of the tick and is transmitted via saliva, which is injected alternately with blood uptake during the tick bite.³

In addition to the transfer of bacterial and viral illness, tick bites have been found to result in subsequent meat allergy. Multiple tick bites may result in the development of an allergy to alpha-gal, which is a carbohydrate found in meats and also found in the medication cetuximab. The characteristics of the IgE-mediated allergic reaction are different from typical allergic reactions.⁴ Symptoms do not start until two hours after ingestion of mammalian meat, with many reactions delayed three to five hours after ingestion. Many patients develop nausea and diarrhea as the first symptoms, and the most common symptom is itching. Typical anaphylaxis symptoms, including hives, angioedema, and respiratory distress, occur. In the United States, this allergy has been found predominately in the Southeast and is associated with tick bites by the Lone Star tick (A. americanum). Cases have been reported in Europe, Australia, and Asia as well and are attributed to several other tick species. Unlike the reaction after meat exposure, the allergic reaction after first exposure to intravenous (IV) cetuximab is immediate in onset.

Lyme Disease

The etiology of Lyme disease was unknown until the early 1980s; Lyme disease rapidly has become the most common tickborne illness in the United States and Europe.⁵ The disease was discovered clinically in 1977 in Connecticut and was found to be caused by a spirochete in the early 1980s. Lyme disease is associated with Borrelia burgdorferi, with a less common genospecies Borrelia mayonii found in the midwestern United States. In Europe and Asia, Borrelia afzelii, Borrelia garinii, and B. burgdorferi cause Lyme disease. Transmission requires 36 hours of tick adherence, and the incubation period is three to 20 days.⁶ The rapid increase in the number of cases during the past 10 years is thought to be driven partly by environmental factors. Changes in land use practices and a marked increase in the deer population have increased the exposure to ticks in many regions.⁶ Most cases of Lyme disease occur in New England, the mid-Atlantic states, and the northern Midwestern states.⁷ The incidence of Lyme disease is highest in children 5 to 14 years of age and middle-aged adults.⁷ Ixodid ticks that carry Lyme disease also are vectors for other infectious agents, such as anaplasmosis, ehrlichiosis, Powassan disease, and babesiosis, that may result in a coinfection with Lyme disease.

Clinical Presentation

Early, localized infection usually begins with a rash. (See Figures 4 and 5.) Erythema migrans is the most common and characteristic sign, seen in 80% of cases of Lyme disease. Immediately after a tick bite, there may be a local reaction that must be differentiated from erythema migrans. The local reaction results in swelling, warmth, and erythema rapidly after the bite. Erythema migrans will develop three to 20 days after the bite. It starts as an erythematous papule or macule at the site of the tick bite and expands to a large erythematous patch up to 20 cm in diameter. The lesion may have central vesicles or necrotic areas. It may be pruritic or asymptomatic. The classic teaching is that it will have a bull’s eye appearance, but a review of the literature found central clearing occurs only 19% of the time in the United States.⁸ Often, it will be uniformly erythematous or have an enhanced central erythema. The most common associated symptoms were fever, headache, neck stiffness, arthralgia, myalgia, or fatigue.^9,10

STARI often is mistaken for Lyme disease and is associated with a bite from the Lone Star tick. It presents with a similar bull’s-eye rash, fever, fatigue, headache, and myalgia. STARI is diagnosed based on the symptoms and geographical location. Most patients will receive doxycycline because of the similarity of STARI to Lyme disease, but it is unknown if this treatment hastens recovery.¹¹

Early disseminated Lyme disease infection can present with multiple smaller erythema migrans lesions, Lyme carditis, or neurologic findings such as cranial nerve palsy or lymphocytic meningitis. Lyme carditis presents as an atrioventricular block or, less commonly, as myocarditis. The heart block is of varying degrees and may alternate from hour to hour. It is transient and rarely requires a permanent pacemaker. Heart block occurs in 1-5% of cases of Lyme disease and begins three to six weeks after illness.¹²

The most common cranial nerve affected by palsy is the facial nerve. Lyme disease is one of a few causes of bilateral facial nerve palsy.

Late disease includes arthritis, cutaneous findings, encephalopathy, and polyneuropathy. These symptoms occur several months to years after infection. Lyme arthritis presents as intermittent episodes of joint pain and swelling that mostly affect one or a few joints at a time.⁹ Recurrent attacks decrease every year; however, a small number of patients have chronic synovitis. Acrodermatitis chronica atrophicans is rare in the United States but occurs in up to 10% of cases in Europe. It manifests as a blue-red erythema and swelling of the extensor surfaces of the hands and feet. Nodules may develop later, particularly on the knees and elbows.

