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Tickborne Illnesses
Key Concepts
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Tickborne illnesses frequently are misdiagnosed as common viral or bacterial infections. Diagnosis can be facilitated by considering tickborne illnesses in patients who recently have been in endemic areas and routinely asking for a history of recent tick or insect bites in patients with febrile illnesses.
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Lyme disease should be suspected in patients who present with signs of a viral illness, monarticular arthritis, meningitis, multiple neurologic abnormalities, or heart block. Diagnosis can be confirmed with serologic testing of acute and convalescent serum samples.
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Normal physiologic changes from tick bites should not be confused with erythema migrans.
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Relapsing fever should be suspected in patients who present with recurrent viral-like illness associated with high fever. The diagnosis can be confirmed by identifying spirochetes on a blood smear obtained during a period of rising temperature.
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Ulceroglandular tularemia should be suspected in patients with slow-healing extremity ulcers associated with large lesions of regional adenopathy (buboes). The diagnosis can be confirmed with serologic testing.
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Rocky Mountain spotted fever should be considered in patients who present with an unexplained febrile illness, even in the absence of a rash or known tick exposure. Delayed diagnosis and late initiation of specific anti-rickettsial therapy may lead to a fatal outcome. Treatment never should be delayed pending laboratory diagnosis.
Overview
Ticks are hematophagous parasites of humans and animals, distributed worldwide. They transmit rickettsial, bacterial, spirochetal, viral, and protozoal diseases and cause disease employing their own toxins ( Table 123.1 ). As vectors of human disease, ticks rank second in importance only to mosquitoes. Although it is generally understood that people who travel during the summer months may return from endemic areas with tickborne disease, increasing reports of infection acquired within urban areas emphasize the need to consider tickborne illness even in the absence of a history of travel to high-risk areas. In addition, tularemia and Q fever are now considered by the Centers for Disease Control and Prevention (CDC) to be significant threats during biologic warfare, adding to the importance of research on ticks and tickborne diseases.
TABLE 123.1
Tickborne Illnesses
| Type | Disease | Pathogen | Arthropod Vector | Geographic Distribution |
|---|---|---|---|---|
| Bacterial (including spirochetal) | Lyme disease | Borrelia burgdorferi | Ixodes scapularis | Northeastern United States |
| Ixodes pacificus | Upper Midwestern United States | |||
| Ixodes ricinus | Pacific Coast Europe |
|||
| Tularemia | Francisella tularensis | Ixodes scapularis | Southwest central United States | |
| Amblyomma americanum | ||||
| Dermacentor variabilis | ||||
| Rickettsial | Rocky Mountain spotted fever | Rickettsia rickettsii | Dermacentor andersoni Dermacentor variabilis |
Predominantly southeastern United States |
| Rhipicephalus sanguineus | Arizona | |||
| Q fever | Coxiella burnetii | Dermacentor andersoni | Worldwide | |
| Human monocytic ehrlichiosis | Ehrlichia chaffeensis | Amblyomma americanum | South central and southeastern United States | |
| Human granulocytic anaplasmosis | Anaplasma phagocytophilum | Ixodes scapularis | New England and north central United States | |
| Ixodes pacificus | Northern California | |||
| Parasitic (protozoal) | Babesiosis | Babesia microti | Ixodes scapularis | Coastal New England |
| Viral a | Colorado tick fever | Orbivirus | Dermacentor andersoni | Mountain areas of western United States and Canada |
| Miscellaneous | Tick paralysis | Ixobotoxin | Dermacentor andersoni Dermacentor variabilis Amblyomma americanum Ixodes scapularis Ixodes pacificus Ixodes holocyclus |
Worldwide |
a Many other viruses are transmitted to humans by ticks. In the United States, only Colorado tick fever occurs with any significant frequency.
Reports on ticks, their feeding habits, and their possible relation to disease can be found from early human history. Tickborne illness was first recognized on the North American continent by Native Americans. The causative association of the tick vector with Rocky Mountain spotted fever (RMSF) was noted by missionaries and early settlers, who named the affliction tick fever, and physicians in Idaho and Montana recorded the classic clinical descriptions of the disease in 1899.
