Paul G. Auwaerter
John A. Flynn
Lyme disease is the most common tick-borne illness in the United States. Although it rarely causes mortality, it can have morbid complications and generates concern among patients. Other arthropod-borne illnesses such as Rocky Mountain spotted fever (RMSF) and ehrlichiosis, although less common than Lyme disease, are among the diseases requiring prompt recognition, because death can occur without proper treatment. The number of recognized tick-borne human diseases other than Lyme disease continues to expand in the United States (Table 38.1).
Lyme Disease
Epidemiology
Since the original clinical description in 1977 of infection by the spirochete Borrelia burgdorferi, Lyme disease has become the most common arthropod-borne illness in the United States (1). It is endemic in more than 15 states and is responsible for an increasing number of cases primarily in Eastern coastal areas and the upper Midwest (Fig. 38.1) (2). This spirochete was originally isolated from the Ixodes scapularistick in the northeastern United States (3). Subsequently, other Ixodes species were found to carry this infection in California (I. pacificus) and throughout Europe (I. ricinus) and Asia (I. persulcatus). In addition to the transmitting tick vector, other animal reservoirs are involved in the tick life cycle maintaining Borrelia infection. In the United States, the white-footed mouse and the white-tailed deer are the preferred hosts for this very small tick, also known as the black-legged deer tick, which is no larger than 2 by 3 mm in its adult form. Ticks become infected through horizontal transmission among these reservoirs. In endemic areas, up to 50% of ticks may be infected (4). Despite the high carriage rate in ticks, the probability of acquiring Lyme disease from a single tick bite is at most 3.5% in highly endemic areas (5). The disease incidence is greatest in the mid-spring through late fall. This correlates with periods of increased tick populations, especially biting nymphs (less than 2 mm), as well as increased outdoor activities of people in endemic areas. Effective transmission to humans appears to require at least 36 to 48 hours of tick attachment.
Surveillance of this nationally notifiable disease has been conducted by the Centers for Disease Control and Prevention (CDC) since 1982. The following clinical case definition for this surveillance has been established and is discussed later in this chapter:
The highest number of cases in the United States is reported in the northeastern and mid-Atlantic regions. Endemic pockets also exist in northern California and in regions of Minnesota and Wisconsin. Cases of Lyme disease have been reported in 49 states and the District of Columbia; Connecticut, Rhode Island, New York, and Pennsylvania have reported the highest rates (1). There is no gender predilection, although persons 5 to 19 years of age and 30 years or older appear to have the highest risk of infection. Significant outdoor exposure (e.g., hiking, gardening) in endemic regions increases risk, although cases have occurred without a history of much outdoor activity. In those cases for which the month of illness was identified, June and July were reported most frequently.
Clinical Manifestations and Stages
Patients may develop erythema migrans (EM) and then have no further symptoms even in the absence of antibiotic therapy. Others may present with one of the later manifestations of the infection without any history of EM. Lyme disease is divided into three stages based on its clinical manifestations: 1) early localized disease; 2) early disseminated disease; and, 3) late disease. Approximately 70% to
P.561
P.562
85% of patients with definite Lyme disease present with early localized disease. In most patients, there is no characteristic progression from one stage to the next.
|
TABLE 38.1 North American Tick-Borne Infections and Common Characteristics |
||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||
|
FIGURE 38.1. National Lyme Disease Risk Map. This map demonstrates an approximate distribution of predicted Lyme disease risk in the United States. The true relative risk in any given county compared with other counties might differ from that shown here and might change from year to year. Available at: http://www.cdc.gov/ncidod/dvbid/lyme/riskmap.htm.). |
||||||||||||||||||||||||||||||||||||||||||||||||||
|
FIGURE 38.2. (See also Color Plate.) Classic erythema migrans rash of early Lyme disease with bright red border and partial central clearing, the so-called “bull's-eye” rash. (Photograph courtesy of Paul Auwaerter, MD) (See color image.) |
Early Localized Disease
After a bite from an infected tick, an incubation period of several days to 1 month may elapse before the patho-gnomonic skin lesion, EM, forms at the site of the bite. Common sites include the axillae, popliteal area, groin, and waistline. This lesion starts as an erythematous macule or papule with an outer border and clearing center that can expand beyond 15 cm in a circumferential manner over several days (Fig. 38.2; see also Color Plate). The border is sharply demarcated, warm to touch, nontender, although sometimes it is pruritic. Only one third of patients are aware of a recent tick bite. If left untreated, EM resolves spontaneously within several weeks. If appropriate antibiotic therapy is initiated, the rash resolves in days. This rash is the single best clinical marker for this condition and occurs in up to 90% of cases (6). Most patients have some nonspecific constitutional symptoms, such as myalgia, fatigue, arthralgia, or headache. Twenty percent of patients have no manifestation other than the rash. Though often described as a “bull's-eye” rash because of central clearing, this feature is frequently not present. In one study of culture-proven Lyme disease less than 40% of rashes had central clearing, and a homogenous or central redness pattern was more common (7).