Diagnosis and Treatment

The diagnosis is made clinically in patients with an erythema migrans rash and who have been in an endemic area. Serologic testing does not help in these patients because of the poor sensitivity. However, serologic testing can be helpful as an adjunct to clinical diagnosis.¹³ The CDC recommends a two-tiered method of serologic testing. First, an enzyme immunoassay is used to screen for antibodies. If that is negative, testing is performed. If it is positive or equivocal, then a Western blot is completed for immunoglobulin M (IgM) and immunoglobulin G (IgG); if it has been more than four weeks since symptom onset, Western blot is completed only for IgG. Sensitivity increases as the duration of symptoms lengthens. Only one-third of patients with an erythema migrans rash will test positive, but this increases greatly in patients with early disseminated disease and late disease.¹⁴ If test results are negative but suspicion remains high, repeat testing should be conducted in two to four weeks.

Treatment for early disease is with doxycycline, amoxicillin, or cefuroxime, according to the Infectious Diseases Society of America (IDSA) guidelines.¹⁵ Doxycycline has the additional advantage of covering anaplasmosis as well if there is coinfection. The second-line option is macrolide antibiotics. Patients with a tick attached for 36 hours or more can receive a single prophylactic dose of doxycycline 4 mg/kg up to 200 mg for children and 200 mg for adults. See the section on prophylaxis at the end of this monograph for more information. Those with symptoms should be treated for 10-21 days, although a recent study found the same effectiveness with 15-day and 10-day courses of doxycylcine.¹⁶ The CDC guidelines recommend either amoxicillin or doxycycline for treatment of early Lyme disease in pediatric patients. A 2015 study in the Journal of Pediatrics found no tetracycline-like staining in children younger than 8 years of age who received doxycycline for a typical treatment course.¹⁷ (See Table 2.) Later manifestations of Lyme disease require IV medication treatment, typically with ceftriaxone.

Anaplasmosis

Human granulocytotropic anaplasmosis (HGA) is caused by the bacterium Anaplasma phagocytophilum. Ehrlichia phagocytophia and Ehrlichia equi were found to be the same organism and were renamed A. phagocytophilum. The disease is spread by a tick bite from the I. scapularis tick in the Northeast and Midwest (the same tick that transmits Lyme disease, babesiosis, and Powassan virus), or the Ixodes pacificus tick on the West Coast. A. phagocytophilum can be transmitted through blood transfusion. Since 2007, at least eight cases of HGA acquired from transfusions of leuko-reduced blood products have been reported.¹⁸ The number of cases reported to the CDC has steadily increased from 348 cases in 2000, to 4,151 cases in 2016. The cases occur predominantly during the summer months and peak in June and July. It is most frequently reported in the upper Midwestern states and Northeastern United States.

Initial symptoms start one to two weeks after a tick bite and include high fever, headache, myalgias, chills, nausea, and abdominal pain. Rash is a very infrequent finding in anaplasmosis, and the occurrence of a rash should lead toward a different diagnosis such as Lyme disease or RMSF. The diagnosis of anaplasmosis should be suspected in patients who are in an endemic area and have a viral-like illness. Laboratory findings may show leukopenia, thrombocytopenia, or elevated liver function tests. During the acute phase of HGA, diagnosis is made by polymerase chain reaction (PCR) testing.¹⁹ It is most sensitive in the initial seven days of infection. Do not delay treatment while awaiting test results; the initial, presumptive diagnosis is made clinically. A negative PCR does not exclude the diagnosis of HGA. During infection, antibodies are detectable in seven to 10 days and remain elevated for months after illness resolution. At that time, serological immunofluorescence assay (IFA) tests and enzyme-linked immunosorbent assay (ELISA) tests are useful in diagnosis. Another option to help make the diagnosis is a peripheral blood smear. In 20% of patients, microcolonies of Anaplasma known as morulae are found in the cytoplasm of white blood cells on blood smear.²⁰

Treatment of HGA in adults is doxycycline 100 mg twice a day orally or IV for 10-14 days.²¹ This will provide treatment for possible coinfection with Lyme disease as well. In pediatric patients, the treatment is doxcycyline 2.2 mg/kg per dose twice a day orally or IV for 10-14 days. (See Table 3.) As noted, evidence has not shown any staining of teeth in children younger than 8 years of age who receive a course of doxycycline. When patients are treated with doxycycline, fever generally subsides within 24-48 hours.

