Tickborne Illnesses, with Emphasis on Lyme Disease
August 23, 1999
Tickborne Illnesses, with Emphasis on Lyme Disease
Author: Michael W. Felz, MD, Associate Professor, Department of Family Medicine, Medical College of Georgia, Augusta, GA.
Peer Reviewers: Lance A. Durden, PhD, Associate Professor and Associate Curator, U.S. National Tick Collection, Statesboro, GA; and Leonard Sigal, MD, Professor and Chief, Division of Rheumatology, Departments of Medicine and Pediatrics, UMDNJ—Robert Wood Johnson Medical School, New Brunswick, NJ.
Editor’s Note—Ticks! How alarming to patients and challenging to professionals. Tick-bite victims often insist on immediate evaluation by their physicians for advice about tick removal, symptoms to watch for, probability of each infectious syndrome, and prevention of further bites. Many clinicians, however, find themselves unable to respond with precision or confidence due to lack of concise, inclusive, published data on tickborne illnesses. In fact, the public is often influenced more by speculation or hearsay than by scientific information about ticks and the diseases they transmit. To complicate matters, new tickborne illnesses have emerged in certain regions of the United States in the past decade without timely physician education materials to keep pace with rapidly evolving clinical and laboratory diagnostic strategies. Furthermore, each tickborne disease has a different presentation, severity, pathogenesis, laboratory evaluation, and management.
How can a busy primary care physician ever handle tick bites, much less ill tick-bite victims, with up-to-date expertise? This review merges extensive firsthand clinical and research experience with published data on seven illnesses commonly occurring across the United States and the pathogens transmitted by hard shell (Ixodid) ticks. Lyme disease is selectively emphasized due to intense public concern, broad distribution of reported cases, and recent recommendations for diagnosis, treatment, and preventive vaccination. This focused summary of all seven syndromes can serve as a readily available "field guide" for practicing clinicians in need of current, concise, and consistent information on tickborne disease as seen in everyday practice. And for patients and professionals alike, such an easily consulted guide can provide an added benefit—reassurance.
Introduction
Tick bites are distressing occurrences for adults and children venturing into wooded areas for vocational or recreational endeavors. Due to the frequency of outdoor activity among most Americans, exposure to ticks and the pathogens they carry is increasingly common in all but the most scrupulous of circumstances. Yet, busy physicians are often unprepared to manage tick bites and related illnesses. Most clinicians have limited understanding of the nature of tickborne disease unique to certain species or to the particular geographic regions in which they practice. Furthermore, public concern is intense in many areas due to reports of adverse outcomes of patients with unrecognized or mismanaged tick-associated syndromes. To add to the widespread confusion already prevalent in professional and public circles, new tickborne syndromes have emerged in recent years, necessitating even more laboratory confirmation, physician updating, and epidemiologic analysis.1
Practitioners must be prepared to evaluate seven different tickborne illnesses occurring in the United States. Each requires precise diagnosis and treatment in office practice. All pathogens are transmitted by bites of Ixodid (hard shell) ticks, parasites with obligatory requirements for blood meals. Ixodid tick species collectively display strong host preference for a variety of mammals, birds, reptiles, and amphibians. When humans intrude into tick habitats for work or play, tick chemoreceptors, located on the forelegs, detect carbon dioxide released from human skin. Chemoreceptor-triggered feeding behaviors stimulate ticks to crawl onto and parasitize humans as an alternative host. The barbed hypostome ("harpoon") is inserted into host integument for pharyngeal ingestion of blood and body fluids. Cementum secreted by mouthparts helps anchor the tick to the feeding site. Salivary exchange during the first few days of feeding fosters transmission of tickborne pathogens into the host. Longer duration of attachment, especially exceeding 48 hours, predicts greater likelihood of disease transmission. Most Ixodid species feed for 5-7 days or longer to full engorgement, then detach to molt (larvae, nymphs), lay eggs (adult females), or die (adult males).
The seven tickborne illnesses most likely to confront patients and their physicians in the United States are Lyme disease, Rocky Mountain spotted fever, Ehrlichiosis, Babesiosis, Tularemia, Colorado tick fever, and tick paralysis. Each syndrome presents with distinct clinical, laboratory, and geographic features. Management is far from simplistic. Each illness demands careful diagnostic reasoning, depending upon host susceptibilities and virulence factors of specific pathogens involved. Due to rapid and widespread airline travel to and from endemic areas, tick-bite victims may be encountered in any medical facility in the nation. Ill patients may present at the conclusion of the incubation period with symptomatic disease acquired in tick habitats hundreds of miles away. Hence, medical professionals in a broad variety of specialties and geographic locations must be current in their understanding of each of these seven potentially serious illnesses.