Early Disseminated Disease
Early localized Lyme disease often progresses to hemato-genous dissemination within the first month. During summertime, flu-like illnesses with headache, myalgia, arthralgia, and fever, without EM rash, may also represent Lyme disease. End-organ effects develop within several weeks or up to 1 year after the primary infection in untreated patients. Unusual manifestations include optic neuritis, hepatitis, myositis, and pneumonitis. The section as listed below describes the more common manifestations.
Dermatologic
Multiple secondary annular lesions develop in half of untreated patients because of hematogenous spread (11). These disseminated erythema migrans lesions are smaller than the initial lesion and resolve with appropriate antibiotic therapy.
Neurologic
Ten to fifteen percent of untreated patients develop neurologic involvement including meningitis, cranial neuropathy, or radiculoneuropathy, within 4 to 8 weeks after resolution of EM (8). Patients with meningitis, the most common manifestation, present with fever, meningismus, photophobia, and headache. The cerebrospinal fluid (CSF) typically demonstrates a mild lymphocytic pleocytosis (100 to 500 cells), and an increased protein level. A peripheral seventh nerve palsy (Bell palsy) is the most common cranial neuropathy; it is bilateral in up to a quarter of cases (9). Most cases resolve within 1 month regardless of treatment. Peripheral radiculoneuropathies occur less often. They may involve one or more motor or sensory nerves of the thorax or limbs in an asymmetric pattern, mimicking, for example, spinal nerve root compression or manifesting as focal weakness in the involved areas.
Cardiac
Involvement of the heart can occur in up to 10% of patients with untreated Lyme disease, typically within 3 months of developing EM. The precise incidence of Lyme carditis is unclear because the most common finding when a patient has carditis is asymptomatic first-degree atrio-ventricular (AV) block. Complete heart block requiring temporary pacemaker placement may occur (10). Cardiomyopathy, pericarditis, and myocarditis have been described but are rare. All cardiac involvement usually resolves within 8 weeks, and complete heart block usually recedes with antimicrobial treatment, making permanent pacemaker placement unnecessary.
Musculoskeletal
Roughly half of untreated patients develop migratory arthralgias, myalgias, tendonitis, bursitis, or bone pain. A self-limited monoarticular or oligoarticular arthritis may
P.563
develop, primarily in the large joints, most often the knee. Polyarthritis is distinctly unusual. Large synovial effusions contain inflammatory fluid (5,000 to 20,000 white blood cells [WBCs] per cubic millimeter) with neutrophilic predominance.
Late Manifestations
The late manifestations of Lyme disease occur many months to years after the initial infection.
Musculoskeletal
A migratory oligoarthritis develops in up to 60% of patients with untreated disease (12). Recurrent attacks of oligoarthritis chiefly affect weight-bearing joints, most commonly the knee, and persist for weeks to months before resolving. Synovial effusions may be large and inflammatory (up to 100,000 WBCs per cubic millimeter). Even in untreated patients, the arthritis usually improves. A minority of patients go on to develop a chronic arthritis, despite extensive antibiotic therapy and apparent eradication of all spirochetes. In these unresponsive cases, certain human leukocyte antigen (HLA) haplotypes (DR4 and DR2) have been linked to a robust antibody response to outer surface proteins of the spirochete (OspA and OspB), suggesting a perpetuating immune reaction rather than persistence of Borrelia spirochetes (13,14).
Neurologic
The most common neurologic manifestation of late Lyme disease is a chronic encephalopathy that occurs years after the initial infection (15). Patients experience memory impairment and mood changes. Additionally, a poly-radiculopathy with paresthesia or radicular pain of the extremities may develop with or without encephalopathy. Motor involvement is unusual. Partial improvement may occur in half of those patients who are treated with antibiotics, but the natural history tends toward a chronic progressive course. All forms of chronic neurologic Lyme disease are believed to be uncommon, occurring in fewer than 5% of people with untreated Lyme disease.