Ehrlichiosis

Human monocytic ehrlichiosis (HME) is reported most frequently in the Southeastern and south-central United States. Missouri, Arkansas, New York, and Virginia account for 50% of all reported cases. The first case of ehrlichiosis was described in the late 1980s, and it became a reportable disease in 1999. The number of cases reported to the CDC has increased from 200 in the year 2000 to more than 1,377 cases in 2016. As is typical for tickborne illnesses, the months of greatest transmission are during the summer. It is spread by a tick bite from the Lone Star tick (A. americanum). The white-tailed deer is the host for the tick in all of its stages. The main bacteria responsible for infection is Ehrlichia chaffeensis, with some cases by Ehrlichia ewingii. In addition, since 2009, cases of ehrlichiois caused by Ehrlichia muris eauclarensis have been identified in patients from the upper Midwest (Wisconsin and Minnesota).²³ This broadens the locations where HME is seen. These bacteria are obligately intracellular gram-negative bacteria that replicate and form microcolonies called morulae, similar to Anaplasma bacteria.²⁴ HME is a more severe disease than anaplasmosis, with 42% of cases requiring hospitalization, and it has a mortality rate of 3%.²⁵ The initial presentation is similar to that of anaplasmosis.

Symptoms typically begin a week after a tick bite. Fever is the most common symptom, and most patients have headaches, myalgias, and arthralgias.²⁵ A skin rash is not a common symptom in adults, and is reported in fewer than 30% of cases. Rash is more common in children, occurring in 60% of cases. Laboratory abnormalities may include leukopenia, thrombocytopenia, or elevated liver enzymes. Although not always seen, these laboratory abnormalities are quite common. Thrombocytopenia is a hallmark of HME and is found in 70-90% of cases. Meningitis is a severe complication of HME. It is not common, but is potentially fatal.²⁶

The diagnosis of HME is based primarily on clinical suspicion, as culturing ehrlichiosis is extremely difficult. The prognosis worsens with a delay of treatment, so treatment should begin promptly based on clinical suspicion and initial laboratory abnormalities. PCR assay is the most useful test to determine if a patient has ehrlichiosis. This test is most sensitive during the first week and then quickly loses sensitivity following antibiotic administration. Serologic testing using indirect immunofluorescence assay is performed on serial samples. The first sample is taken as early as possible, and the second sample is taken two to four weeks later. A fourfold increase in IgG antibody levels is diagnostic. It is important to note that titers do not become detectable until two to three weeks after the infection began. A blood smear looking for morulae, which are present in 20% of cases, also can be used to confirm diagnosis.

Treatment for HME is the same as for anaplasmosis. (See Table 3.) Doxycycline is given in both adults and children for 10 days. If treatment begins within the first five days of the disease, the fever typically subsides within one to three days. Lack of response to treatment suggests the patient’s condition is not due to ehrlichiosis.

Rocky Mountain Spotted Fever

RSMF is one of the oldest and most severe tickborne illnesses. It was first described in the early 1900s, when it had a fatality rate of 70%.²⁷ Rickettsia rickettsii was found to be the bacteria that causes the disease. It is a gram-negative, obligate intracellular bacteria that causes an infection resulting in small-vessel vasculitis. RMSF has been a reportable condition since the 1920s. Since 2010, cases of RMSF are reported under a general category of spotted fever rickettsiosis (SFR). This includes multiple Rickettsia species that cannot be differentiated by commonly used serological tests. The incidence of SFR increased during the last decade from two cases per million persons in 2000, to 11 cases per million in 2014. During this same period, the fatality rate decreased to less than 0.5%. Inclusion of the less severe rickettsiosis in the numbers gathered over that time likely led to the lower fatality rate.

Cases of RMSF have been reported throughout the United States, although five states (North Carolina, Oklahoma, Arkansas, Tennessee, and Missouri) account for more than 60% of the cases. D. variabilis (the American dog tick) is the main vector for RMSF in the eastern and south central United States. It is associated most frequently with the transmission of RMSF. Dermacentor andersoni (the Rocky Mountain wood tick) is the main vector for RMSF in the mountain states west of the Mississippi River.²⁷

More recently, the brown dog tick (Rhipicephalus sanguineus) has been found as a vector along the United States-Mexico border. (See Figure 6.) It has been a known vector in Mexico since the 1940s, but it was not discovered as a vector in the United States until 2003, when it was confirmed in Arizona.²⁸ The outbreak in Arizona with this novel new vector had a fatality rate of 12%. Domestic dogs are the preferred host for the brown dog tick, and humans are incidental hosts. The climate allows R. sanguineus to remain active year-round in Arizona, and the regions most affected had a lot of free-roaming dogs.²⁹ RMSF occurs in several northern and central Mexican states because of similar weather conditions and dogs as carriers of R. sanguineus. Beginning in the mid-2000s, there has been a surge of RMSF cases in these areas. There were 1,394 cases from 2003-2016, including 247 deaths, in the Sonara region (northern Mexico). This was an aggregate case fatality rate of 18%.³⁰ Fifty-eight percent of all cases and 60% of the deaths were in patients younger than 18 years of age. The regions associated with outbreaks were economically depressed and had a high dog population carrying many ticks.

