Tick-Related Infections

Published March 3, 2003

Alan Taege, MD

Department of
Infectious Disease

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Ticks are the vectors of at least 10 clinically significant zoonotic illnesses in the United States (Table 1). These illnesses may be caused by bacterial, viral, and parasitic pathogens, some of which may occur simultaneously during the bite of a single tick. Humans are often an accidental host to these increasingly recognized conditions by virtue of our intrusion into the natural habitat of the ticks and their reservoirs, the white-footed mouse and the whitetail deer. Geographically distinct areas exist for most of the vectors, reservoirs, and diseases; however, recreational travel into these regions may result in illness for nonresidents. Continued encroachment into forested and uncultivated areas will likely lead to a further increase in the incidence of tick-related infections. Many of these infections may be contracted in urban or semirural areas as well. Therefore, they should not be viewed as occurring only in remote or rural regions.

The common arthropod vectors are listed in Table 2. Each has the potential to carry more than one pathogen. The illnesses they cause often have a nonspecific presentation that requires astute physician recognition. A careful history and physical examination, with particular attention to travel and recreational activities, may be life saving. Early recognition, diagnosis, and treatment result in fewer complications and less morbidity and death. Seroconversion is often delayed; therefore, empiric therapy is frequently necessary.

A dated but useful overview of these infections may be found in reference 1.

Lyme Disease

Rocky Mountain
Spotted Fever

Ehrlichiosis

Babesiosis

Tularemia

Miscellaneous

References

LYME DISEASE

Lyme disease is currently the most common vector-borne disease in the United States. It was described in Lyme, Connecticut, in the 1970s and also exists in Europe with a different clinical presentation. Although rarely fatal and seldom a serious illness, Lyme disease has been widely publicized, frequently overdramatized, and sometimes linked to unproven conditions. Borrelia burgdorferi, a gram-negative spirochete, is the causative organism. Ixodes scapularis ticks in the eastern and midwestern regions of the United States and Ixodes pacificus in the northern Pacific areas carry this bacterium. The white-footed mouse is the natural reservoir. Although Lyme disease has been reported in nearly every state, it is considered endemic to the northeast coastal, mid-Atlantic, upper Midwest, northern California, and Pacific northwest regions (Figure 1), with seasonal peaks of infection occurring May through August.

Ixodes tick attachment for 48 to 72 hours is generally required for infection.² After an incubation period of 7 to 10 days (range 3 to 30 days), the illness may evolve through three stages. Other than erythema migrans (EM), the characteristic rash of Lyme disease, symptoms of Lyme disease are nonspecific. Stage 1, or early localized disease, is characterized by EM in approximately 90% of cases. EM is a rapidly expanding erythematous macule varying in size from 5 to 70 cm. It is generally solid, especially in the early period, but may show central clearing or a targetlike appearance (Figure 2). EM may resolve without therapy. It is usually asymptomatic but may be associated with fever, malaise, arthralgia, myalgia, or headache. Occasionally, the lesion may be pruritic. A history of a tick bite or exposure and the development of EM are diagnostic for Lyme disease.

Stage 2, early disseminated disease, may occur if stage 1 was not treated. It may manifest as multiple EM lesions (generally smaller), 3 to 5 weeks after the bite. Cranial nerve palsies (especially 7th nerve, or Bell's, palsy), meningitis, or carditis (variable atrioventricular block) may also occur.

Stage 3, late disease, may evolve if stage 2 was not treated. Monoarticular or oligoarticular arthritis is the most common manifestation of stage 3. The knee is the most commonly involved joint. It is likely an autoimmune arthritis, which does not respond well to antibiotic therapy. Encephalitis, encephalopathy, or polyneuropathy may be late-stage sequelae, but are uncommon.

Diagnosis is best accomplished by recognition of EM and the compatible history in stage 1 or 2. Culture of the organism, most often from an EM lesion, is the standard of diagnosis but is technically slow and difficult.³ Serology detects antibodies but does not establish the diagnosis by itself since other spirochetes (syphilis, relapsing fever, and oral spirochetes) as well as Varicella, Cytomegalovirus, Epstein-Barr virus, and Parvovirus may cause false-positive tests. In addition, rheumatoid arthritis and systemic lupus may cause erroneous serologic results. Serology is best performed as a two-step process utilizing an enzyme-linked immunosorbent assay (high sensitivity) as the first step followed by a Western blot for confirmation (high specificity). IgM antibodies may be detected in only 20% to 30% of cases during the first 2 weeks; however, 70% to 80% of cases will develop IgM antibodies by 1 month. IgG antibodies will be present by 6 to 8 weeks. Early antibiotic therapy may delay, blunt, or block the antibody response, making the clinical diagnosis even more important.

