TAKE-HOME MEDICAL GRAND ROUNDS WILLIAM S. WILKE, MD, EDITOR POINTS FROM LECTURES BY CLEVELAND CLINIC AND VISITING FACULTY

Tick trouble: Overview of tickrborne diseases

ALAN J. TAEGE, MD positive until several weeks after the patient Department of Infectious Diseases, Cleveland Clinic has been infected; therefore, these tests must be used for confirmation, not screening. • ABSTRACT It is important for physicians to learn Tick-borne diseases can be severe or about the varying clinical characteristics and even fatal, but when identified early, the epidemiology of these diseases. In this most can be easily treated. Tick-borne article, I will first call attention to three of the diseases often present with nonspecific less familiar tick-borne diseases: Rocky symptoms. Therefore it is important for Mountain spotted fever, ehrlichiosis, and the primary care physician to be familiar babesiosis. I will conclude with an update on with the epidemiology of these diseases the most common of the tick-borne diseases, and their presentations. Although Lyme Lyme borreliosis. disease is the most common and well- • ROCKY MOUNTAIN SPOTTED FEVER known of the many tick-borne diseases, Rocky Mountain spotted fever, An acute febrile illness, Rocky Mountain ehrlichiosis, and babesiosis are also spotted fever is caused by Rickettsia rickettsii, a More threats throughout the United States. gram-negative intracellular bacillus transmit- Americans are ted by tick bites. The disease is misnamed: not S SUBURBS EXPAND and deer populations all patients develop rash, and fewer than 2% coming into 0continue to increase, more Americans of cases occur in Rocky Mountain states. contact with are coming into contact with rural problems Symptoms and course. The onset of such as tick-borne disease. Caused by symptoms begins 4 to 14 days after exposure tick-borne microorganisms endemic among white-tailed (mean, 7 days). Almost all patients have diseases deer, white-footed mice, or other mammals, fever. Headache, rash, or myalgia is experi- these diseases may be transmitted to humans enced by 80% or more of patients. Between through the bite of several species of ticks. one third and two thirds of patients experi- Identifying tick-borne diseases is difficult ence abdominal pain, nausea, or vomiting. for three reasons. First, tick-borne diseases However, the classic triad of fever, headache, often present with nonspecific symptoms that and rash is experienced by only about half of can be confused with a wide variety of unre- patients. The characteristic rash, which is not lated illnesses. Second, many patients never pruritic or painful, develops as macular lesions know that they have been bitten. Even though 3 to 5 days after the onset of the illness, pro- ticks may remain attached for hours or days, gressing to maculopapules and petechiae. they are tiny, their bites are painless, and they Starting on the wrists and ankles, it spreads to seek out hidden locations such as the axilla the palms and soles and then to the trunk. and the groin. Third, although serologic tests Between 9% and 16% of patients never expe- are available, they generally do not become rience a rash. In severe cases, patients may enter deliri-

PATIENT INFORMATION um, shock, and renal failure. Mortality is # Avoiding tick bites, page 249 about 5%, being highest in older patients,