The majority of tickborne diseases in the United States occur east of the Mississippi River ( Fig. 123.1 ). The reported cases of these diseases have nearly doubled since 2008, led by Lyme disease, the ehrlichioses, and the Rocky Mountain or other spotted fever rickettsioses ( Table 123.2 ).
TABLE 123.2
Tickborne Disease Surveillance Data Summary
From: Centers for Disease Control and Prevention. Ticks: tickborne disease surveillance data summary. https://www.cdc.gov/ticks/data-summary/index.html .
| Reported Tickborne Diseases, US | 2016 | 2017 | 2018 |
|---|---|---|---|
| Lyme disease (confirmed and probable) | 36,429 | 42,743 | 33,666 |
| Anaplasmosis/ehrlichiosis | 5,750 | 7,718 | 6,123 |
| Spotted fever rickettsisosis | 4,269 | 6,248 | 5,544 |
| Babesiosis | 1,910 | 2,368 | 2,160 |
| Tularemia | 230 | 239 | 229 |
| Powassan virus | 22 | 33 | 21 |
| Total | 48,610 | 59,349 | 47,743 |
Identification of Ticks
Ticks are arthropods but not insects. They have eight legs instead of six and generally two fusing body parts—a capitulum (head) and opisthosoma (abdomen)—instead of three. Identification of an arthropod as a tick is not difficult ( Figs. 123.2 and 123.3 ), but speciation requires a trained acarologist. However, tick identification has limited importance in clinical decision making. Color, which varies seasonally, and size, which varies by amount of blood ingested at the time of presentation, are unreliable criteria for identification purposes.
Physiology of Tick Feeding
An understanding of the physiology of feeding in arthropods is helpful when assessing the risks of disease transmission. Blood-sucking (hematophagic) arthropods are divided into two groups according to their method of acquiring blood. The solenophagic feeders insert their mouthparts directly into capillaries to obtain blood. Telmophagic feeders insert their mouthparts indiscriminately, lyse tissue along with capillaries, and feed on the resultant pool of blood, extracellular fluid, and tissue. Ticks and deer flies, for example, are telmophagic feeders, whereas mosquitoes are mostly solenophagic.
Argasid ticks (soft-bodied ticks) are short, rapid feeders with preformed distensible endocuticles. They therefore need to feed for only minutes to hours to acquire a full meal. As a result, they tend to be found in nests and burrows where their hosts visit frequently. The soft tick genus Ornithodoros is the vector for relapsing fever. Ixodid ticks (hard-bodied ticks) include the genera Ixodes, Dermacentor, Amblyomma, and Rhipicephalus, which are those responsible for the remainder of human tickborne diseases in the United States discussed in this chapter.
Two mechanisms prevent many species of tick from being removed from the skin—the barbed hypostome, or a calcified mouth-piece that anchors the tick to the skin, and a cement-like salivary secretion from the base of the hypostome, composed of lipoproteins and glycoproteins. This allows ixodid ticks to remain attached for as long as 2 weeks. Because argasids are much faster feeders, they secrete no cement substance.
During a bite, trauma and salivary gland products can cause local inflammation, hyperemia, edema, hemorrhage, and skin thickening. Hard and soft ticks produce a histolytic secretion injected during feeding that liquefies tissue, which is then sucked into the gut. Eventually, the secretion breaks down the walls of the dermal blood vessels and the released blood is ingested. To prevent hemostasis, the saliva contains a thrombokinase inhibitor, apyrase, which prevents platelet aggregation by depleting adenosine diphosphate, prostaglandin E 2 , and prostacyclin (prostaglandin I 2 ) to prevent vasoconstriction, and cytolysins. Ixodes scapularis also secretes a carboxypeptidase that destroys other inflammatory mediators, such as anaphylatoxins and bradykinin, as well as anti–complement C3 factor. These other mediators normally would cause further inflammation, which would enhance hemostasis. The neurotoxins responsible for tick paralysis also are found in tick saliva. All infectious agents and excretory liquids from some argasids are transmitted through this saliva. Transmission of a disease from Ixodes ticks is unlikely if the tick is not yet engorged with blood at the time of removal.