Therapy is well established and defined (Table 3). There appears to be no indication for prolonged therapy. Shorter courses may be as effective as the current recommendations. Stage 1 is treated with oral antibiotics for 14 to 21 days with doxycycline, amoxicillin, or cefuroxime. Stage 2 disease may be treated with the same regimens as for stage 1 unless meningitis or severe carditis occurs, in which case ceftriaxone 100 mg/kg/day (maximum 2 g/day) for 14 to 28 days is recommended. Stage 3 arthritis may be treated with oral doxycycline or amoxicillin for 14 to 21 days. If it recurs, therapy with ceftriaxone would be used for 14 to 28 days. Late-stage neurologic disease is also treated with ceftriaxone.⁴

Human Lyme disease vaccine is no longer available in the USA (it is available in Europe), but animal vaccine is still used. Also, Lyme vaccine will result in reactive ELISA (but negative western blot) testing.

ROCKY MOUNTAIN SPOTTED FEVER

Rocky Mountain spotted fever (RMSF) is caused by the obligate intracellular pleomorphic gram-negative rod Rickettsia rickettsii. Although it is considered the most common rickettsial disease in the United States, its declining incidence (Figure 3) may yield this position to ehrlichiosis. RMSF occurs in the south Atlantic coastal, south central, and western regions, being most concentrated in North and South Carolina, Tennessee, and Oklahoma. The tick vectors are Dermacentor variabilis in the east and Dermacentor andersoni in the west.

Infection can occur year round but is most commonly encountered from April through September. Most cases occur in children with exposures to dogs and wooded areas. Tick attachment of 6 to 10 hours is required for transmission, followed by an incubation period of 5 to 7 days (range 2 to 14 days) until infection is manifest. Only 60% to 70% of patients recall a tick bite.

The classic triad of fever, rash, and headache occurs in a minority of cases, particularly early in the course. The vasculitic rash, which often begins on the wrists and ankles and then spreads centrally (Figure 4), is uncommon during the first 3 days of illness. Ten percent of patients may not develop a rash. When it occurs, it may first have a maculopapular appearance, which progresses to a petechial rash. Abdominal symptoms of nausea, vomiting, and diarrhea may be present in one third of cases.⁵ Myalgia, arthralgia, and confusion may also be part of the clinical picture.

Early diagnosis may be difficult due to the nonspecific nature of the symptoms. Because of overlapping symptoms and geographic distribution, RMSF may be confused with ehrlichiosis. Fortunately, both may be treated with doxycycline. Serologic diagnosis is delayed and therefore seldom useful in the acute situation. Antibodies measured by indirect immunofluorescence have a 90% sensitivity but do not become positive until 10 to 14 days into the course.⁶ Direct immunofluorescence of a skin biopsy from the rash may prove useful early in the course of illness. General laboratory tests have a limited role, although a finding of thrombocytopenia may be helpful. Ehrlichiosis is more likely to be associated with leukopenia and elevated liver enzymes whereas RMSF is more likely to have thrombocytopenia.

Recommended treatment is doxycycline 100 mg bid for 5 to 7 days or for 2 days after defervescence occurs.⁷ Many believe doxycycline may be used to treat children, as this short course has a low risk for staining teeth. Chloramphenicol may be the best therapy during pregnancy.

Adverse prognostic factors include age >40 years, male gender, thrombocytopenia, hyponatremia, renal insufficiency, neurologic symptoms, delayed diagnosis, and lack of initial treatment with doxycycline.

EHRLICHIOSIS

Ehrlichiosis is a relatively recent rickettsial infection. This pleomorphic gram-negative rod infects white blood cells (WBCs). Two geographically distinct but clinically similar diseases exist and are named for the WBCs they inhabit: human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE) (Table 4). Ehrlichia chaffeensis is responsible for HME, and Anaplasma phagocytophila and Ehrlichia ewingii are associated with HGE. Clumps of organisms, morulae, may be found in the cytoplasm of the WBCs (Figure 5).