Early signs and symptoms of RMSF are not particularly specific. The disease can progress rapidly and become very severe, so quick identification is key. Symptoms begin two to 14 days (average seven days) after the tick bite. Unfortunately, half of the time there is no known history of a tick bite.³¹ Common signs and symptoms include fever, headache, rash, nausea and vomiting, and myalgia. The rash is a common sign in people with RMSF, but it usually develops three to four days after the fever begins, with less than one-half of patients having the rash before three days.³² (See Table 4 and Figure 7.) The result is that many patients do not have the rash at first visit with a healthcare provider. The appearance of the rash varies over the course of the disease. It can be macular and blanching or petechial. The rash usually begins on the ankles and wrists and spreads centrally. A rash on the palms and soles of the feet usually occurs later in the disease process. Interestingly, 10% of people never develop a rash. This is a major concern in recognition of the disease.

Laboratory tests are marginally useful in helping to identify RMSF. Typically, patients have a normal white blood cell count at presentation. As the illness progresses, thrombocytopenia develops as well as elevated liver function test results. Serological testing is necessary to confirm the disease, but, unfortunately, antibodies are not detectable until seven to 10 days after disease onset. The indirect fluorescent antibody test is highly sensitive and is recommended by the CDC. Aside from the time needed to receive results, the main weakness is that the test cannot distinguish between R. rickettsii and other spotted fever group Rickettsia.

Treatment should be started within five days of symptom onset. A delay in treatment results in an increased risk of mortality.³² A case review of the first 205 cases in Arizona from 2002 to 2015 found that doxycycline was started significantly later in fatal cases (seven days) than nonfatal cases (three days), despite both groups presenting for care early (two days).²⁹ The decision to treat is based on a careful history and examination of the patient in an endemic area (such as Arizona or North Carolina), and there should be a low threshold to treat,²⁹ rather than relying on the characteristic rash, which may not occur until later in the disease process. Confirmation is made later with serological testing. The treatment of choice for most patients, including children, is doxycycline. In addition to treating RMSF, doxycycline also treats other tickborne illnesses that may coinfect. The dose for adults is 100 mg twice daily for a minimum of one week. If the patient is not critically ill, doxycycline can be given orally. If the patient is critically ill or has vomiting, IV doxycycline is recommended.^33,34 (See Table 5.) As noted in prior sections, doxycycline is not contraindicated in children younger than 8 years of age, and a single course of antibiotics does not cause the dental discoloration historically associated with the medication. A study in the Journal of Pediatrics found that 80% of providers correctly identified doxycycline as the appropriate treatment for RMSF in patients older than 8 years of age, but only 35% correctly chose doxycycline for patients younger than 8 years of age.³⁵

Babesiosis

Babesiosis is a parasite that invades red blood cells. It is transmitted via ticks, via blood transfusion, or transplacentally. There are many Babesia species, but only a few cause disease in humans. The most common organism that causes disease in humans is Babesia microti¸ and the less common ones are B. microti-like, Babesia duncani, Babesia divergens, and Babesia venatorum. The B. microti genome was sequenced in 2012,^36,37 which helped to increase understanding of the biology of the parasite and future treatment options. In the Northeast and upper Midwest, the white-footed mouse is the main reservoir host for B. microti. The parasite also has been found in chipmunks, voles, and rats. The primary vector for transmission is the tick I. scapularis (which also is the vector for transmission of Lyme disease, anaplasmosis, ehrlichiosis, and Powassan virus). The reported incidence of babesiosis is lower than the incidence reported for Lyme disease.³⁸ This could be because of less severe illness and awareness.

During a blood meal, an infected tick transmits sporozoites to the mouse host. The sporozooites enter erythrocytes and undergo asexual reproduction. In the blood, some parasites become male and female gametes. A tick again has a blood meal from the mouse, ingesting the gametes. After the tick ingests the gametes, the gametes undergo a sporogonic cycle that results in sporozoites. Humans enter the cycle when they are bitten by infected ticks as dead-end hosts. The Babesia parasites infect and destroy red blood cells, resulting in hemolytic anemia.