The local physiologic changes associated with tick feeding produce the characteristic 1- to 4-mm erythematous mark typically seen on the skin after a tick bite. This is a common finding from most blood-sucking arthropods. The mark should not be confused with certain rashes associated with disease progression—for example, erythema migrans. Informing patients of this difference may be reassuring.
Lyme Disease
Lyme disease, the most common vector-borne disease in the United States, is a tickborne illness caused by six species in the spirochete family Borreliaceae. In North America, infection is caused primarily by Borrelia burgdorferi . The recognition of Lyme disease began in 1975, when health officials at the Connecticut State Department of Health and physicians at Yale University were alerted by two skeptical mothers to an unusually large number of cases of apparent juvenile rheumatoid arthritis occurring in their small coastal community of Old Lyme, Connecticut. Investigation led to the description of a new entity called Lyme arthritis. The causative agent of Lyme disease was isolated in 1982.
Lyme disease occurs worldwide and has been reported on every continent except Antarctica. It now accounts for more than 95% of all reported cases of US vector-borne illness. The incidence of Lyme disease is unknown because many cases go unreported. Lyme disease occurs in people of all ages but is more common in children younger than 15 years and in adults 30 to 60 years of age. Persons at greatest risk live or vacation in endemic areas. In the United States, three distinct endemic foci are recognized—the northeastern coastal, Mid-Atlantic, and north central states. Twelve states (Connecticut, Maine, Maryland, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, Pennsylvania, Vermont, Washington, and Wisconsin) account for 92% of US cases reported ( Fig. 123.4 ).
The principal tick vectors are I. scapularis in the Northeast and Midwest and Ixodes pacificus in the West. The I. scapularis population density depends on that of its preferred hosts, the white-footed field mouse, Peromyscus leucopus, for the larval and nymphal forms, and the white-tailed deer, Odocoileus virginianus, for the adult form. The white-footed mouse readily becomes infected after being bitten by infected ticks and remains highly infectious for periods that approach its life span, thereby providing an important reservoir for B. burgdorferi . Adult I. scapularis ticks feed primarily on deer, which are key hosts in the tick life cycle and in whose fur the adult tick may survive the winter. The repopulation of several areas in the United States by white-tailed deer preceded the recent emergence of Lyme disease in those regions.
Although all stages of the tick may feed on humans, the nymph is primarily responsible for transmitting Lyme disease. It is not surprising that more than two-thirds of patients with Lyme disease do not recall a tick bite, given the small size (1–2 mm) of nymphs ( Fig. 123.5 ). The nymph feeds in the spring and summer, correlating with a peak incidence of early Lyme disease between May and August. In addition, recreational and occupational exposure is greatest during this time. Later manifestations of Lyme disease may appear throughout the year.
The spirochete Borrelia burgdorferi persists and multiplies in the midgut of its tick vector, I. scapularis . Transmission of the spirochete to humans occurs during feeding, generally about 2 days after attachment. The mechanism of transmission probably is inoculation with infectious saliva or with tick gut fluids periodically regurgitated during the feeding process.
After an incubation period that lasts several days to weeks, spirochetemia develops, and Borrelia organisms may migrate outward in the blood or lymph to virtually any site in the body. The spirochete appears to be tropic for synovial tissue, skin, and cells of the nervous system, but the mechanism of this tropism is not yet understood. Infection by the spirochete itself accounts for early clinical manifestations. It remains unclear whether late disease manifestations require the continued presence of viable spirochetes or whether an ongoing host immune response to initial infection is sufficient to cause some late disease effects, but persistent live spirochetes are likely responsible for most later manifestations of the disease. The variable severity of Lyme disease may in part result from genetic variations in the human immune system. For example, patients with chronic Lyme arthritis have an increased frequency of human leukocyte antigen (HLA) specificity, in particular for HLA-DR4 and, less often, for HLA-DR2.