Lyme Disease
Occurring in 48 of 50 states, but endemic in far fewer, Lyme disease (LD) is the most frequent tickborne illness reported today. (See Table 1.) Up to 16,000 cases have been recorded annually in recent years by the CDC.2 Public awareness is heightened by extensive media exposure and support group activity. True illness occurs most commonly in three geographic regions: northeastern states, upper Midwest, and western states. The pathogen, Borrelia burgdorferi, is a spirochetal organism transmitted by the bites of infected Ixodes scapularis (northeast, upper Midwest U.S.) or I. pacificus (western U.S.) ticks. The illness develops in three stages, each with distinct manifestations and incubation periods.3
| Table 1. Features of Lyme Disease |
| Etiology |
| • Borrelia burgdorferi, a flagellated spirochete |
| Vectors |
| • Ixodes scapularis (eastern and midwestern U.S.); |
| I. pacificus (western U.S.) |
| Distribution |
| • 48 of 50 states; mainly in northeast, upper Midwest, and western United States |
| Incubation period |
| • Early LD: 7 days (range, 1-31); Disseminated LD: 1-4 months; |
| Late LD: 4 months-years |
| Symptoms and signs |
| • Early LD—Erythema migrans and virus-like illness |
| • Disseminated LD—Recurrent arthritis; aseptic meningitis; cranial neuropathy; radiculopathy; carditis, usually with conduction block |
| • Late LD—Chronic arthritis; encephalopathy |
| Diagnosis |
| • Serology—Two-step methodology (ELISA and Western immunoblot) for anti-B. burgdorferi IgM and/or IgG |
| • Biopsy, special histology, culture, or PCR of EM lesions |
| • CSF evidence of intrathecal synthesis of anti-B. burgdorferi IgG |
| Treatment |
| • Doxycycline 100 mg bid or amoxicillin 500 mg tid, each × 2 days or longer |
| • In seventh nerve palsy with abnormal CSF, IV ceftriaxone 2 g/d or cefotaxime 3 g bid × 14 days recommended |
| • For late LD with arthritis, oral therapy required for 4-6 weeks |
| • For late LD with refractory arthritis or CNS involvement, IV ceftriaxone 2 g/d or cefotaxime 3 g bid × 4 weeks is required |
Early localized LD occurs 1-31 days following tick bite and is characterized by the presence of erythema migrans (EM), a progressively expanding red ring or patch at the bite site, exceeding 5 cm in diameter and persisting over seven days.4 Biopsies of EM lesions reveal B. burgdorferi migrating peripherally in the upper dermis, correlating with lesion expansion. A small percentage of patients with EM also experience a viral-like syndrome for 3-5 days, with fever, myalgia, headache, and malaise, probably from immunologic responses to spirochetal multiplication. Coryza, cough, and gastrointestinal symptoms are absent, in contrast to upper respiratory and enteric viral infections. It is noteworthy that EM is a dermal process not affecting epidermal structure. Scaling rashes, therefore, are more suggestive of non-LD erythematous entities such as tinea corporis or contact dermatitis. Isolation of B. burgdorferi in cultures of skin biopsies from EM is confirmatory of LD infection but is not widely practiced or available. Polymerase chain reaction (PCR) assays have been used to demonstrate B. burgdorferi DNA in tissue sections from EM lesions as well, but such assays remain experimental. Serologic testing by enzyme-linked immunosorbent assay (ELISA) techniques is the most widely accepted laboratory modality and may reveal IgM against B. burgdorferi in the first 3-6 weeks after infection and/or IgG within 1-3 months. Serology, however, is much less sensitive during early stage illness when EM is present than in later stages of disease. Clinical recognition of EM, then, remains the cornerstone of early LD diagnosis.
Disseminated LD arises 1-4 months after the bite of infected I. scapularis or I. pacificus ticks and can affect several organ systems, due to hematogenous spread of spirochetes. Multiple EM lesions may appear in distributions remote from tick-bite sites but without the expanding borders typifying EM of early stage disease. Relapsing and remitting arthritis of large joints, most commonly knees, leads to sizable effusions that abate gradually, usually in days to weeks. Patients typically complain more of joint stiffness than of pain and are not significantly disabled. Neurologic evidence of disseminated infection includes peripheral seventh nerve (facial) palsy, aseptic meningitis, or painful cervical or lumbar radiculopathy. Involvement of cardiac tissues may lead to high-grade atrioventricular conduction block with syncope; mild cardiomyopathy may also be present. Since each of the above manifestations has a broad differential diagnosis in office practice, clinicians are wise to inquire about a preceding tick bite or EM lesion previously noted by the patient. Historical recall of a bite or expanding erythema strengthens the likelihood of B. burgdorferi as the etiology of the multiple presentations of disseminated LD. Fortunately, serologic confirmation of B. burgdorferi infection during the disseminated stage is practical and widely available by a two-step methodology recommended by the CDC.5 Step 1 involves ELISA testing for anti-B. burgdorferi IgM or IgG antibodies. If ELISA is positive or equivocal, confirmation of true infection is possible by Step 2, Western immunoblotting (Wb). In patients with true LD, serum analyzed by Wb reveals specific IgM or IgG antibody patterns corresponding to the known molecular weight bands of structural antigens in B. burgdorferi. Negative ELISA and/or Wb serologic testing in patients with clinical syndromes resembling disseminated LD is strong evidence that LD is not present and that other diagnoses must be entertained. A positive ELISA followed by a negative Wb represents a false-positive ELISA, not a diagnosis of LD. Isolation of B. burgdorferi is absolute confirmation of LD. Spirochetes have been cultured from blood, synovial fluid, and cerebrospinal fluid (CSF) in patients with disseminated manifestations of LD. Intrathecal synthesis of anti-B. burgdorferi IgG in CSF is confirmatory of central nervous system (CNS) invasion by the spirochete.
Late LD refers to symptoms and signs arising several months to years after infection with B. burgdorferi. Chronic arthritis of large joints, particularly the knees, occasionally leads to articular erosions. Encephalopathic findings, such as memory loss, confusion, fatigue, and impaired performance on objective neuropsychiatric testing, are the key neurologic manifestations of late LD in the United States. Whether these synovial and CNS disorders represent irreversible prior damage or autoimmune response to antecedent infection is uncertain. Both joint and neurologic manifestations typically respond well to antibiotic therapy, although objective CNS disease may require up to 1-2 years for full resolution. Serologic confirmation by two-step testing procedures is strongly positive in high titers in most patients. Negative LD serology in the presence of symptoms of late LD is once again persuasive evidence for lack of B. burgdorferi as the etiology of the patient’s complaints.