Dermatologic
A peculiar cutaneous affliction, acrodermatitis chronica atrophicans, is primarily seen in untreated patients in Europe (16). This red to blue nodular plaque develops mostly on the dorsal aspect of the hand, elbow, and extensor surface of the foot and ankle. Over time, the involved skin becomes atrophic or sclerotic. B. burgdorferi has been cultured from these lesions.
Diagnosis
The diagnosis of Lyme disease should be based primarily on the presence of characteristic clinical findings, exposure to an endemic area, and response to appropriate antibiotic therapy (17). The clinical presentation of EM is so distinctive that any patient presenting with this rash requires treatment for early Lyme disease with no specific labora-tory testing required. In patients with other associated findings (e.g., facial nerve palsy, complete heart block) and no history of EM, serologic testing should be performed if the likelihood of exposure is significant.
With the exception of skin samples from lesions and blood in patients with EM, it is difficult to culture B. burgdorferi from any site (4,18). Because this technique is difficult and the skin lesion is pathognomonic, attempts at culturing the organism are limited to research settings.
Routinely available diagnostic testing determines whether there has been an immune response to the spirochete, using an enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin (Ig)M and IgG antibodies to B. burgdorferi. In patients infected with Lyme disease it can take several weeks before detection of an IgM response. This may be completely abrogated with early antibiotic treatment of EM. Once positive, the IgM response can remain present for longer than a year. Although it helps to confirm exposure, it does not establish active infection. After 4 to 8 weeks, the IgG antibody response should develop in untreated patients. False positive results have been noted in a number of situations, including viral infections, rheumatoid arthritis, and other autoimmune diseases as well as in healthy people living in endemic areas (4). In the absence of appropriate clinical and environmental findings, these laboratory studies do not have sufficient sensitivity or specificity to establish or exclude the diagnosis of Lyme disease (19).
Although criteria have been established for the interpretation of Western blot studies of Lyme disease–related antibodies, there is still difficulty with standardization and reliability of this testing (20). The CDC recommends a two-step Lyme diagnostic test strategy in which positive or equivocal ELISA studies are confirmed by Western blot testing for Lyme-specific IgM and IgG bands. These tests are available routinely. The IgM Western blot is often falsely positive and therefore should be obtained only in patients with symptoms of less than 1 month's duration. In these cases, the test is considered positive if two of three Lyme-specific bands are present. The IgG Western blot requires that at least 5 of 10 specific bands be present. Polymerase chain reaction (PCR) testing has detected B. burgdorferideoxyribonucleic acid (DNA) in blood, synovial fluid, spinal fluid, and skin specimens (21). DNA detection with PCR for B. burgdorfericontinues to be fraught with technical difficulties, risk of contamination, poor sensitivity, and lack of standardization that has prevented wide clinical use (16). Its main role may be in confirming active Lyme infection in synovial fluid.
The CDC has issued a recent warning regarding certain commercial laboratories that present themselves as Lyme
P.564
specialty centers (22). These labs use assays for which accuracy and clinical utility have not been adequately established, including urine antigen tests, immunofluorescent staining of blood for B. burgdorferi, and lymphocyte transformation tests. These laboratories may also use inappropriate specimens such as blood or urine for B. burgdorferi DNA PCR tests or interpret Western blots using unvalidated criteria. If unsure, healthcare providers and patients are urged to should ask whether the laboratory offers validated, Food and Drug Administration (FDA)-approved Lyme testing.
Occasionally patients suffering from B. burgdorferi may be coinfected with other tick-borne pathogens such as Ehrlichia or Babesia species. This is an uncommon situation that appears to represent no more than 2% of Lyme disease cases even in highly endemic areas (23).
Treatment
Lyme disease in all stages should respond with clinical improvement to appropriate antibiotic therapy. Recognition and treatment of early Lyme disease prevents development of later manifestations. A Jarisch–Herxheimer reaction with spiking fever, rigor, and rarely hypotension occurs in some patients within several hours after treatment. It peaks in approximately 12 hours and then resolves over 1 to 2 days, and is treated with supportive care.
Early Manifestations
EM can be treated successfully with oral doxycycline in adults, or amoxicillin in pregnant or lactating women (Table 38.2). For people who are allergic to these medications, oral cefuroxime is an effective alternative (24). Although azithromycin has been studied, it is less effective than amoxicillin against EM (25). Most cases of EM resolve within days after initiation of therapy. Although the optimal duration of antibiotic therapy has not been established conclusively, one study suggested that 10 days of doxycycline is sufficient for the treatment of EM (26). A reasonable approach at this time is to treat for 10 to 14 days with doxycycline or 14 to 21 days with amoxi-cillin (27).