Clinical Features
Lyme disease, a multisystem disorder, can be classified into three stages—early localized, early disseminated, and late disease. Virtually any clinical feature may occur alone or recur at intervals, and some patients who had no early symptoms may have late symptoms. The disorder usually begins with a rash and associated constitutional signs and symptoms, suggesting a viral syndrome (early Lyme disease). Neurologic, joint, or cardiac manifestations may emerge weeks to months later (early disseminated Lyme disease), and chronic arthritic and neurologic abnormalities may appear weeks to years later (late Lyme disease). The time course for the clinical features of untreated Lyme disease is illustrated in Fig. 123.6 .
Early Lyme Disease
Ticks may attach to human hosts at the initial point of contact, generally around ankle level, or move about until they encounter an obstruction. The groin, popliteal fossae, gluteal folds, axillary folds, and earlobes are common sites of attachment. With transmission of B. burgdorferi through a tick bite, the initial site of infection is the skin at the site of the bite. After an incubation period of approximately 1 week (range, 1–36 days), the spirochetes cause a gradually spreading localized infection in the skin and a resultant skin lesion, erythema migrans. Erythema migrans (EM) is the most characteristic clinical manifestation of Lyme disease and is recognized in 90% or more of patients. EM may go unnoticed if the entire skin surface is not examined. The characteristic rash begins at the site of the tick bite with an erythematous papule or macule. The lesion expands gradually (1–2 cm/day, a rate of expansion slower than cellulitis). The patch of erythema may be confluent or may have bands of normal-appearing skin. Central clearing may occur but is not an invariable feature. The lesion borders usually are flat but may be raised. The lesions generally are sharply demarcated and blanch with pressure. Most lesions are oval or round, but triangular and elongated patches may occur. In patients presenting 1 to 7 days after the appearance of lesions, the average lesion size is approximately 8 by 10 cm (range, 2 by 3 cm to 25 by 25 cm). In some cases, the center of some early lesions becomes red and indurated or vesicular and necrotic. The lesion is warm to the touch and may be described by the patient as nontender to minimally tender ( Figs. 123.7 and 123.8 ).
Hematogenous spread of viable spirochetes (not additional tick bites) may result in one or more secondary lesions. These secondary lesions are smaller, migrate less, and typically spare the palms and soles. In all, 10% to 15% of patients have more than 20 such lesions; on rare occasions, they may number more than 100. Blistering and mucosal involvement do not occur. The primary and secondary skin lesions generally fade after approximately 28 days (range, 1 week to 14 months) without treatment and within several days of antibiotic therapy. Recurrent lesions may develop in patients who do not receive antibiotic therapy but not in those who receive appropriate antibiotics.
Constitutional signs and symptoms commonly appear in early Lyme disease ( Table 123.3 ). Malaise, fatigue, and lethargy are most common (seen in ≈80% of patients) and may be severe. Fever typically is low grade and intermittent. Lymphadenopathy usually is regional in the distribution of EM or may be generalized; splenomegaly may occur. Musculoskeletal complaints, such as arthralgias and myalgias, are common, and the discomfort typically is short-lived and migratory, sometimes lasting only hours in one location. Frank arthritis may occur at this stage but is rare.
TABLE 123.3
Early Clinical Manifestations of Lyme Disease
From: Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical manifestations of Lyme disease. Ann Intern Med . 1983;99:76-82.