Babesiosis also may be transmitted by transfusion of blood products. The incidence of this occurring is 1.1 cases per million red blood cell units given, although it is more common in endemic areas.³⁹ More than 170 cases have been reported. Babesiosis is endemic primarily in the Northeast and upper Midwest. The incidence of babesiosis has increased greatly since reporting began in 1986. Both the geographic range and the number of cases have increased steadily, with 1,744 cases reported in 2014.⁴⁰ The infection is transmitted most commonly in the summer months, increasing in May and tapering off by September.

Babesiosis infections range from asymptomatic to severe. Researchers who conducted a cohort study in Rhode Island found asymptomatic infection in 20% of adults and 40% of children.⁴¹ In mild to moderate illness, patients present with fever, fatigue, chills, sweats, headache, gastrointestinal symptoms, and myalgia. Rash seldomly is noted and, if present, suggests Lyme disease. The examination may reveal splenomegaly, hepatomegaly, or jaundice. Laboratory abnormalities include hemolytic anemia secondary to the invasion and lysis of red blood cells, thrombocytopenia, and elevated liver enzymes. Patients more likely to have severe disease are those older than 50 years of age, those who are immunocompromised, or those who have comorbidities such as asplenia. Complications resulting from babesiosis include acute respiratory distress syndrome and disseminated intravascular coagulation.

The clinical diagnosis of babesiosis should be considered when a patient is in an endemic area and presents with symptoms and laboratory findings consistent with babesiosis. A history of a tick bite is useful, but often patients will not notice this. The diagnosis is confirmed by identification of the organism on a Giemsa or Wright stained blood smear, although it is hard to detect and may take multiple smears. PCR also can be used for diagnosis and is more sensitive for B. microti infection than a blood smear.⁴²

Treatment depends on the severity of the disease. For asymptomatic infection, the CDC does not recommend administering antimicrobial therapy.⁴³ The CDC recommends consulting the agency if there are any questions about treatment. For ill patients, babesiosis is treated for seven to 10 days with a combination of two medications: either atovaquone and azithromycin or clindamycin and quinine. Patients who are severely ill receive the latter treatment and often will require hospitalization. (See Table 6.)

Tularemia

Tularemia is a zoonotic infection caused by Francisella tularensis, an aerobic gram-negative bacteria. F. tularensis is a facultative intracellular pathogen that replicates primarily within host macrophages. It will multiply locally at the site of infection, spreads to the regional lymph nodes, and then spreads systemically. Human infection most often occurs from tick exposure during the summer months, but it also is transmitted from contact with contaminated animals, a biting insect, contaminated meat and water, or inhalation of contaminated aerosols.⁴⁴ The incidence of reported cases of tularemia to the CDC has declined over the years, with 230 cases reported in 2016. Tick transmission is via the dog tick (D. variabilis), the wood tick (D. andersoni), and the Lone Star tick (A. americanum).

The CDC has identified F. tularensis as a category A bioterrorism agent because of its virulence and ability to be aerosolized. A weapon using airborne F. tularensis most likely would result in an outbreak of inhalational tularemia three to five days later presenting as an acute febrile illness with pneumonia.⁴⁵

The average incubation period following exposure is three to five days. Tularemia presents with fevers, chills, anorexia, or malaise. The fever may abate after a few days, but then quickly returns. Additional signs depend on the portal of entry. There are six major clinical forms of tularemia:

• Ulceroglandular tularemia: This is the most common and presents after a tick or deer fly bite. A skin ulcer appears at the site of infection, with swelling of lymph nodes around the area.
• Glandular: Similar to ulceroglandular, but without the ulcer.
• Oculoglandular: This form occurs on exposure of bacteria to the eye. Symptoms include eye inflammation and swelling of the lymph gland in front of the eye.
• Oropharyngeal: This form results from consuming contaminated food or water. It presents with sore throat, mouth ulcers, tonsillitis, and swollen lymph nodes in the neck.
• Pneumonic: This is the most serious form. The symptoms include cough, chest pain, and dyspnea. It results from breathing aerosolized F. tularensis or when other forms are left untreated.
• Typhoidal: This form presents with a combination of general symptoms.

Diagnosis of tularemia requires a high degree of suspicion, given the rarity of the disease. It is based on the clinical presentation in association with the background information. Routine laboratory tests are nonspecific. The diagnosis is confirmed serologically by detecting antibodies via tube agglutination or microagglutination assay. These antibody titers will not reach detectable levels until after two weeks of infection, but then will remain elevated for years.