Patients with isolated facial palsy, minor cardiac abnormalities (e.g., first-degree AV block), or disseminated annular lesions at the time of diagnosis should be treated with a 21- to 28-day oral regimen (27). Patient with complete AV block, meningitis, or other early neuroborreliosis syndromes should receive intravenous ceftriaxone therapy for 14 to 28 days (28). Some practitioners use parenteral therapy until acute symptoms have resolved (e.g., in cases of cardiac conduction abnormalities) and then complete the course of antibiotics with oral therapy. Parenteral penicillin is equally efficacious, although ceftriaxone is used more frequently because of dosing simplicity. Patients with significant cardiac involvement may require monitoring and a temporary pacemaker.
|
TABLE 38.2 Antibiotic Therapy for Lyme Diseasea,b |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Late Manifestations
Late manifestations of Lyme disease require longer courses of antibiotics (Table 38.2). Lyme arthritis should be treated with a 28-day course of oral antibiotics. If the patient does not respond, a 14- to 28-day course of intravenous ceftriaxone should be given (29). A small percentage of patients develop a postinfectious immune response with persistent arthritis despite extensive antibiotics (see Late Manifestations, Musculoskeletal). Patients with late neurologic manifestations should be treated with a 28-day course of intravenous ceftriaxone (28). Prolonged treatment with antibiotics, beyond this, is no more effective than placebo in improving persistent symptoms in patients with a
P.565
history of acute Lyme disease (30). Some patients exhibit features of fibromyalgia or chronic fatigue syndrome despite eradication of Lyme spirochetes. Sometimes termed “post-Lyme disease syndrome” or “posttreatment chronic Lyme disease,” this entity is poorly understood regarding its pathogenesis, and its treatment is not defined (31). Overall, though, the long-term outcome for most patients with Lyme disease is favorable. For example, one study showed no differences between patients with Lyme disease and age-matched controls without Lyme disease in difficulties with activities of daily living 1 to 11 years after diagnosis (32).
Prevention
The risk of infection with B. burgdorferi depends on several variables, including the prevalence of Lyme-infected ticks in the area, the number of tick bites received, and the duration that the tick is attached. If tick feeding is less than 36 to 48 hours, the risk of transmitting infection is very low. Risk increases with more extended attachment or if the tick is obviously engorged with blood. Lyme disease is not an adequately immunizing condition. Recurrent exposure may lead to recurrent infection and clinical symptoms. An FDA-approved Lyme vaccine was withdrawn by the manufacturer from the U.S. market in 2002 following allegations that recipients developed chronic musculoskeletal complaints.
Antibiotic Prophylaxis
Several studies have examined the efficacy and cost-effectiveness of antibiotic prophylaxis after a tick bite. One report based on a decision analysis model recommended that if the risk of infection after the bite is >3.6% (33), antibiotic prophylaxis should be given for anyone known to have been bitten by a tick. This threshold risk of infection, however, is higher than that observed in field studies in well-recognized endemic areas. In two placebo-controlled trials, the risk of becoming infected in an endemic area was <1.5% and was no greater than the risk of developing side effects from the 14 days of antibiotic treatment (5,34). An additional randomized, double-blind, placebo-controlled trial was conducted using a single 200-mg dose of doxycycline as prophylaxis within 72 hours after a tick bite (35). In this study, EM at the site of the tick bite developed in 0.4% of the treated group, compared with 3.2% of the placebo group. Interestingly, EM occurred only in those bitten by nymphal ticks. Adverse effects, particularly nausea, developed in 30% of the treatment group and 11% of the placebo group. Based on these data, some authorities recommend prophylactic therapy for early Lyme disease with a single dose of doxycycline (200 mg) if an engorged nymphal tick, acquired in an area in which I. scapularis is endemic, is identified on a patient (36).
Rocky Mountain Spotted Fever
RMSF is the most lethal of tick-borne illnesses in the United States. Mortality rates of 1% to 5% occur despite appropriate treatment of RMSF, whereas more than 20% of untreated patients die. First described in early 20th-century Montana and Idaho, this infection is most commonly seen east of the Mississippi River, especially in the southeastern United States. RMSF is caused by an obligate intracellular bacterium, Rickettsia rickettsii, a member of a large group of worldwide zoonotic rickettsia causing spotted fevers. The common dog tick,Dermacentor variabilis, transmits most cases of RMSF in the eastern United States. Transmission requires at least 6 hours of attachment to the human host. In the far western states, Dermacentor andersoni, the Rocky Mountain wood tick, is the main reservoir. The common brown dog tick (Rhipicephalus sanguineus) has been recently described as a new tick vector in Arizona, portending expansion of the range of infection (37). Most cases of RMSF occur in the late spring or summer, although infections are reported during the winter mainly in southern states. Between 500 to 1,000 cases of RMSF were reported annually during the 1990s. Other rickettsial group members may be responsible for cases of spotted fever in parts of the United States. Rickettsial parkeri was recently identified as the cause of a febrile illness with eschar transmitted by either a Lone Star (Amblyomma americanum) or Gulf Coast (Amblyomma maculatum) tick (38).