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 • NUMBER 4 APRIL 2000 14 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. men, blacks, and those who do not receive it difficult to diagnose. prompt treatment. The Ehrlichia organisms, members of the Epidemiology and demographics. Rocky Rickettsiaceae family, are gram-negative, Mountain spotted fever has been reported in intracellular pleomorphic bacilli. The disease 48 states of the United States, Mexico, and has two forms: human monocytic ehrlichiosis, Central and South America. About half of the found in the southeastern states, and human 600 American cases every year occur in North granulocytic ehrlichiosis, found in the Carolina, South Carolina, Tennessee, or Northeast, Midwest, and the West. The dis- Oklahoma. Although cases may occur at any eases, although clinically indistinguishable, time of year, about 90% of them occur arc caused by different organisms and carried between April and September during peak by different species of ticks, with white-tailed tick season. The age distribution of patients is deer and white-footed mice as reservoirs. bimodal, with most cases occurring among Symptoms and course. More than 60% of children age 5 to 9 years or among adults older those infected may be asymptomatic. than 60. The disease is somewhat more com- Symptoms, when they do develop, begin 7 to mon among men than women (1.7 to 1) and 14 days after exposure. Virtually all sympto- in whites than in blacks. Only about two matic patients have fever, and up to 85% have thirds of patients recall the tick bite. headache. Myalgia, malaise, and nausea are Differential diagnoses include measles, common. One third of patients with human meningococcemia, influenza, enterovirus, lep- monocytic ehrlichiosis and 2% to 11% of tospirosis, mononucleosis, viral hepatitis, those with human granulocytic ehrlichiosis typhoid fever, or idiopathic or thrombotic have a truncal rash, most commonly macu- thrombocytopenia purpura. Rocky Mountain lopapular, distinguishing it from Rocky spotted fever may also resemble another tick- Mountain spotted fever. The rash rarely affects borne disease, ehrlichiosis. the hands and feet. In fatal cases, an associa- Diagnosis should be made on the basis of tion has been noted with opportunistic infec- clinical symptoms and a careful patient histo- tions, leading to the possible conclusion that ry searching for any recent tick bites or out- ehrlichiosis may cause some degree of Serology door activity. Serologic tests can identify anti- immunosuppression. is used to bodies to the rickettsial organism, but only Severe disease may be characterized by after 7 to 10 days of infection; therefore, these seizures, coma, and renal, respiratory, and car- confirm, not tests are best used for confirmation after treat- diac failure, with mortality between 2% and diagnose, tick- ment has already begun. 10%. Laboratory tests are not particularly help- Characteristic laboratory findings are the borne disease ful. Although most patients become mildly combination of leukopenia, low platelet anemic, and some may have some thrombocy- counts, and elevated hepatic enzymes. About topenia, hyponatremia, or elevated liver half of patients become anemic. Blood sam- enzymes, these changes are not frequent ples from some patients will also have leuko- enough or severe enough to be diagnostic. An cytes with characteristic black spots called elevation in white blood cell counts at the morulae, intracellular cytoplasmic vacuoles beginning of the disease resolves quickly. occupied by Ehrlichia organisms. Treatment. Doxycycline is the preferred Epidemiology and demographics. Like treatment. It is also effective against ehrli- other tick-borne diseases, ehrlichiosis can chiosis, with which Rocky Mountain spotted occur at any time of year but is most common fever may be confused. Tetracycline may also between April and September. It is more com- be used. Chloramphenicol is recommended mon in men than women and is most frequent for children and pregnant women. between the ages of 43 and 60. About two thirds of patients recall being bitten by a tick. • EHRLICHIOSIS The tick must be attached for 24 to 48 hours to transmit the disease; therefore, daily tick Ehrlichiosis is an acute, febrile, multisystem checks can be an effective means of preven- disease with nonspecific symptoms that make tion.