HME occurs in the mid-Atlantic, southeast, and south central regions, and in California, most often from April through September (Figure 6). The largest number of cases have been encountered in Missouri, Oklahoma, Arkansas, and North Carolina.

Transmission occurs after 24 to 48 hours of attachment by Amblyomma americanum (the Lone Star tick) followed by a 7- to 10-day incubation period. The illness may be mild or progress to multiorgan system failure and death. The onset is abrupt with fever, chills, myalgia, arthralgia, and headache. Rash may occur in as many as 40% of HME cases but is uncommon early in the illness. It manifests as a macular or maculopapular exanthem, which may become petechial. In contrast to RMSF, the rash generally starts centrally and moves peripherally. Secondary opportunistic infections may occur and may be the result of an immunosuppressive phenomenon. A 2% to 3% mortality has been noted. HME may be a more severe infection than HGE and particularly severe in immunocompromised patients.⁸

HGE occurs in southern New England, the mid-Atlantic coastal and upper Midwest regions, and northern California (Figure 7). The tick vectors are Ixodes scapularis in the east and Ixodes pacificus in the west. The white-footed mouse is the reservoir for both HGE and HME. Both may also infect whitetail deer, coyotes, and rats.

HGE occurs most often in the summer months after a 1- to 2-week incubation. The symptoms are similar to those of HME, although rash is less common (2% to 5%), and HGE may be less severe.

Laboratory evaluation may reveal leukopenia, thrombocytopenia, and elevated transaminases in both forms. Serologic diagnosis by immunofluorescent assay is delayed as antibodies are seldom present in the first week. A fourfold rise from acute to convalescent sera or titers of 1:256 for HME or 1:80 for HGE is considered diagnostic. Polymerase chain reaction may be useful in the first week, and has a sensitivity of 67% to 87% and a specificity of approximately 100%.⁹ Morulae may be found in peripheral blood smears in about 50% of cases of HGE and 7% to 17% of HME, although a trained microscopist and a careful search are necessary. Morulae may also be found in bone marrow aspirates.

Doxycycline 100 mg bid for 14 days is the treatment of choice. Shorter courses may be as effective. The organisms appear to be resistant to chloramphenicol. Quinolones may be second-line therapy.

BABESIOSIS

Babesiosis is a protozoan, parasitic, malaria-like infection of red blood cells that results in hemolysis. The causative organisms are Babesia microti in the northeast United States, Babesia divergins in California, and unnamed Babesiae in Washington (WA-1) and Missouri (MO-1). It may be transmitted by tick bites or, rarely, through blood transfusions. It is not a reportable disease; therefore, the incidence and number of infections are unknown.

The vectors and reservoirs are the same as for ehrlichiosis and Lyme disease, resulting in occasional cases of coinfection.

Infection occurs in the summer months. The Northeast, Midwest, and upper Pacific regions harbor the most cases (Maryland, Virginia, Georgia, Wisconsin, California, and Washington). Disease occurs in all age groups but is more severe in those older than 50 years, splenectomized individuals, and immunocompromised patients. After a 1- to 6-week incubation, infection may result in subclinical, mild, or fulminant disease. Mortality may be 5 to 10%.¹⁰ Symptoms include fever, chills, drenching sweats, headache, nausea, and abdominal pain. Mild hepatosplenomegaly may be found on examination.

Diagnosis is made by a compatible clinical picture and laboratory findings of hemolytic anemia, thrombocytopenia, and elevated transaminases. Thick and thin blood smears may show the parasite in the ring form (Figure 8) or its characteristic tetrad which resembles a Maltese cross. Serologic testing with an immunofluorescence assay may help confirm the diagnosis. Polymerase chain reaction is also available and may be a useful diagnostic modality.

Treatment with clindamycin 600 mg qid and quinine 650 mg tid is the standard therapy, although atovaquone 750 mg bid and azithromycin 500 to 600 mg followed by 250 to 600 mg daily for 7 to 10 days may be better tolerated and as effective. Exchange transfusions may be helpful in severe cases.