Treatment of tularemia should begin with suspicion of the disease and should not wait for the confirmatory test. Because of its high cure rate and minimal relapses, streptomycin is the preferred antibiotic for all forms of tularemia except meningitis. Gentamicin is an acceptable alternative that can be given intravenously and is available more readily.⁴⁶ In children, gentamicin is the preferred agent. For milder forms of the disease, ciprofloxacin or doxycycline can be used.⁴⁷ (See Table 7.)

Powassan Virus

Powassan virus is a flavivirus that causes an extremely rare tickborne illness. Approximately 100 cases of Powassan virus have been reported in the United States during the past 10 years. Prior to that, there were only 27 cases from 1958 to 1998, revealing a 671% increase in reported cases.⁴⁸ Powassan virus results in a very severe disease with a high mortality rate and significant morbidity. Approximately 10% of Powassan virus encephalitis cases are fatal, and severe long-term neurological sequelae are present in more than 50% of the survivors.⁴⁹ Cases have been reported in the Northeast and north central regions of the United States, as well as in western states and broadly throughout Canada.

The vector for Powassan virus is the I. scapularis tick (the deer tick) primarily. It is the same tick that transmits Lyme disease, anaplasmosis, and babesiosis. The virus also has been isolated from D. andersoni ticks as well as other Ixodes species. The incubation period is anywhere from one to five weeks, after which fever, sore throat, drowsiness, headache, and disorientation begin. In more severe cases, patients present with meningoencephalitis with symptoms such as altered mental status, seizures, aphasia, meningeal signs, paresis, movement disorders, or cranial nerve palsies.⁵⁰ Laboratory findings include lymphocytic pleocytosis in the cerebrospinal fluid, with normal or mildly elevated protein and normal glucose. There are no commercially available tests for confirmatory diagnosis, but testing is available through the CDC and some state health departments. Serum testing for IgM antibodies via ELISA and immunofluorescence can be performed. Unfortunately, there is no specific treatment to cure this infection. Supportive care is provided in the hospital, often involving respiratory support, IV fluids, and monitoring for cerebral edema. The role of antiviral therapy is unknown.

Prevention

Ticks generally are found near the ground in woody and weedy areas. They cannot jump or fly and are transmitted by a potential host rubbing against tall grasses or shrubs. To prevent tick bites, recommendations are as follows:

• Cover exposed areas, such as legs, when walking through woods to prevent attachment.
• Use repellant that contains 20% or more DEET, picaridin, or IR3535 on exposed skin. Wear clothing that contains permethrin.⁵¹
• Treat dogs and cats for ticks.
• Bathe after an outdoor activity.⁵²
• Check for ticks daily, paying particular attention to hard-to-see areas.⁵¹

The CDC recommends using tweezers or forceps for tick removal. Using fine-tipped forceps, grasp the tick as close to the skin surface as possible. Pull upward with a steady pressure. After removal of the tick, clean the area with rubbing alcohol or soap and water. If mouth parts remain in the skin and cannot be removed easily with forceps, they should be left in place rather than using aggressive methods to remove them.

Prophylaxis

Antibiotic treatment following a tick bite is not recommended to prevent RMSF, anaplasmosis, babesiosis, or ehrlichiosis, according to the CDC recommendations.⁵³ There is no evidence that it is effective, and it has the potential to just delay the onset of disease. Prophylaxis after a tick bite for Lyme disease is supported by the Infectious Diseases Society of America if the following conditions are met:⁵⁴

• Doxycycline is not contraindicated.
• The attached tick is an I. scapularis tick.
• The estimated time of attachment is > 36 hours based on tick engorgement or likely time of exposure.
• Prophylaxis can be started within 72 hours of tick removal.
• Lyme disease is common in the state where the patient lives or recently traveled.

For adults, the prophylactic dose is doxcycyline 200 mg for one dose; for children older than 8 years of age, the dose is 4 mg/kg up to 200 mg.

Summary

Tickborne illnesses range from those commonly seen, such as Lyme disease, to those extremely rare but potentially increasing, such as Powassan virus. Because initial symptoms often are nonspecific, providers should start therapy if a tickborne illness is suspected. Often, the patient is not aware of a tick bite and may not include that in the history.