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FIGURE 1. Blood smear from a patient with FIGURE 2. Erythema migrans, the charac- babesiosis. Note the infected red blood teristic lesion that develops soon after cells bearing the characteristic ring forms being bitten by a tick infected with of Babesia microti (arrow). Borrelia burgdorferi, the causative agent of Lyme disease. Differential diagnosis. This disease may resemble Rocky Mountain spotted fever, range of the disease, but it appears to be most thrombotic thrombocytopenia purpura, hema- common in the Northeast, upper Midwest, tologic malignancy, hepatitis A, pneumonia, and West, with concentrations on Shelter, or viral diseases such as mononucleosis. Block, and Fire Islands in New York State. Diagnosis. Clinical findings, including Peak incidence occurs in June and July, but leukopenia and thrombocytopenia, with a the disease may occur from May to patient history of tick bite or possible tick September. The seroprevalence of babesiosis exposure, are important. Morulae are charac- in endemic areas is 9% to 21%, indicating teristic but do not occur in many patients and that many exposed to the disease are asymp- are difficult to recognize by the unsuspecting tomatic. It is more common among men The Lyme microscopist. Serologic testing can detect than women, and most common among disease antibodies to human monocytic ehrlichiosis those between ages 40 and 50. Fewer than after 2 to 3 weeks of infection. 10% of patients recall a tick bite. vaccine is not Treatment. Doxycycline is the treatment Differential diagnosis. The severe fever approved of choice, but chloramphenicol and rifampin of babesiosis once led it to be called North are also effective. American malaria, but true malaria is charac- for children terized by periodic fevers. Other differential • BABESIOSIS diagnoses are drug reactions, sickle cell crisis, thrombotic thrombocytopenia purpura, A zoonotic infection caused by an intraery- Escherichia coli 0157:H7 infection, mononu- throcytic protozoan, babesiosis is suspected to cleosis, brown recluse spider bite, and have affected humans and cattle since Biblical mycoplasma or viral infections. times. In North America, the disease is trans- Diagnosis. A careful history focusing on mitted by several species of ticks, and the possible exposure to ticks is important. A reservoirs are again white-footed mice and blood smear may show parasitemia, with the white-tailed deer. organisms forming characteristic ring forms Symptoms and course. The incubation and x-shaped "Maltese crosses" within ery- period ranges from 1 to 6 weeks. About 90% throcytes (FIGURE 1). Serology generally shows of patients experience fever with drenching antibodies only after 7 to 10 days of infection. sweat. Nausea, headache, and myalgia are Patients typically exhibit hemolytic anemia also common, and some patients also experi- and elevated liver enzymes. A few patients ence arthralgia. Mortality is about 5%. have thrombocytopenia or leukopenia. Epidemiology and demographics. The Treatment. Clindamycin, quinine, ato- lack of national reporting requirements vaquone, and azithromycin are all effective makes it difficult to determine the exact therapies.

246 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 • NUMBER 4 APRIL 2000 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. • LYME DISEASE the earlier stages. It is of interest to note that European forms of borrelial infection show Although Lyme disease may have occurred in somewhat different patterns of signs and the 19th century, it was named in the 1970s symptoms, with cutaneous and cardiac symp- after an outbreak in Old Lyme, CT. This mul- toms being more frequent. tisystem inflammatory disease is the most fre- Epidemiology and demographics. Lyme quent vector-borne disease in the United disease has been reported in 48 states, but 90% States. In 1998, 16,000 cases were identified. of cases occur in New England, the upper The disease is caused by Borrelia burgdor- Midwest, and northwestern California. Lyme feri, a slow-growing motile, flagellated spiro- disease is most common from May to chete that is endemic among many white- November. The age distribution is bimodal, tailed deer and white-footed mouse popula- with peaks between 5 and 9 years and then 30 tions. It can be transmitted to humans to 59 years of age. It is more common in men through the bite of an infected tick from the than women. Ixodes genus. Differential diagnosis. The list of differ- Symptoms and course. Lyme disease is ential diagnoses is vast and may include spider not transmitted unless the infected tick has bite, urticaria, reactive arthritis, scleroderma, remained attached for 36 hours or longer. The multiple sclerosis, chronic fatigue syndrome, disease goes through three stages if untreated. fibromyalgia, and other disorders. In stage 1 disease, most patients develop ery- Diagnosis. Again, a history of a tick bite thema migrans, the characteristic round or in an endemic area should prompt considera- oval expanding lesion around the tick bite tion of tick-borne disease. The erythema which sometimes clears in the middle to form migrans lesion is characteristic. Serologic test- a bull's-eye (FIGURE 2). The lesion, which is not ing should begin with ELISA, followed by a usually pruritic or painful, spontaneously Western blot for confirmation. Unfortunately, resolves in 1 to 4 weeks without treatment. false-positive tests are common, and patients During this stage, many patients experience who have already begun treatment may dis- flulike symptoms: fatigue, headache, fever, and play false negatives. Borrelia can be cultured Prophylactic muscle aches are all common. Adenopathy is from erythema migrans biopsies, but requires a antibiotics found in 23% to 40%. The onset of stage 1 special bacteriological medium. Newer poly- symptoms occurs after an incubation period of merase chain reaction (PCR) tests are not are not 4 to 30 days. reliable or standardized at this time. recommended Stage 2 Lyme disease, which develops in Treatment. Prophylactic antibiotic treat- untreated patients after 1 to 4 months, may ment after tick bites is not recommended. after a tick bite include symptoms that may be neurologic Early-stage Lyme disease can be treated with (Bell palsy), cutaneous (secondary erythema oral antibiotics, but disease that is permitted migrans), rheumatic (intermittent, asymmet- to progress may require more intensive thera- ric joint stiffness, swelling, and pain), or car- py including intravenous antibiotics. diac (atrioventricular block, myopericarditis). Doxycycline, amoxicillin, cefuroxime, ceftri- Patients often experience headache, muscu- axone, and penicillin are all effective thera- loskeletal pain, and fatigue. peutic options. Untreated or inadequately treated Lyme Vaccine. A vaccine against Lyme disease, disease may then enter stage 3. Patients may LYMErix (SmithKline Beecham Pharmaceu- develop intermittent attacks of chronic ticals), was approved in 1998 for individuals inflammatory arthritis, often in the large between 15 and 70 years of age. (A second joints. Encephalopathy or encephalomyelitis vaccine, ImuLyme, from Pasteur Merieux may also occur. Chronic neurological involve- Connaught, has not yet been approved.) ment may develop months to years after infec- LYMErix uses a unique mechanism of action: tion. Despite the vast array of manifestations, antibodies produced in response to the vac- Lyme disease is rarely a fatal disease. cine are transmitted to the tick from the Patients showing signs of the later stages human host during its blood meal. Once of disease may not have experienced any of ingested, the antibodies kill the Borrelia