Treatment of LD involves published antibiotic regimens and is determined by stage of illness at time of diagnosis.6 For early LD, regimens including doxycycline 100 mg po bid for 21 days, or amoxicillin 500 mg po tid for 21 days, are preferred. Either regimen usually leads to rapid resolution of EM lesions and virus-like symptoms. Disseminated LD requires longer duration of treatment, as with doxycycline 100 mg po bid for four weeks, or amoxicillin 500 mg tid for four weeks, in cases involving arthritis, cardiac, and most neurologic manifestations. However, in aseptic meningitis or seventh nerve (facial) palsy with positive LD serology, clinicians are prudent to evaluate CSF for the presence of intrathecal IgG synthesis against B. burgdorferi. Abnormal CSF in disseminated LD indicates the need for intravenous, not oral, therapy. The preferred regimens include ceftriaxone 2 g daily or cefotaxime 3 g bid, intravenously for 14 days. Recovery is usually prompt but may be gradual in disseminated LD. For the arthritis of late LD, initial therapy with oral doxycycline or amoxicillin for 4-6 weeks is usually effective. For arthritis refractory to oral regimens, intravenous ceftriaxone or cefotaxime can be used for four weeks. Late LD with CNS involvement is not likely to respond to oral therapy and should be treated with intravenous ceftriaxone or cefotaxime for four weeks. Whatever the antibiotic regimen, slow or subtotal recovery is often the rule in late LD. Clinicians should be cognizant of the fact that positive LD serology may persist for several years after successful eradication of spirochetal infection and should not be interpreted as treatment failure.
Prevention of LD involves precautions against tick bites in wooded areas and prompt removal of embedded ticks (see Prevention of Tickborne Illness, p. 152). In recent years, exciting breakthroughs in immunologic research have led to the development of effective vaccines for protection against EM due to LD. In one large study of 10,936 adult patients in endemic areas, a three-dose regimen of outer surface protein A vaccine (30 mcg/dose) at 0, 1, and 12 months conferred 76% reduction in the occurrence of EM after two years of follow-up,7 while another study involving 10,305 adults demonstrated 92% vaccine efficacy in prevention of EM.8 While these results are encouraging, current LD vaccines have been tested only in northeastern and upper Midwest states and may not be as effective in other regions, such as the lower Midwest and southeastern states, where EM may be due to antigenically variant strains of B. burgdorferi (Felz M, et al. Arch Derm. In press).
Controversy prevails as to how to manage patients with subjective complaints occasionally resembling known manifestations of various stages of LD, but in whom objective testing of serum, CSF, and neuropsychiatric parameters is normal.9 Such patients have often consulted numerous physicians and received a "laundry list" of diagnoses, none of which is satisfying or responsive to treatment.10 Eventually, physicians may be tempted to attribute symptoms to "possible LD" and embark upon prolonged and fruitless antibiotic treatment regimens that are expensive, exhaustive, and risky. Many of these patients, on evaluation by experts, actually have fibromyalgia. In such cases, the value of negative serology cannot be overestimated, since the immunobiology of B. burgdorferi infection predicts that longstanding symptoms of LD will almost invariably be accompanied by a measurable, antigen-specific immunologic response.11 Hence, the absence of anti-B. burgdorferi IgG in the serum of patients with suspected late LD symptoms allows clinicians to confidently pursue non-LD etiologies for the chronic complaints and avoid lengthy antibiotics for patients with no objective evidence for LD.
Other controversial LD issues include: 1) the exact etiology of EM lesions in areas where confirmation of B. burgdorferi infection by culture and laboratory testing is frequently negative; alternative Borrelia species are suspected; 2) prophylactic treatment of all tick-bite victims with doxycycline or amoxicillin prior to symptoms or confirmation of any tickborne illness; thus far, data indicate that risks of side effects of antibiotics outweigh potential benefits of therapy; 3) proper selection of serologic testing procedures; studies demonstrate much interlaboratory variation in results from identical serum samples and uncertainty as to which ELISA methodology or office kit is optimal for confirmation of LD diagnosis in all regions of the United States.
Rocky Mountain Spotted Fever
The second most frequently reported tickborne illness in the United States is Rocky Mountain spotted fever (RMSF) (see Table 2). Since most of the approximately 300-600 cases reported annually occur in the southern and southeastern United States and along the eastern seaboard, exceeding cases occurring in the Rocky Mountain states, the syndrome is a modern geographic misnomer. The pathogen is Rickettsia rickettsii, a small gram-negative coccobacillus transmitted by bites of infected Dermacentor variabilis, or D. andersoni, ticks in the eastern and western United States, respectively. Following an incubation period of seven days (range, 2-14 days), patients experience progressively worsening fever, headache, photophobia, myalgias, and malaise for 3-7 days, followed on days 5-7 by a petechial rash on the ankles and wrists.12 Petechiae constitute a key diagnostic sign and are reflective of endothelial invasion by rickettsial organisms with resultant widespread vascular microthrombi—a cascade heralding worsening morbidity and mortality if treatment is delayed. Undiagnosed cases may deteriorate into high fever, severe abdominal pain, acute respiratory distress syndrome (ARDS), rhabdomyolysis, acute tubular necrosis (ATN), confusion, seizures, coma, fulminant prostration, and death on days 7-10. Mortality rates vary from 2-20%, depending upon timing of diagnosis and age of patient. Diagnosis is clinical, and a high index of suspicion for RMSF is essential in endemic areas.13 For clinicians evaluating an ill tick-bite victim with fever and centripetal petechial rash, a compatible clinical picture is sufficient enough to start empiric antibiotic therapy for RMSF. Serologic confirmation may be obtained by demonstration of anti-R. rickettsii IgM detectable two weeks following infection and/or IgG thereafter. Early treatment is crucial and must not be delayed while awaiting serology results. Biopsy of petechial lesions reveals obliterative endarteritis with thrombi and vessel rupture, with intraendothelial R. rickettsii seen on special histologic stains. Culture is not practical except in certain research centers. Hyponatremia, thrombocytopenia, normal WBC, and normal CSF are supportive of the diagnosis of RMSF but by no means specific.