Children and young adults are most commonly infected, probably because of increased outdoor exposure. Symptoms arise 2 to 14 days after the tick bite; the average incubation period is 7 days. Initial symptoms of fever, severe headache, myalgia, and arthralgia are often mistakenly dismissed as a summertime viral illness. Rash is the major diagnostic sign, but it tends to occur later, eventually appearing in 90% of infected patients 3 to 5 days after the initial onset of symptoms. The rash typically begins on the wrists and ankles as a maculopapular eruption and then spreads inward toward the trunk with evolving petechiae. Involvement of the palms and soles has been considered a standard presentation of RMSF, but it does not occur in some patients. So-called “spotless” RMSF occurs in up to 10% of infected patients, especially in darker-skinned populations, necessitating a high index of diagnostic suspicion.
Once introduced to lymphatics and small blood vessels after a tick bite, R. rickettsii tends to invade endothelial cells, leading to a vasculitic mechanism of injury (39). Myocarditis is a leading cause of death, although pneumonitis and coma (from central nervous system vasculitis) are also common. Lumbar punctures are frequently performed for the evaluation of headache and fever. The cerebrospinal fluid (CSF) is normal in most patients but shows lymphocytic or neutrophilic predominance in up to one third. Platelets are consumed at the many sites of
P.566
endovascular infection, often resulting in thrombocytopenia. Elevated transaminases are noted in about half of infected patients, although clinical jaundice is seen in fewer than 10%.
The prognosis in RMSF is mainly related to the timeliness of antibiotic administration. Waiting for a characteristic rash or laboratory confirmation of infection heightens the likelihood of death. The challenge, therefore, is to recognize clinical and epidemiologic features that prompt early diagnosis. The differential diagnosis of the manifestations of RMSF includes measles, rubella, respiratory tract infections, gastroenteritis, disseminated meningococcal and gonococcal disease, typhoid, syphilis, other rickettsial infections, autoimmune vasculitides, thrombotic thrombocytopenic purpura, and adverse drug reactions. Although there is no uniform patient profile, consideration of this diagnosis should be prompted by a warm-weather illness in a previously healthy patient with potential tick exposure who is ill with fever and possible rash. Definitive diagnosis can be made by culture of R. rickettsii from blood, although few laboratories are equipped for this specialized undertaking (40). Skin biopsy with application of rickettsia-specific immunohistochemical antibodies may offer early diagnosis. Serologic antibody testing serves to provide only retrospective diagnosis, because sufficient antibody titers develop only during convalescence. Early clinical diagnosis remains imperative for this life-threatening infection, and empiric therapy should not be withheld pending the results of diagnostic testing.
Standard therapy requires administration of doxycycline (100 mg twice daily) or chloramphenicol (50 to 75 mg/kg/day), usually for 7 days. Although tetracyclines are not usually given to children because of drug staining of dental enamel, it can probably be given safely to youngsters with suspected RMSF since a single course is unlikely to damage teeth (41).
Ehrlichioses
Only in the last 20 years has human infection by the genus Ehrlichia been known in the United States. Infection with this rickettsial agent tends to produce an illness very similar to RMSF but without rash. The Ixodidae family of ticks transmits these intracellular pathogens, usually during warm weather months. There are two different kinds of Ehrlichia infection, defined by whether these bacteria invade monocytes or granulocytes. A third type of ehrlichiosis, caused by the agent of canine ehrlichiosis, Ehrlichia ewingii, has also been described in humans (42).
Human Monocytic Ehrlichiosis
Human monocytic ehrlichiosis (HME), first described in 1986, is an infection by Ehrlichia chaffeensis that occurs most commonly in the southeastern and south-central portion of the United States, tracking the distribution of its main vector, the Lone Star tick (Amblyomma americanum).