The incidence of Lyme disease has grown rapidly in the past 10 years, and the disease has spread to new regions. Left untreated, it can result in serious complications. Ehrlichiosis and anaplasmosis are less common, but also have been increasing during the past 10 years. RMSF has become an increasing problem near the United States-Mexico border and into Arizona because of the prevalence of the ticks on free-roaming dogs. Finally, there are concerns that cases of Powassan virus are increasing, with severe associated morbidity. Being aware of these diseases and educating patients on prevention is an important task for the clinician.

REFERENCES

1. Rosenberg S, Lindsey N, Fischer N, et al. Vital Signs: Trends in reported vectorborne disease cases — United States and territories, 2004-16. MMWR Morb Mortal Wkly Rep 2018;67;496-501.
2. Wilson K, Elston D. What’s eating you? Ixodes tick and related diseases, Part 1: Life cycle, local reactions, and Lyme disease. Cutis 2018;101;187-190.
3. Simo L, Kazimirova M, Richardson J, Bonnet S. The essential role of tick salivary glands and saliva in tick feding and pathogen transmission. Front Cell Infect Microbiol 2017;7:1-23.
4. Steinke J, Platts-Mills T, Commins S. The alpha gal story: Lessons learned from connecting the dots. J Allergy Clin Immunol 2015;135:589-597.
5. Burgdorfer W, Barbour AG, Hayse SF, et al. Lyme disease a tick-borne spirochetosis? Science 1982;216:1317-1319.
6. Piesman J, Gern L. Lyme borreliosis in Europe and North America. Parasitology 2004;129(Suppl):S191.
7. Centers for Disease Control and Prevention. Lyme disease. Data and statistics. Available at: http://www.cdc.gov/lyme/stats. Accessed Aug. 5, 2018.
8. Tibbles CD, Edlow JA. Does this patient have erythema migrans? JAMA 2007;297:2617-2627.
9. Nadelman RB, Nowakowski J, Forseter G, et al. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med 1996;100:502-508.
10. Smith RP, Schoen RT, Rahn DW, et al. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med 2002;136:421-428.
11. Wormser GP, Masters E, Nowakowski J, et al. Prospective clinical evaluation of patients from Missouri and New York with erythema migrans-like skin lesions. Clin Infect Dis 2005;41:958-965.
12. McAlister HF, Klementowicz PT, Andrews C, et al. Lyme carditis: An important cause of reversible heart block. Ann Intern Med 1989;110:339-345.
13. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med 1987;107:725.
14. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18:484-509.
15. Wormser GP, Dattwyler RJ, Shapiro EE, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-1134.
16. Stupica D, Lusa L, Ružić-Sabljić E, et al. Treatment of erythema migrans with doxycycline for 10 days versus 15 days. Clin Infect Dis 2012;55:343-350.
17. Todd SR, Dahlgren FS, Traeger MS, et al. No visible dental staining in children treated with doxycycline for suspected Rocky Mountain spotted fever. J Pediatr 2015;166:1246-1251.
18. Townsend RL, Mortiz ED, Fialkow LB, et al. Probable transfusion-transmission of Anaplasma phagocytophilum by leukoreduced platelets. Transfusion 2014;54:2828-2832.
19. Chapman AS, Bakken JS, Folk SM, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis — United States — A practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep 2017;55:1-27.
20. McFee RB. Tick borne illness — Anaplasmosis. Dis Mon 2018;64:181-184.
21. Centers for Disease Control and Prevention. Anaplasmosis. Available at: https://www.cdc.gov/anaplasmosis/symptoms/index.html. Accessed Aug. 5, 2018.
22. Ismail N, Bloch KC, McBride JW. Human ehrlichiosis and anaplasmosis. Clin Lab Med 2010;30:261-292.
23. Pritt BS, Sloan LM, Johnson DK, et al. Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. N Engl J Med 2011;365:422.
24. Dumler JS, Bakken JS. Ehrlichial diseases of humans: Emergening tick-borne infections. Clin Infect Dis 1995;20:1102-1110.
25. Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 1996;275:199-205.
26. Ratnasamy N, Everett ED, Roland WE, et al. Central nervous system manifestations of human ehrlichiosis. Clin Infect Dis 1996;23:314-319.
27. Tomassone L, Portillo A, Novakova M, et al. Neglected aspects of tick-borne rickettsioses. Parasit Vectors 2018;11:263.
28. Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Mountain spotted fever from an unexpected tick vector in Arizona. N Engl J Med 2005;353:587-594.