TULAREMIA

Table 5:

Tularemia Syndromes

Ulceroglandular
Glandular
Oculoglandular
Oropharyngeal
Typhoidal
Pneumonic

Tularemia is caused by Francisella tularensis, a gram-negative coccobacillus that is virulent and highly infectious. Tick (Dermacentor and Amblyomma), deer fly, or mosquito bites, or contact with or consumption of poorly cooked infected meat (rabbit) may result in infection. Accidental aerosolization may cause outbreaks as well.¹¹ Most cases occur in geographic regions similar to those for RMSF, but they also reach Texas and Utah. The largest number of infections is concentrated in Missouri, Oklahoma, Arkansas, and Tennessee; however, the incidence is declining.¹² Six clinical syndromes exist (Table 5), corresponding to the portal of entry or the clinical manifestation. Ulceroglandular tularemia is the most common type. An incubation period of 2 to 14 days leads to a clinically variable illness depending on the form that develops.

The organism can be cultured from blood, body fluids, and tissues but requires special media (cysteine-enriched). Laboratory personnel should be notified, as it is highly contagious and represents a laboratory hazard. Serodiagnosis may be obtained through agglutination tests. Elevated liver enzymes occur in about 50% of cases.

The standard of treatment is streptomycin, but because of difficulties in procurement, gentamicin has been substituted. Tetracyclines and quinolones may also be effective but usually require longer courses of therapy. Mortality may occur in 2% to 4% of cases.

MISCELLANEOUS

Coxiella burnetti, the agent of Q-fever, is another gram negative intracellular organism. It's nonspecific presentation of fever and headache may be associated with a variety of clinical syndromes, most commonly pneumonia, hepatitis and endocarditis. Based on serology, however, the majority appear to have an asymptomatic illness. Although Q-fever has been associated with ticks, acquisition usually occurs by inhalation of the organism during exposure to infected animals, ie cattle, sheep or goats, although many other animals have been known to be sources.

Most infections are self-limited. Pneumonia frequently resembles an atypical pneumonic picture. Multiple round infiltrates have also been described. Hepatitis is usually anicteric. Endocarditis occurs in the setting of previous valvular disease where the patient is frequently immunocompromised.

Doxycycline or a tetracycline derivative remains the mainstay of therapy. Quinolones and Rifampin also have therapeutic efficacy. A brief course of a tetracycline suffices for acute disease, when not self-limited. The chronic form of Q-fever may require months or years of treatment.

Relapsing fever is another tick-borne disease caused by the spirochete Borrelia hermsii or Borrelia duttonii occurring in the southwest United States. After approximately 7 days of incubation, a 3- to 6-day illness characterized by fever, headache, and rash will be followed by an asymptomatic week, and then a recurring cyclic illness. The organism can be demonstrated on thick and thin blood smears. Treatment with Doxycycline or Ceftriaxone is effective. A Jarisch-Herxheimer reaction may occur during treatment.

Colorado tick fever is a viral illness caused by the Coltivirus, which is transmitted by Dermacentor andersoni tick bites in the Rocky Mountains, California, and Pacific Northwest. Clinical manifestations include high fever, chills, headache, and myalgia. Serologic diagnosis is available. No specific treatment is known; therefore, supportive and symptomatic care is administered.

Tick paralysis is caused by a neurotoxin elaborated by female Dermacentor, Amblyoma, and Ixodes tick after prolonged attachment of 2 to 7 days. It is most common in young children, especially girls in the northwest and Rocky Mountain areas. It presents as a rapidly progressive Guillain-Barré-like syndrome with ascending motor paralysis and sparing of sensation and the sensorium.¹³ It can be fatal unless the tick is located and removed. Thereafter, rapid improvement ensues.

Tick encephalitis, an arbovirus belonging to the Flaviviridae family, is endemic in Russia and Eastern and Central Europe but is rare in the United States.¹⁴ Ixodes ticks transmit it. After 1 to 2 weeks of incubation, a biphasic illness may occur, characterized by fever, headache, and myalgia. After a 2- to 4-week asymptomatic period, aseptic meningitis or meningoencephalitis may occur. No specific therapy is available; therefore, supportive care is rendered.

Southern tick rash is an incompletely characterized illness probably transmitted by Amblyoma americanum, infecting the individual with a Borrelia species that causes an erythema migrans-like rash. It responds to the same treatment as does Lyme disease.

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REFERENCES

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