Probably most patients with HME do not have symptoms or have only mild symptoms that are self-limited and do not seek medical advice. Of those patients seeking medical attention, the acuity of illness tends to be more severe. Up to 40% of these patients require hospitalization for fever, headache, rigors, myalgia, nausea, vomiting, and abdominal pain that manifest an average of 7 days after a tick bite (43). A maculopapular rash, sometimes with petechial features, occurs in up to one third of cases. Laboratory hallmarks of HME include leukopenia and thrombocytopenia, both observed in a majority of cases, and elevations in liver transaminases. Patients who are severely ill may be admitted to the intensive care unit with an evolving picture of multiorgan system failure. Death occurs in 3% of patients, especially among immunosuppressed patients.
Diagnosis may be rapidly accomplished by demonstrating characteristic morulae (mulberry-like clusters of bacteria) within monocytes or lymphocytes on examination of a peripheral blood smear. However, only about 7% of patients with HME have observable morulae. Some laboratories offer PCR detection of the organisms in blood, and this may be the most sensitive test (44). Paired acute/convalescent serologies can confirm diagnosis retrospectively. However, as with RMSF, clinical suspicion of ehrlichial infection is necessary, because delayed treatment increases the likelihood of severe infection or death.
Doxycycline (100 mg twice daily) is the treatment of choice, with mild symptoms often resolving within 24 to 48 hours after initiation (45). Optimal duration of therapy is uncertain, but current recommendations suggest treatment for at least 3 days after cessation of fever and clinical improvement, for a minimum course of 5 to 7 days. Severe illness can take weeks for resolution despite appropriate therapy.
Human Granulocytic Anaplasmosis
First described in 1994, this infection of granulocytes, previously known as human granulocytic ehrlichiosis, is more properly termed human granulocytic anaplasmosis (HGA). It is caused by an agent closely related to Ehrlichia now designated Anaplasma phagocytophilum. This bacterium is transmitted mostly by Ixodes persulcatus–complex ticks, and therefore has the same distribution as Lyme disease. Much like HME, HGA probably produces subclinical disease in many cases, because populations in areas of the United States such as Wisconsin have seroprevalence rates up to 15%. HGA is more common than HME, with cases seen mostly in adult males older than 60 years of age (46).
Symptoms are similar to those of HME with the exception that rash is even less prevalent, affecting less than 10%
P.567
of patients (47). Leukopenia, thrombocytopenia, and liver function abnormalities are common, although neutropenia specifically distinguishes HGE from HME (48). Severe illness can occur, including death. Morulae are identified much more commonly than in HME, with characteristic clusters identified within granulocytes in 20% to 80% of patients (49). Empiric therapy with doxycycline remains critical, because timely diagnosis cannot be achieved with available serologies, and PCR testing of blood is not widely available. The treatment regimen is identical to that for HME (see Monocytic Ehrlichiosis section).
Southern Tick-Associated Rash Illness
EM-like rashes have been described after bites of the Lone Star tick (A. americanum), which is not known to carry B. burgdorferi, the agent of Lyme disease (50). This rash has been described primarily in southern states such as Missouri and the Carolinas. A new member of theBorrelia species, Borrelia lonestari, has been identified by PCR genetic analysis as the cause of Southern tick-associated rash illness in one patient (51), but it has not been identified in a larger cohort of patients with Southern tick-associated rash illness (52). A recent study suggested that Southern tick-associated rash illness patients in Missouri were more likely to have a single EM-style lesion, and more commonly recollect a tick bite compared to patients with Lyme EM from New York (52). Southern tick-associated rash illness appears to respond to doxycycline, and to date no chronic sequelae have been identified.
Babesiosis
Babesiosis, a protozoal tick-borne infection, occurs in a similar distribution to Lyme disease because its primary vector is I. scapularis. New England and mid-Atlantic regions report most cases, especially coastal regions such as Cape Cod, Nantucket, Martha's Vineyard, Block Island, and Long Island. Once thought to be rare, this infection may be increasingly common in some parts of New England (53). Babesia, a one-celled parasite, infects a wide range of animals, but the rodent strain Babesia microti accounts for most human cases in the United States. Two strains, WA1 and MO1, have been isolated from ill patients residing in the states of Washington, California, and Missouri (54,55, 56).
Illness typically begins 1 to 6 weeks after a tick bite with malaise, fever, headache, myalgia, and loss of appetite. Babesia invades erythrocytes and may cause a malaria-like illness with rigors, high fevers to 101.3°F (40°C), hepatosplenomegaly, hemolytic anemia, and pancytopenia (57). Illness may progress to include the adult respiratory distress syndrome. Persons infected with Babesia tend to be older than 50 years of age with intact spleens, but individuals at greatest risk of severe disease include immunocompromised patients and those of any age who have undergone splenectomy. Chronic infection with Babesia and recrudescence of symptoms after acute infection may occur, although the exact clinical significance of this condition is unknown (58).