| Table 2. Features of Rocky Mountain Spotted Fever |
| Etiology |
| • Rickettsia rickettsii, a rickettsial bacterium |
| Vectors |
| • Dermacentor variabilis (eastern U.S.); D. andersoni (western U.S.) |
| Geography |
| • Eastern, southern, and western United States |
| Incubation period |
| • Seven days (range, 2-14 days) |
| Symptoms and signs |
| • Fever, headache, myalgias, photophobia, severe malaise; centripetal petechiae on days 5-7; ARDS, rhabdomyolysis, ATN, prostration, confusion, coma, death (severe cases) |
| Diagnosis |
| • Endarteritis on biopsy of petechial lesions |
| • Serology—Anti-R. rickettsii IgM or IgG |
| • Hyponatremia and thrombocytopenia are suggestive of RMSF |
| Treatment |
| • Doxycycline 100 mg bid, or chloramphenicol 50 mg/kg/d, for 5-7 days |
Treatment of RMSF is best initiated with doxycycline 100 mg po or IV bid for 5-7 days. Dramatic clinical improvement within hours to days is highly supportive of the diagnosis of RMSF, and confirmatory serology will follow 2-4 weeks later. Chloramphenicol (50 mg/kg/d) is an older, alternative therapeutic agent but offers no advantage over doxycycline and may confer hematologic risk. Prognosis for recovery in RMSF is good for patients diagnosed and treated within the first 5-7 days of illness. Appearance of petechiae, while helpful in differential diagnosis, is indicative of more advanced disease and may result in slower recovery or intercurrent complications, such as mental status changes or ARDS, despite appropriate antibiotic regimens.
Prevention of RMSF involves avoidance of D. variabilis (eastern U.S.) and D. andersoni (western U.S.) tick bites by repellents or barrier methods. Prompt removal of embedded ticks discovered on careful body search after outdoor exposure is also prudent. No vaccine is available nor are prophylactic antibiotics advocated.
Ehrlichiosis
This recently described tickborne syndrome involves two separate illnesses differing in geographic distribution, hematologic and serologic findings, and tick vector species (see Table 3).
| Table 3. Features of Ehrlichiosis |
| Etiology |
| • Ehrlichia chaffeensis (Human Monocytic Ehrlichiosis/HME); E. phagocytophila/E. equi (Human Granulocytic Ehrlichiosis/HGE), rickettsial-like bacteria |
| Vectors |
| • Amblyomma americanum (HME); Ixodes scapularis (eastern and upper Midwest U.S.) and I. pacificus (northwestern U.S.) (HGE) |
| Distribution |
| • Southeastern and southern U.S. (HME); northeastern, upper Midwest, northwestern U.S. (HGE) |
| Incubation period |
| • Seven days (range, 1-30) |
| Symptoms and signs |
| • Fever, headache, myalgias, abdominal pain; rash uncommon, and not petechial; rhabdomyolysis, multiorgan failure, and severe prostation in extreme cases |
| Diagnosis |
| • Serology—Anti-E. chaffeensis IgM or IgG (HME); anti-E. phagocytophila/E. equi IgM or IgG (HGE) |
| • Morulae on peripheral smear inside monocytes (HME) or granulocytes (HGE) |
| • Leukopenia, thrombocytopenia, and elevated AST and CPK are suggestive of ehrlichiosis |
| Treatment |
| • Doxycycline 100 mg bid × 7-14 days |
| • Co-infection with B. burgdorferi and/or Babesia microti may occur and necessitate simultaneous treatment of ehrlichiosis, Lyme disease, and babesiosis |
Human monocytic ehrlichiosis (HME) was first described in 1987 in a seriously ill tick-bite victim from Fort Chaffee, Ark.14 Rickettsial-like organisms in clusters ("morulae") were visualized in monocytes in the patient’s peripheral blood smear and designated Ehrlichia chaffeensis based on serologic reactivity. Since then, cases have been clinically and serologically diagnosed in at least 21 states, predominantly in the south central and southeastern U.S. regions. The most frequently associated tick vector species is Amblyomma americanum, also known as the lone star tick, for the prominent white pigment patch (star) on the back of the adult female. In contrast, human granulocytic ehrlichiosis (HGE), was first reported in 1994 in 12 patients in Wisconsin and Minnesota15 with a febrile illness similar to HME. Two patients, both age 80, died despite aggressive management. Ehrlichia-like inclusions (morulae) were noted in the cytoplasm of granulocytes in peripheral smears of all patients. Serologic analysis revealed antibody titers reactive to E. phagocytophila and/or E. equi, organisms recognized previously as pathogens of veterinary importance in cattle and horses, respectively. Cases of HGE have subsequently been more widely reported in expanding regions of the United States. The tick vector most closely linked to HGE cases is Ixodes scapularis (northeast, upper Midwest states) or I. pacificus (western states), just as in LD. In both HME and HGE, clinical manifestations are similar and may differ only in severity of illness.16 Patients usually present after an incubation period of seven days (range, 1-30 days) with progressively worsening fever, chills, headache, myalgias, and malaise, reminiscent of RMSF. Most are diagnosed initially as bacterial sepsis syndromes and treated with broad-spectrum antibiotics. Unlike RMSF illness, however, rash is not a defining feature and centripetal petechiae are absent. Only 30% of cases may develop a transient erythematous macular rash on the trunk. Thus, clinicians may be reminded to consider ehrlichiosis as "Rocky Mountain spotless fever" in febrile tick-bite victims lacking petechiae. Diagnosis is clinical, based on the sentinel manifestations described above, and treatment must be initiated early, as in RMSF. Morulae may be visualized in buffy coat preparations of monocytes (HME) or granulocytes (HGE), but prolonged search by trained observers is required. Serologic confirmation is more practical and relies on detection of antibodies to E. chaffeensis (HME cases) or E. phagocytophila/E. equi antibodies (HGE cases), in convalescent sera. Supportive laboratory data include leukopenia, thrombocytopenia, and elevation in AST and CPK values. Complications of severe or untreated infection include ARDS, ATN, severe abdominal pain, multiorgan dysfunction, and death.