| Manifestation | No. of Patients (%) |
|---|---|
| Signs | |
| Erythema chronicum migrans a | 314 (100) |
| Multiple annular lesions | 150 (48) |
| Lymphadenopathy | |
| Regional | 128 (41) |
| Generalized | 63 (20) |
| Pain on neck flexion | 52 (17) |
| Malar rash | 41 (13) |
| Erythematous throat | 38 (12) |
| Conjunctivitis | 35 (11) |
| Symptoms | |
| Malaise, fatigue, lethargy | 251 (80) |
| Headache | 200 (64) |
| Fever and chills | 185 (59) |
| Stiff neck | 151 (48) |
| Arthralgias | 150 (48) |
| Myalgias | 135 (43) |
| Backache | 81 (26) |
| Anorexia | 73 (23) |
| Sore throat | 53 (17) |
| Nausea | 53 (17) |
| Dysesthesia | 35 (11) |
| Vomiting | 32 (10) |
Clinical manifestations of meningeal irritation are frequently seen. Headache, the most common symptom, usually is intermittent and localized. Nausea, vomiting, and photophobia occasionally accompany the headache. Kernig and Brudzinski signs typically are absent, and neck stiffness usually is noted only on extreme forward flexion. At this stage, the neurologic examination and cerebrospinal fluid (CSF) assessment usually yield normal findings.
Signs and symptoms of hepatitis, including anorexia, abdominal pain, right upper quadrant tenderness, nausea, and vomiting, may be present. Mild pharyngitis also may be present, but other upper respiratory symptoms, such as rhinorrhea, do not occur. Although the systemic symptoms of early Lyme disease often are described as flulike, that term can be misleading because clinically significant cough usually does not occur. Conjunctivitis develops in approximately 10% of patients.
The incidence of Lyme disease without EM appears to be approximately 10%. Because of the variety of nonspecific signs and symptoms at this stage, in the absence of the characteristic rash or history of tick bite, early Lyme disease may be easily confused with a viral or collagen vascular disease. The intermittent and rapidly changing nature of the early signs and symptoms of Lyme disease may be a helpful distinguishing feature, especially in a patient from an endemic area. In untreated disease, early symptoms usually last for several weeks but may persist for months.
Acute Disseminated Infection
Shortly after disease onset, hematogenous spread can cause various systemic signs and symptoms and result in secondary sites of infection. Organ systems commonly affected are the nervous system, heart, and joints. Less commonly, the eyes, liver, skeletal muscle, subcutaneous tissue, and spleen are infected.
Neurologic Manifestations
A relatively symptom-free interval usually occurs between early and disseminated infection; however, neurologic signs and symptoms may be the presenting manifestations of Lyme disease or may overlap with early or late manifestations. Beginning at an average of 4 weeks (range, 0–10 weeks) after the onset of erythema migrans, neurologic involvement occurs in approximately 15% of untreated patients.
The most common neurologic manifestation of Lyme disease is a fluctuating meningoencephalitis, with superimposed symptoms of cranial neuropathy, peripheral neuropathy, or radiculopathy. A triad of lymphocytic meningitis, cranial neuropathies (usually Bell palsy), and radiculoneuritis (motor or sensory or both) has been described, but each entity may occur alone. Headache of variable intensity usually is present; other signs and symptoms of a mild meningoencephalitis may be noted, including lethargy or irritability, sleep disturbances, poor concentration, and memory loss. At this point, the disease often is misdiagnosed as viral meningitis. As in early disease, Kernig and Brudzinski signs are absent and computed tomography (CT) findings are normal. Unlike in early disease, however, findings on CSF examination often are abnormal, with a lymphocytic pleocytosis and moderately elevated protein level. CSF glucose concentration usually is normal. Intrathecal B. burgdorferi antibody (usually immunoglobulin G [IgG] or IgA) is present in 80% to 90% of patients. CSF polymerase chain reaction (PCR) assay results are positive in less than 50% of patients, probably reflecting the low number of organisms usually present in spinal fluid. Routine testing of CSF by PCR assay is not recommended.
Cranial neuropathies are common, occurring in approximately 50% of patients with Lyme meningitis; the seventh nerve is usually involved. Other cranial nerves are affected less often. Bell palsy is bilateral in approximately one-third of patients. Its duration usually is weeks to months, and the condition generally resolves spontaneously without treatment.