Diagnosis is established by examination of a peripheral blood smear and the observation of small, oval-ring forms of the parasite in 1% to 10% of erythrocytes (Fig. 38.3). This sometimes causes confusion with ring forms of falciparum malaria. Rarely, characteristic tetrad formations of Babesia organisms (resembling a Maltese cross) in red blood cells easily permit confirmation. Increased antibody titers to B. microti (greater than 1:256) are considered diagnostic of infection, but the WA1 strain cannot be identified by standard Babesia serology and requires specific antibody testing. Serology rarely offers the timely diagnosis needed for patients severely ill from Babesia, but these patients usually have easily recognized levels of parasitemia on blood smear. PCR, not widely available, may ultimately
P.568
prove to be the fastest and most reliable method for diagnosis, as with many of the tick-borne disorders. Clinical suspicion of this infection remains essential based on epidemiologic risks and presenting symptoms.
|
FIGURE 38.3. Human erythrocytes infected with Babesia microti. Cells display both the more commonly observed ring forms (large arrow) with pale central area, occasionally mistaken for malaria parasites, and the rare, pathognomonic tetrad form (small arrow). (Photograph courtesy of Steve Dumler, MD) |
Many patients infected with Babesia recover without treatment. Splenectomized patients seem to be at greatest risk of life-threatening illness with high levels of parasitemia, but severe infection may also afflict those individuals who were previously healthy. Treatment traditionally has incorporated a combination of oral clindamycin (600 mg) and quinine (650 mg) every 8 hours for 7 or more days. One nonblinded trial suggested that use of both atovaquone (750 mg every 12 hours) and azithromycin (500 mg on day 1 and then 250 mg daily) for 7 days offers equal efficacy with fewer side effects (59). Patients with severe illness and profound anemia may benefit from exchange transfusion.
Relapsing Fever
Relapsing fever is an arthropod-borne spirochetal disease that is caused by at least 13 different species of Borrelia that occur in a worldwide distribution. Historically, Borrelia recurrentis has achieved greatest notoriety through louse-borne person-to-person transmission causing vast epidemics of relapsing fever in poor socioeconomic settings. Tick-borne infections in North America are transmitted by hard ticks, except endemic relapsing fever (e.g., B. hermsii and B. duttonii), which is transmitted by the soft tick genus Ornithodoros. These soft ticks are found mainly in arid, mountainous regions such as the southwestern United States but also extend to northwestern and midwestern states (60). Since soft ticks bite nocturnally without attachment, the risk of acquiring relapsing fever is especially high in individuals sleeping in primitive dwellings or natural sites infested with ticks or rodents (61).
Symptoms of relapsing fever tend to include high fever with shaking chills, headache, myalgia, arthralgia, photophobia, and lethargy. Hepatosplenomegaly, lymphadenopathy, petechial rash, neurologic abnormalities (such as facial palsy, myelitis, or radiculopathy) are present in only a minority of infected patients (62). As the name suggests, episodes of symptoms and fever alternate with an afebrile phase for 1 week or longer before returning—usually with symptoms milder than those of the initial phase. The return of fever correlates with the presence of spirochetes in the blood. Most patients have two to four relapses.
Examination of the peripheral blood either by Giemsa- or Wright-stained thick and thin smears or by dark field microscopy reveals spirochetes in up to 70% of infections, although the blood rarely contains Borrelia during afebrile periods. Repeated examination of blood smears may be necessary. Lyme serology tests may be falsely positive. Patients with neurologic disease may have abnormal cerebral spinal fluid.
For endemic relapsing fever, doxycycline (200 mg first dose, followed by 100 mg twice daily) is the preferred treatment for 5 to 10 days, with erythromycin (500 mg four times a day) an alternative choice (63). Neurologic disease is treated with parenteral antibiotics such as ceftriaxone (2 g intravenously every day) or penicillin G (4 mU intravenously every 4 hours) for 14 or more days. Epidemic relapsing fever, which can respond to a single (500 mg) dose of tetracycline, can have a mortality rate of up to 40%, but endemic tick-borne disease is much milder, although death can occur. Jarisch–Herxheimer reactions have been described after initial antimicrobial therapy for relapsing fever. Because this reaction can be life-threatening, observation is urged for the first 2 hours after the start of therapy.