Treatment of ehrlichiosis can be lifesaving, as with RMSF, and is best initiated with doxycycline 100 mg po or IV bid for 7-14 days until symptom resolution is complete. Chloramphenicol is ineffective. Prognosis for recovery is good with early onset of therapy, but unpredictable severity and progression of illness underscores the necessity for prompt diagnosis and treatment. Fortunately, serosurvey data suggest that ehrlichial infections are often mild or subclinical illnesses. As with RMSF, a rapid antigen detection assay would be most helpful to clinicians for earlier diagnosis. Prevention is possible by avoidance of tick bites and forest habitats. Research is under way for improved methodologies for detection of these two emerging ehrlichial syndromes. Enhanced antibiotic regimens, like diagnostic advances, await better characterization of the vectors and rickettsial-like pathogens responsible for HME and HGE. In fact, recent literature suggests that a third ehrlichial pathogen, E. ewingii, possesses unique DNA sequences and may be causing human illness in Missouri.17 Further investigation will be necessary to clarify the clinical significance of this report.
Babesiosis
Yet another recently described tickborne illness is confronting physicians in the United States. Since 1989, small clusters of babesiosis cases have been clinically described and serologically confirmed in a number of regions, from the northeastern states, to the upper Midwest, and lately in the northwestern United States (see Table 4). The pathogen, Babesia microti, is an erythrocytic protozoan, microscopically similar to Plasmodium parasites responsible for malaria in equatorial zones. Illness is related to bites of infected I. scapularis (Northeast, Midwest) and I. pacificus (northwest) ticks, the identical vectors involved in LD transmission. White-footed mice in forested habitats appear to be reservoirs for Babesia. Following an incubation period of 1-3 weeks, symptoms in humans are usually mild and nonspecific, resembling viral syndromes.18 Fever, malaise, myalgias, headache, and fatigue are common early manifestations and may be self-limited and trivial. Yet in certain patients, especially those older than 50 years of age, illness is much more severe, with shaking chills, prolonged high fever, myalgias and arthralgias, ARDS, splenomegaly, and hemolytic anemia described in small case series. Splenectomized or immunocompromised patients are at greater risk for severe disease as well. The distinctive feature of B. microti infection in febrile humans is the presence of hemolysis, as detected by schistocytes on peripheral smear, elevated bilirubin and reticulocyte counts, positive Coomb’s test, or depressed haptoglobin levels. Diagnosis is accomplished by visualization of trophozoites (ring-like forms) of B. microti inside erythrocytes on Wright’s or Giemsa stains of thin blood smears. Since parasitemia may involve only 1-10% of RBCs, a meticulous search is often required, reminiscent of a similar illness, malaria. Additional confirmation is available by immunofluorescence assay for B. microti antibody at reference laboratories, and PCR of blood is emerging as a promising diagnostic tool.
| Table 4. Features of Babesiosis |
| Etiology |
| • Babesia microti, an intraerythrocytic protozoan |
| Vectors |
| • Ixodes scapularis (eastern and upper midwestern U.S.); |
| I. pacificus (western U.S.) |
| Distribution |
| • Northeastern, upper midwestern, and northwestern states |
| Incubation period |
| • 1-6 weeks (range, 1 week-3 months) |
| Symptoms and signs |
| • Fever, chills, sweats, fatigue, headache, arthralgias, myalgias, hemolysis |
| Diagnosis |
| • Intraerythrocytic ring forms of B. microti on peripheral smear |
| • Serology—Anti-B. microti IgG |
| • PCR for B. microti in blood |
| • Hemolytic anemia is strongly suggestive of Babesiosis |
| • Co-infection with B. burgdorferi and/or ehrlichiosis may occur |
| Treatment |
| • Quinine (or Quinidine) 10 mg/kg tid, with clindamycin 600 mg qid, for 7-10 days. |
| • Azithromycin 500 mg/d with atovaquone 750 mg bid may prove effective as well. |
| • Exchange transfusion beneficial in severe cases. |
Treatment of babesiosis is merely symptomatic in mild illness, while more serious infections require oral or intravenous quinine (or quinidine) 10 mg/kg tid with clindamycin 600 mg qid for 7-10 days. More recent regimens using azithromycin and atovaquone (Mepron) are under evaluation for babesiosis refractory to quinine and clindamycin. In severe cases, exchange transfusion has proven to be of clinical benefit. Similarities between symptomatic B. microti infection and malaria are noteworthy and include chills, fever, myalgias, arthralgias, and hemolysis. Therefore, clinicians must clarify recent travel histories to northeastern, midwestern, or northwestern states (babesiosis) or equatorial regions (malaria) in febrile patients with illness compatible with this syndrome.
To add to the complexity, some patients with documented B. microti illness are also coinfected with B. burgdorferi, the agent of LD, and ehrlichial pathogens of HGE. Such patients usually require treatment for all three syndromes for full recovery. Simultaneous transmission of these three pathogens by similar species of Ixodes ticks probably accounts for multiple infectious processes in the same individual. Prevention of B. microti infection is possible only by avoidance of bites of I. scapularis and I. pacificus ticks and prompt removal of embedded specimens.