Peripheral nervous system manifestations also may occur in early disseminated Lyme disease. The spinal root and plexus and peripheral nerves may be involved in the form of thoracic sensory radiculitis, brachial plexitis, mononeuritis, and motor and sensory radiculoneuritis in the extremities. Patients may complain of weakness, pain, or dysesthesia. Examination may reveal loss of reflexes. Involvement of the extremities usually is asymmetrical, but cervical and thoracic dermatomes may be affected. Radiculoneuritis can mimic a mechanical radiculopathy (such as sciatica) and should be considered in endemic areas in patients without an apparent mechanical cause. Other rare neurologic abnormalities described in association with Lyme disease include chorea, transverse myelitis, ataxia, and pseudotumor cerebri. Cerebral vasculitis associated with Lyme disease also has been reported.
Cardiac Manifestations
Cardiac involvement in Lyme disease is uncommon, with an estimated incidence in untreated patients ranging from 4% to 10%. Carditis occurs during the early disseminated phase of the disease. The average time from initial illness to the development of carditis typically is 3 to 5 weeks (range, 4 days to 7 months). Direct myocardial invasion has been demonstrated with endomyocardial biopsy. Electrophysiologic testing has demonstrated widespread involvement of the conduction system.
The most common cardiac manifestation of Lyme disease is atrioventricular (AV) block, although conduction defects may involve any level of the conducting system. Myopericarditis, tachydysrhythmias including atrial fibrillation, and ventricular impairment occur less often. In a review of 105 reported cases of Lyme carditis, 49% of cases were third-degree, 16% were second-degree, and 12% were first-degree AV block. The degree of AV block seen in a specific patient may fluctuate rapidly.
A commonly observed feature of AV block in patients with Lyme carditis is its gradual resolution, resembling that occurring after an acute inferior wall myocardial infarction and presumably related to the resolution of inflammation. Assessment of the level of the AV block is important to determine the prognosis of a patient with Lyme carditis. In most cases, the block appears to be at or above the AV node; therefore, the prognosis is favorable. However, infranodal AV block does occur and may be characterized by slow escape rhythms of wide QRS pattern, asystole, or fluctuating left and right bundle branch block. Other electrocardiographic findings include nonspecific ST and T wave abnormalities and intraventricular conduction delay.
Patients with high-degree AV block usually are symptomatic. Symptoms include lightheadedness, palpitations, syncope, chest pain, and dyspnea on exertion. The physical examination may reveal flow murmurs and murmurs of mild mitral regurgitation, pericardial friction rub, or evidence of congestive heart failure. Associated left ventricular dysfunction may be present and has been documented by two-dimensional echocardiography and radionuclide studies; in most reported cases, it has been mild and transient. Sudden cardiac death attributable to Lyme disease has also been reported.
Arthritis
Although it is generally considered a sign of late Lyme disease, acute arthritis may begin during the acute disseminated stage. Monarticular or oligoarticular arthritis, primarily affecting large joints, especially the knee, may develop weeks to months after the onset of initial illness. In an early study of the natural history of Lyme arthritis, approximately 50% of untreated patients experienced one episode or multiple intermittent attacks of arthritis. Acute arthritis typically is monarticular, with involvement of only one knee. The shoulder, elbow, temporomandibular joint, ankle, wrist, hip, and small joints of the hands and feet are involved less commonly. Episodes of arthritis typically are brief (lasting weeks to months) and are separated by variable periods of remission.
Arthrocentesis generally is nondiagnostic, yielding an inflammatory synovial fluid with a mean white blood cell count of approximately 25,000 cells/μL (75% polymorphonuclear leukocytes). Higher white blood cell counts have been reported, simulating septic arthritis. The synovial glucose concentration usually is normal, and protein levels are variable, ranging from 3 to 8 g/dL. Cultures of the fluid rarely identify the causative spirochete. The complement level generally is greater than one-third that of serum. Synovial biopsy reveals hypertrophy, vascular proliferation, and a mononuclear cell infiltrate. Findings, therefore, are similar to those in rheumatoid arthritis, except that rheumatoid factor and antinuclear antibody assays yield a negative result in Lyme arthritis. Radiography may reveal nonspecific abnormalities such as juxtaarticular osteoporosis, cartilage loss, cortical or marginal bone erosions, and joint effusions.