29. Traeger MS, Regan JJ, Humpherys D, et al. Rocky Mountain spotted fever characterization and comparison to similar illnesses in a highly endemic area — Arizona, 2002–2011. Clin Infect Dis 2015;60:1659-1666.
30. Alvarez-Hernandez G, Roldan JFG, Milan NSH, et al. Rocky Mountain spotted fever in Mexico: Past, present, and future. Lancet Infect Dis 2017;17:e189-e196.
31. Helmick CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: Clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis 1984;150:480.
32. Gottlieb M, Long B, Koyfman A. The evaluation and management of Rocky Mountain spotted fever in the emergency department: A review of the literature. J Emerg Med 2018;55:42-50.
33. Holman RC, Paddock CD, Curns AT, et al. Analysis of risk factors for fatal Rocky Mountain spotted fever: Evidence for superiority of tetracyclines for therapy. J Infect Dis 2001;184:1437.
34. Centers for Disease Control and Prevention. Consequences of delayed diagnosis of Rocky Mountain spotted fever in children — West Virginia, Michigan, Tennessee, and Oklahoma, May-July 2000. MMWR Morb Mortal Wkly Rep 2000;49:885.
35. Zientek J, Dahlgren FS, McQuiston JH, Regan J. Self-reported treatment practices by healthcare providers could lead to death from Rocky Mountain spotted fever. J Pediatr 2014;164:416-418.
36. Cornillot E, Dassouli A, Garg A, et al. Whole genome mapping and re-organization of the nuclear and mitochondrial genomes of Babesia microti isolates. PloS One 2013;8:e72657.
37. Cornillot E, Hadj-Kaddour K, Dassouli A, et al. Sequencing of the smallest Apicomplexan genome from the human pathogen Babesia microti. Nucleic Acids Res 2012;40:9102-9114.
38. Diuk-Wasser MA, Liu L, Steeves TK, et al. Monitoring human babesiosis emergence through vector surveillance New England USA. Emerg Infect Dis 2014;20:225-231.
39. Tonnetti L, Eder AF, Dy B, et al. Transfusion-transmitted Babesia microti identified through hemovigilance. Transfusion 2009;49:2557.
40. Centers for Disease Control and Prevention. Surveillance for babesiosis — United States, 2014 Annual Summary. Atlanta, Georgia: U.S. Department of Health and Human Services, CDC, 2016.
41. Krause PJ, McKay K, Gadbaw J, et al. Increasing health burden of human babesiosis in endemic sites. Am J Trop Med Hyg 2003;68:431-436.
42. Krause PJ, Telford S 3rd, Spielman A, et al. Comparison of PCR with blood smear and inoculation of small animals for diagnosis of Babesia microti parasitemia. J Clin Microbiol 1996;34:2791-2794.
43. Centers for Disease Control and Prevention. Parasites — Babesiosis: Treatment. Available at: https://www.cdc.gov/parasites/babesiosis/health_professionals/index.html#tx. Accessed Aug. 5, 2018.
44. Ellis J, Oyston PC, Green M, Titball RW. Tularemia. Clinical Microbiol Rev 2002;15:631-646.
45. Dennis DT, Inglesby TV, Henderson DA, et al. Tularemia as a biological weapon: Medical and public health management. JAMA 2001;285:2763-2773.
46. Enderlin G, Morales L, Jacobs RF, Cross JT. Streptomycin and alternative agents for the treatment of tularemia: Review of the literature. Clin Infect Dis 1994;19:42.
47. Weber IB, Turabelidze G, Patrick S, et al. Clinical recognition and management of tularemia in Missouri: A retrospective records review of 121 cases. Clin Infect Dis 2012;55:1283.
48. Fatmi SS, Zehra R, Carptenter DO. Powassan virus — A new reemerging tick-borne disease. Front Public Health 2017;5:342.
49. Hermance ME, Thangamani S. Powassan virus: An emerging arbovirus of public health concern in North America. Vector Borne Zoonotic Dis 2017;17:453-462.
50. Ebel GD. Update on Powassan virus: Emergence of a North American tick-borne flavivirus. Annu Rev Entomol 2010;55:95-110.
51. Vazquez M, Muehlenbein C, Cartter M, et al. Effectiveness of personal protective measures to prevent Lyme disease. Emerg Infect Dis 2008;14:210.
52. Connally NP, Durante AJ, Yousey-Hindes KM, et al. Peridomestic Lyme disease prevention: Results of a population-based case-control study. Am J Prev Med 2009;37:201-206.
53. Centers for Disease Control and Prevention. Tick bite prophylaxis. Available at: https://www.cdc.gov/ticks/tickbornediseases/tick-bite-prophylaxis.html. Accessed Aug. 14, 2018.
54. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089-1134.