Tularemia
In contrast to LD, ehrlichiosis, and babesiosis, cases of tularemia date back to the early 1900s in the United States (see Table 5). Between 100-200 cases are reported annually to the CDC. The pathogen, Francisella tularensis, is a tiny gram-negative coccobacillus harbored in several mammalian reservoirs, particularly rabbits, as well as squirrels, voles, muskrats, and beaver. Infection may occur through inoculation of organisms from infected mammals into skin breaks, or by aerosol spread into airways or conjunctiva, as with taxidermists, trappers, hunters, and veterinarians. Some cases are related to bites of infected deerflies in the western United States. Once entry into human hosts is achieved, F. tularensis may disseminate widely and cause multisystem manifestations.19 Tick-related illness, however, requires parasitism of human skin by any of a dozen species of ticks, mainly D. variabilis, D. andersoni, and A. americanum. A small painful papule forms at the site of the tick bite in 3-5 days, ulcerates 2-4 days later, and is followed by tender regional adenopathy. The necrotic papule has a raised sharp margin, is tender, and may require weeks to heal if untreated. Of all the possible manifestations of tularemia, this "ulceroglandular" presentation is most common and easiest to recognize clinically, especially in patients reporting recent tick bite. Some cases present only with tender inguinal adenopathy and no preceding papule. Diagnosis is clinical and rests on visualization of, or convincing history of, an ulcerated papule at the site of prior tick bite, demonstration of tender regional adenopathy without other proven etiology, and serologic confirmation of F. tularensis by ELISA methodologies performed 2-4 weeks after initial infection. Routine blood and chemistry tests are normal. Gram stains of papule smears or node aspirates are often unrevealing, but culture for F. tularensis may be diagnostic.
| Table 5. Tularemia |
| Etiology |
| • Francisella tularensis, a gram-negative coccobacillus |
| Vectors |
| • Dermacentor variabilis, D. andersoni, Amblyomma americanum, and several other tick species |
| Distribution |
| • Mainly in south central United States |
| Incubation period |
| • 3-5 days (range, 1 day-3 weeks) |
| Symptoms and signs |
| • Ulcerated papule with tender sharp margins at site of tick bite, followed by tender local adenopathy |
| Diagnosis |
| • Isolation of F. tularensis from primary ulcer or regional lymph node |
| Serology |
| • Anti-F. tularensis IgM antibody |
| Treatment |
| • Gentamicin (or streptomycin) 7.5 mg/kg IM bid × 10 days |
| • Tetracycline, doxycycline, erythromycin, or ciprofloxacin may be effective orally |
Treatment of tularemia has been historically centered on streptomycin or gentamicin injections for 7-14 days, but recent data suggest that more convenient regimens involving oral tetracycline, erythromycin, or ciprofloxacin for 14 days can be effective in ulceroglandular cases. Prevention requires avoidance of tick bites, prompt tick removal, and careful skinning of potentially infected mammals by hunters, trappers, and others at risk, in whom gloves, long sleeves, and eye shields would be prudent to reduce dermal and aerosol inoculation.
Colorado Tick Fever
For backpackers, hunters, and outdoorsmen in the western United States, Colorado tick fever (CTF) poses a unique risk.20 (See Table 6.) Acquisition of illness is restricted to mountainous regions with altitudes of 1500-3500 m in at least 10 Rocky Mountain and western states. The pathogen, a double-stranded RNA Coltivirus, is transmitted to humans by only one species of tick, D. andersoni. Viremic chipmunks and ground squirrels residing at high altitudes serve as reservoirs. Ticks who previously fed on infected mammals transmit the virus to humans bitten in these mountainous habitats. Following an incubation period of 3-5 days, patients experience fever, chills, headache, retroorbital ache, photophobia, myalgias, abdominal pain, and malaise lasting 7-10 days. There is usually no rash. One unique feature of CTF is the "double-hump" fever pattern with temperature spikes, remission, and spikes again at 2-3 day intervals. For obvious reasons, earlier physicians referred to CTF as "mountain fever." Most cases are mild, brief, and well tolerated by patients. Case reports from earlier literature documented rare but serious complications such as encephalitis, pericarditis, pneumonitis, and disseminated intravascular coagulation. Leukopenia and thrombocytopenia are common, and CSF may reveal a lymphocytic pleocytosis. Diagnosis is based on influenza-like symptoms, tick bite, and recent exposure in ecologic habitats and elevations in western U.S. mountains. Confirmation is now possible by isolation of Coltivirus from blood culture or by demonstration of intraerythrocytic viral particles by immunofluorescence of peripheral smears. Convalescent sera may contain anti-Coltivirus antibodies on ELISA testing, but sampling must occur at least one month after illness as antibody detection is difficult early on. Treatment of CTF patients is limited to antipyretics and analgesics for symptomatic relief. In severe cases, ribavirin has been proposed based on limited studies in experimentally infected animals; no human data exist to date. Prevention is possible by avoidance of D. andersoni ticks in high-altitude settings.