Ophthalmic Manifestations
Ocular involvement also may be seen in early disseminated disease; manifestations include conjunctivitis, keratitis, choroiditis, retinal detachment, optic neuritis, and blindness. These findings also may be seen in late disease.
Late Lyme Disease
The chronic phase of Lyme disease is characterized by arthritic and, less commonly, neurologic symptoms. Over time, the pattern of episodic inflammation in early disease transitions to a more indolent persistent inflammation. The term chronic (or late ) Lyme disease describes continuous inflammation in an organ system for more than 1 year.
A pattern of exacerbation and remission of arthritis may extend for several years, with a gradual tendency toward less frequent and less severe occurrences. The spontaneous long-term remission rate approximates 10% to 20% annually in untreated patients. However, patients commonly have episodes of periarticular involvement, arthralgias, or fatigue interspersed between attacks of frank arthritis. During the second or third year of illness, attacks of joint swelling sometimes become longer in duration, lasting months rather than weeks. Chronic arthritis eventually develops in approximately 10% of patients.
Late neurologic complications include a wide variety of abnormalities of the central and peripheral nervous systems and fatigue syndromes. Diagnosis may be difficult because of the large number of other neurologic conditions that Lyme disease may imitate and because late neurologic symptoms may be the first symptoms of the disease. The manifestations of chronic neuroborreliosis (the neurologic manifestations of Lyme disease) usually appear months to years after the onset of infection.
The most common late neurologic manifestation of Lyme disease is a chronic encephalopathy manifested as a mild to moderately severe impairment of memory and learning. Hypersomnolence and mild psychiatric disturbances (depression, irritability, paranoia) also may develop.
Peripheral nervous system manifestations often are seen in late disease, with involvement of cranial nerves, spinal roots, spinal plexuses, and peripheral nerves. A predominantly sensory polyradiculoneuropathy that is manifested as radicular pain or distal paresthesia is common. Significant overlap occurs with early symptoms. Less commonly, a demyelinating condition resembling multiple sclerosis may appear in late disease. Symptoms are variable and, as in multiple sclerosis, may undergo exacerbations and remissions. CT and magnetic resonance imaging (MRI) may reveal multiple white matter lesions.
Chronic inflammation also may occur in the skin, causing a seldom-recognized late cutaneous manifestation of Lyme disease, acrodermatitis chronica atrophicans. This condition usually involves the skin of distal extremities at the site of a tick bite. It is characterized in its initial stages by an edematous infiltration, which progresses to an atrophic lesion resembling localized scleroderma in its more established form. B. burgdorferi has been demonstrated in the skin of patients with acrodermatitis chronica atrophicans and positive findings on serologic studies.
Differential Diagnoses
The diagnosis of Lyme disease should be considered based on clinical and epidemiologic features. Identification of the disorder often is difficult, however, especially in the early stage. Although Lyme disease manifests in many ways, each stage has characteristic clinical findings that narrow the differential diagnosis. Early Lyme disease (EM and associated constitutional symptoms) may be easily confused with various other diseases, especially if the characteristic rash of EM is absent. A common clinical presentation is an influenza-like illness with headache, nausea, fever, chills, myalgias, arthralgias, stiff neck, and anorexia, occurring during the summer months. Even in endemic areas during the summer months, most patients with such symptoms do not have Lyme disease. When headache and stiff neck are the predominant symptoms, the principal diagnostic distinction to be made is between Lyme disease and the enteroviral diseases (and other causes of aseptic meningitis). The enteroviral diseases also have their peak incidence during the summer months; however, diarrhea, commonly associated with enteroviral infection, is not a feature of Lyme disease. Abdominal pain, anorexia, and nausea suggest hepatitis, sore throat, adenopathy, and fatigue suggest mononucleosis, and myalgias and arthralgias suggest connective tissue diseases. In many areas where Lyme disease is endemic, Ixodes ticks can be infected simultaneously with B. burgdorferi , Anaplasma phagocytophilum , and Babesia microti . Coinfection with more than one of these agents can occur.