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As editors, we'd like you organism in the tick's gut. Three doses over a 1-year period are required for 80% efficacy. to look into every issue, Many questions remain about this vaccine, every page of the including its duration of effectiveness and whether it is safe in children, who represent Cleveland Clinic Journal one of the largest populations of Lyme dis- ease patients. The vaccine has not been test- of Medicine. ed in pregnant women. We'd like to know... A careful risk assessment is necessary before recommending the vaccine. Those at high risk of tick bites are people who hike, 1 How many issues do you look into? camp, hunt, or work (for example, as park Here's our goal: rangers or foresters) in wooded or overgrown H'All " • Most • Half DFew areas known to be infested with ticks, particu- larly in spring and summer. The vaccine should not be used as an excuse to reduce per- 2 How do you read the average issue? sonal protective measures against tick bites Here's our goal: (see "Avoiding Tick Bites," page 249). It has Htover-to-cover been proposed that the vaccine might stimu- • Most articles late autoimmune reactions in some people • Selected articles with treatment-resistant Lyme arthritis; there- fore, at this point, it is not indicated for these patients. ¡M We put it in writing... please put it in writing for us. • FURTHER READING

| We want to hear from you. Boustani MR, Gelfand JA. Babesiosis. Clin Infect Dis 1996; 22:611-615.

CLEVELAND CLINIC JOURNAL OF MEDICINE Dennis DT. Recommendations for the use of Lyme disease vac- The Cleveland Clinic Foundation cine. MMWR 1999;48:1-17.

9500 Euclid Avenue, NA32 Fritz CL, Glaser CA. Ehrlichiosis. Infect Dis Clin North Am Cleveland, Ohio 44195 1998; 12:123-136.

Gorenflot A, Moubri K, Precigout E, et al. Human babesiosis. PHONE 216.444.2661 Ann Trop Med Parisitol 1998; 92:489-501. FAX 216.444.9385 Nladelman RB, Wormser GP. Lyme borreliosis. Lancet 1998; E-MAIL [email protected] 352:557-565.

Sigal LH. Myths and facts about Lyme disease. Clev Clin J Med 1997; 64:203-209.

Spach DH, Liles WC, Campbell GL, et al. Tickborne diseases in the United States. N Engl J Med 1993; 329:936-947.

Walker DH. Rocky Mountain spotted fever: A seasonal alert. Clin Infect Dis 1995; 20:1111—1117.

CME ANSWERS Answers to the CREDIT TEST on page 303 of this issue I B2A3E4A5B6D7E8C9D10E II B 12 A

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