| Table 6. Colorado Tick Fever |
| Etiology |
| • RNA-containing Coltivirus |
| Vector |
| • Dermacentor andersoni |
| Distribution |
| • Western states at altitudes between 1500 and 3500 m |
| Incubation period |
| • Four days (range, 1-19 days) |
| Symptoms and signs |
| • Fever, chills, headache, photophobia, retroorbital pain, myalgias, malaise; double-hump fever in 2- day phases is typical; encephalitis and DIC in severe cases |
| Diagnosis |
| • Isolation of Coltivirus from blood |
| • Immunofluorescence of viral antigen inside RBCs |
| Serology |
| • Anti-Coltivirus IgM antibody (by ELISA) appears 20-45 days after illness |
| • Leukopenia and thrombocytopenia are suggestive of CTF |
| Treatment |
| • Supportive and symptomatic therapy with antipyretics and analgesics; ribavirin remains experimental only (no human data) |
Tick Paralysis
Perhaps the most fascinating of the seven tickborne illnesses is tick paralysis (TP). Not an infectious process at all, this neurologic syndrome is caused by inhibition of axonal transmission by an extremely potent neurotoxin produced by a pregnant tick engorging on a human host.21 (See Table 7.) Most cases are reported in young children, especially girls with long hair obscuring ticks on the scalp. D. variabilis (eastern United States) and D. andersoni (western United States) are the principal species responsible for TP. Cases have been reported from more than 20 states across the United States. Attached females feed for 5-7 days, attain engorgement, reach the size of large raisins, and produce a neurotoxin coincident with internal egg maturation. Cardinal symptoms include paresthesias, ataxia, clumsiness, falls, leg weakness, and ascending paralysis of legs, then arms, and finally, bulbar functions of swallowing, speech, and respiration.22 Hypoventilation is progressive and can lead to coma and death in undiagnosed cases. Many patients are mistakenly diagnosed with Guillain-Barré Syndrome (GBS), with which TP can easily be confused.23 Careful inspection of head, neck, axilla, and groin is essential in patients thought to have GBS and can reveal the attached, solitary, flesh-colored female tick responsible for paralytic neurotoxin production (Felz MW, et al. In press). Furthermore, CSF analysis is normal in TP, in contrast to elevated protein and lack of pleocytosis ("albuminocytologic dissociation") accompanying GBS. Diagnosis, then, of TP is accomplished by meticulous inspection for embedded, engorged ticks, a procedure augmented by a fine toothed comb in longhaired victims. All laboratory tests, CSF analyses, and neuroimaging modalities are normal. Treatment is easily accomplished by removal of embedded tick specimens grasped along mouthparts with tweezers. Dramatic improvement in serious neurologic compromise usually occurs within hours. Paralyzed victims are fully ambulatory again in 1-2 days. Errors in neurologic diagnosis, or therapeutic delays involving plasmapheresis or immunoglobulin therapy for presumed GBS without exclusion of occult ticks, account for unfavorable clinical outcomes. Antibiotics are of no value. The short half-life of the neurotoxin confers tremendous therapeutic importance to prompt tick detection and removal. Avoidance of ticks and removal of attached female specimens prior to full engorgement are the only known preventive measures for TP occurring in the United States.
| Table 7. Tick Paralysis |
| Etiology |
| • Neurotoxin produced by pregnant, engorged female ticks |
| Vectors |
| • Dermacentor variabilis (eastern U.S.), D. andersoni (western U.S.) |
| Distribution |
| • Mainly in southeastern, south central, and northwestern United States; reported in 20 states |
| Incubation period |
| • 5-7 days |
| Symptoms and signs |
| • Ascending symmetric paralysis; acute ataxia; paresthesias; dysphagia, dysphonia, ptosis, hypoventilation; respiratory compromise, coma, and death if diagnosis delayed; often confused with Guillain-Barré Syndrome |
| Diagnosis |
| • Detection of engorged female tick embedded in human skin, often obscured by long hair on scalp |
| • All laboratory tests, CSF analyses, and radiologic studies are normal |
| Treatment |
| • Forceps removal of embedded tick; dramatic neurologic recovery in hours to days |
Prevention of Tickborne Illness
For individuals with exposure to ticks and their habitats, clinicians can recommend certain measures to reduce the risk of acquiring tick-transmitted infection. These interventions are conveniently grouped into memorable categories known as the "Three R’s"—Repel ticks, Remove ticks, and Recognize symptoms.
Repellents for ticks include barrier and chemical methods. Long shirtsleeves and pantlegs tucked into socks create physical barriers to interrupt attachment of ticks attracted by CO2 from human skin. Diethyl-meta-toluamide (DEET) spray formulations are effective repellents for application to exposed skin, and concentrations of 20-30% DEET are recommended. Permethrin 0.50% spray, a repository preparation applied to clothing every 24-48 hours, is a potent repellent and respiratory paralytic for ticks.24 Humans at risk for tick bites are encouraged to use both barrier and spray methods. Since some cases of LD are peridomestically acquired in endemic regions, environmental modifications to eliminate small mammal habitats near residential areas and, therefore, reduce tick density can help protect those at risk.
Removal of ticks requires a careful body search from head to toe for attached specimens within 24 hours of tick exposure. Published data on extraction methods in shaved experimental animals indicate that tweezers (forceps) are effective in achieving prompt, complete removal of tick mouthparts from host integument.25 A study on two removal methods in human skin is now under way (Felz MW, personal communication). Several commercial devices are available and have been tested in animals, but none has any significant advantage over tweezers. Gentle, steady traction perpendicular to the skin surface, without rotation, is recommended. Other methods, such as hot matches, petroleum products, fingernail polish, alcohol, and twisting with fingers, are either unproven or ineffective. Finally, bathing or showering with a cloth or brush after tick exposure may remove ticks prior to initial attachment.
Recognition of "sentinel" symptoms of these seven tickborne illness enables physicians and their patients to initiate diagnostic and therapeutic interventions earlier than in cases complicated by delayed awareness or misdirected treatment. Each syndrome displays clinical features distinctive enough to trigger pattern recognition by clinicians with updated knowledge of tickborne illnesses and transmission patterns. For professionals interested in precise identification of removed tick specimens, a recently published color guide is available and allows medical correlation of each tick vector with diseases transmitted and geographic range of distribution.26 Accurate tick identification in an office setting enables clinicians to confidently advise patients about incubation periods, sentinel symptoms, and prevention strategies, all of which can enhance primary care skills in early diagnosis, prompt therapy, and risk reduction for concerned tick-bite victims.