Tularemia
This infection by the gram-negative bacterium, Francisella tularensis, causes illness in many guises but typically involves suppurative lymph nodes with skin, eye, lung, or throat involvement. The dog tick (D. variabilis) and the Lone Star tick (A. americanum) transmit most cases in the United States, although biting flies predominate as vectors in the western states. The disease may also come from physical contact with infected animals, primarily rabbits but also includes birds, beavers, squirrels, and muskrats—making hunters a group at particular risk. Reports also have traced exposure to pet hamsters and prairie dogs (64,65). Despite the breadth of opportunities to acquire F. tularensis, this mostly rural infection has become increasingly rare since World War II for uncertain reasons. Incidence rates are now less than 0.08 per 100,000 population. In recent years, Arkansas, Missouri, Oklahoma and South Dakota have reported the largest number of cases (66). Diagnosis is more common in the summer because of tick activity, but may occur year-round.
The most common form of tularemia is ulceroglandular, accounting for 70% to 80% of reported cases (67). In this presentation, the skin tends to ulcerate and form an eschar. Regional lymph nodes that drain the ulcer may enlarge with suppuration. Other classic forms of tularemia include oculoglandular, glandular, pneumonic, oropharyngeal, and typhoidal (infection without signs of localization). Fever, chills, headache, and back pain are common with all forms. Diagnoses of pneumonic tularemia should prompt consideration of bioterrorism with notification of public health authorities, although a recent outbreak in Martha's Vineyard was traced to aerosolization of rabbit carcasses by lawn mowing (68).
Because of its rarity, tularemia often is not suspected, especially in its more unfamiliar forms. Cultures of blood, lymph nodes, sputum, or wounds may yield F. tularensis on
P.569
supportive media. A clinician suspecting tularemia should alert the microbiology laboratory, because the organism, once grown, requires careful handling to prevent infection of laboratory personnel. Serologic testing for F. tularensis may also offer diagnostic help by demonstrating a fourfold rise in acute-to-convalescent titer, or if an acute titer higher than 1:160 is demonstrated. Streptomycin (7.5 to 10.0 mg/kg intramuscularly every 12 hours for 7 to 14 days; alternatively, 15 mg/kg intramuscularly every 12 hours for the first 3 days followed by half-dose therapy for the balance of therapy; and in the severely ill, 15 mg/kg dosing continued throughout) or gentamicin (5 mg/kg/day intravenously for 7 to 14 days) is the standard therapy. Treatment with doxycycline may result in unacceptably high rates of relapse.
Tick-Borne Viral Infections
Colorado tick fever is caused by the bite of the wood tick Dermacentor andersoni transmitting a Coltivirus. This summertime illness is most frequently diagnosed in the Rocky Mountains and Pacific Coast regions. Perhaps fewer than 50% of individuals experience symptoms within 2 weeks after a bite by an infected tick. In symptomatic patients, a remitting fever (2-day febrile periods with a 2-day afebrile interval) that lasts for 2 weeks is common along with severe myalgia and headache. About 20% of patients describe abdominal complaints. Leukopenia is frequently observed, but complicated illness is rare. This viral infection is self-limited, usually necessitating only supportive care although ribavirin has been proposed as therapy in severe cases (69). Colorado tick fever is often confused with RMSF, ehrlichiosis, or relapsing fever, so prescription of doxycycline empirically is advised until the diagnosis is established. The diagnosis of Colorado tick fever may be confirmed by viral culture or viral antigen detection assays, although PCR testing may offer the earliest diagnosis.
Tick-borne encephalitis is rare in the United States but much more common in Eurasia (70). Cases in the United States are caused by the Powassan virus, a member of the flavivirus family, transmitted by Ixodes ticks. Fever and headache are a frequent prodrome before evolution into encephalitic symptoms. Only supportive care is available, and chronic neurologic sequelae are common. A commercial vaccine to prevent tick-borne encephalitis is offered frequently to hikers and campers in Eastern Europe and Asia, but no recommendations exist for the United States. Only five cases have been described in this country, including four cases in Vermont and Maine (71).
Avoiding Tick-Borne Illness
Despite the availability of effective antibiotics and vaccines, the best preventive measure to avoid tick-borne illnesses remains patient education about methods to limit exposure to ticks. Long pants tucked into socks should be worn when walking in woods or high grasses. Tick repellants containing 20% to 30% N,N-diethyl-m-toluamide (DEET) decrease the risk of tick bites when applied to the skin and clothing. Permethrin is another type of repellent that may be applied to pants, socks, and shoes and typically stays effective through several washings. Permethrin should not be applied directly to skin. In addition, individuals should carefully inspect their skin after outdoor activities to allow for rapid detection and removal of ticks. Attached ticks should be removed by gently pulling them upwards using a fine set of tweezers.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
P.570