References
1. Fishbein DB, Dennis DT. Tickborne diseases—A growing risk. N Engl J Med 1995;333:452-453.
2. Centers for Disease Control and Prevention. Lyme disease—United States, 1996. MMWR Morb Mortal Wkly Rep 1997;46: 531-535.
3. Verdon ME, Sigal LH. Recognition and management of Lyme disease. Am Fam Physician 1997;56:427-440.
4. Rahn DW, Felz MW. Lyme disease update: Current approach to early, disseminated, and late disease. Postgrad Med 1998;103: 51-70.
5. Centers for Disease Control and Prevention. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme disease. MMWR Morb Mortal Wkly Rep 1995;44:590-591.
6. Rahn DW, Malawista SE. Lyme disease: Recommendations for diagnosis and treatment. Ann Intern Med 1991;114:472-481.
7. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer- surface lipoprotein A with adjuvant. N Engl J Med 1998; 339:209-215.
8. Sigal LH, Zahradnik JM, Lavin P, et al. A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. N Engl J Med 1998;339:216-222.
9. Sigal LH. Pitfalls in the diagnosis and management of Lyme disease. Arthritis Rheum 1998;41:195-204.
10. Steere AC, et al. The overdiagnosis of Lyme disease. JAMA 1993;269:1812-1816.
11. Sigal L. Lyme disease: A review of aspects of its immunology and immunopathogenesis. Annu Rev Immunol 1997;15:63-92.
12. Helmich CG, Bernard KW, D’Angelo LJ. Rocky Mountain spotted fever: Clinical, laboratory, and epidemiologic features of 262 cases. J Infect Dis 1984;150:480-488.
13. Walker DH, Raoult D. Rickettsia rickettsii and other spotted fever group rickettsiae (Rocky Mountain spotted fever and other spotted fevers). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell’s Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill-Livingstone; 1995;1721-1727.
14. Maeda K, Markowitz N, Hawley RC, et al. Human infection with Ehrlichia canis, a leukocytic rickettsia. N Engl J Med 1987; 316:853-856.
15. Bakken JS, Dumler S, Chen SM, et al. Human granulocytic ehrlichiosis in the upper Midwest United States: A new species emerging? JAMA 1994;272:212-218.
16. Dumler JS, Bakken JS. Ehrlichial diseases of humans: Emerging tick-borne infections. Clin Infect Dis 1995;20:1102-1110.
17 Buller RS, Arens M, Hmiel P, et al. Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis. N Engl J Med 1999; 341:148-155.
18. Persing DH. Babesiosis. In: Connor DH, Chandler FW, Jr. eds. Pathology of Infectious Diseases. Stamford, Conn: Appleton & Lange; 1997:1135-1139.
19. Penn RL. Francisella tularensis (tularemia). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell’s Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill-Livingstone; 1995:2060-2068.
20. Knudson DL, Monath TP. Colorado tick fever. In: Fields BN, Knipe DM, eds. Fields’ Virology. 2nd ed. New York: Raven Press, Ltd; 1990.
21. Grattan-Smith PJ, Morris JG, Johnston HM, et al. Clinical and neurophysiological features of tick paralysis. Brain 1997; 120:1975-1987.
22. Mongan PF. Tick toxicosis in North America. J Fam Pract 1979; 8:939-944.
23. Jones HR Jr. Guillain-Barré syndrome in children. Current Opinion in Pediatrics 1995;7:663-668.
24 Mafong EA, Kaplan LA. Insect repellents: What really works? Postgrad Med 1997;102:63-74.
25. Stewart RL Jr, Burgdorfer W, Needham GR. Evaluation of three commercial tick removal tools. Wilderness and Environmental Medicine 1998;9:137-142.
26. Felz MW, Durden LA. Identifying ticks: A pictorial guide. Patient Care 1998;32:172-187.
Physician CME Questions
22. Physician diagnosis of Lyme disease is best accomplished by:
a. observation of erythema migrans followed by two-step serologic testing.
b. presence of influenza-like symptoms in a tick-bite victim with fever.
c. history of chronic fatigue syndrome without alternative explanation.
d. radiologic evidence of symmetric small joint arthritis.
23. The diagnostic hallmark of Rocky Mountain spotted fever is:
a. expanding erythema at tick-bite sites.
b. tender adenopathy of axilla or groin.
c. pleocytosis of CSF.
d. petechiae of wrists and ankles.
24. For both human monocytic ehrlichiosis and human granulocytic ehrlichiosis, the treatment of choice is:
a. ciprofloxacin 500 mg IV or po daily.
b. penicillin G 24,000,000 units IV daily.
c. doxycycline 100 mg IV or po daily.
d. ceftriaxone 2 g IV daily.
25. The laboratory diagnosis of babesiosis is strongly suggested by the presence of:
a. leukocytosis with left shift.
b. hemolytic anemia with ring forms.
c. thrombocytopenia with abnormal clotting studies.
d. elevated ESR with proteinuria.
26. The most common presentation of tularemia in patients in the United States is:
a. tender papule with ulceration at tick-bite site.
b. multiple erythematous plaques on trunk of tick bite victim.
c. transient maculopapular rash on face and extremities.
d. pruritic papules involving wrists and finger webs.
27. Patients with Colorado tick fever often manifest:
a. severe abdominal pain mimicking peritonitis.
b. recurrent arthritis of large joints at 2-3 month intervals.
c. double-hump fever in 2-3 day phases.
d. palpitations with high-grade AV block.
28. The symptoms and signs of tick paralysis are often confused with:
a. myasthenia gravis.
b. facial palsy.
c. aseptic meningitis.
d. Guillain-Barré syndrome.
29. Prompt effective removal of imbedded ticks involves complete extraction of:
a. tick palps.
b. tick forelegs.
c. tick hypostome.
d. tick spiracles.
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