The rash of EM is characteristic of but not pathognomonic for Lyme disease. Some patients are not aware of having had such a rash and, in others, its appearance is atypical. An EM skin lesion is frequently misdiagnosed as a spider bite or community-acquired methicillin-resistant Staphylococcus aureus (MRSA) cellulitis, resulting in treatment with ineffective antibiotics. Other cutaneous entities in the differential diagnosis for EM include fungal infection, plant dermatitis, and fixed drug eruptions. Secondary lesions may be confused with the target lesions of erythema multiforme, which generally are smaller and nonexpanding. Erythema multiforme also may involve the mucous membranes, palms, and soles; EM does not. The presence of a malar rash in association with Lyme disease suggests systemic lupus erythematosus. Erythema nodosum generally causes more painful induration than EM and has a predilection for the extensor surfaces of the legs. Erythema marginatum of acute rheumatic fever also is in the differential diagnosis for EM; the Lyme disease rash differs in comprising generally fewer, larger, less evanescent lesions that migrate more slowly. Atypical EM manifesting as an urticarial rash may suggest hepatitis B infection or serum sickness. Lyme disease should be considered in a patient with an atypical rash accompanied by a viral syndrome or meningitis-like illness, especially during the months of peak incidence.
Acute rheumatic fever, coronary artery disease, or viral myocarditis may be suggested by the cardiac manifestations of Lyme disease. The carditis of Lyme disease, like the carditis of rheumatic fever, may follow pharyngitis and migratory polyarthritis. Erythema marginatum usually occurs with the onset of arthritis, in contrast with EM, which usually precedes the carditis. Although some patients with Lyme disease may satisfy the clinical aspects of the Jones criteria for acute rheumatic fever, they lack evidence of a preceding streptococcal infection; in addition, valvular involvement is not a prominent feature of Lyme carditis.
The differential diagnosis of the neurologic manifestations caused by Lyme disease is extensive. Considerations include aseptic meningitis, herpes simplex encephalitis, Bell palsy of other causes, radiculopathy due to mechanical causes, multiple sclerosis, Guillain-Barré syndrome, dementia, primary psychosis, cerebral vasculitis, and brain tumor. Neurologic symptoms often occur in the absence of any epidemiologic clues or preceding clinical symptoms suggestive of Lyme disease, making the diagnosis particularly challenging.
Lyme arthritis may mimic other immune-mediated disorders. The arthritis of Lyme disease generally is asymmetric, oligoarticular, and episodic. In contrast to patients with rheumatoid arthritis, those with Lyme arthritis rarely have symmetric polyarthritis, morning stiffness, a positive result on rheumatoid factor assay, or subcutaneous nodules. Lyme arthritis is commonly mistaken for seronegative rheumatoid arthritis; however, Lyme arthritis is most similar to the spondyloarthropathies, particularly reactive arthritis. Lyme disease and reactive arthritis both commonly cause huge knee effusions but, in Lyme disease, absence of the extra-articular features of reactive arthritis (conjunctivitis, urethritis or cervicitis, balanitis, keratosis blennorrhagica) at the time of the onset of arthritis helps distinguish it from reactive arthritis. In children, Lyme arthritis may mimic juvenile rheumatoid arthritis, but joint involvement in Lyme disease usually occurs in short intermittent attacks, and iridocyclitis typically is absent. Rheumatoid factor titers will be negative in juvenile rheumatoid arthritis and Lyme disease. The diseases resemble one another closely enough to have been confused at the time of the initial description of Lyme disease. Other diseases in the differential diagnosis for Lyme arthritis include acute gouty arthritis, septic arthritis, gonococcal arthritis, rheumatic fever, polymyalgia rheumatica, and temporomandibular joint syndrome.
Diagnostic Testing
Results of routine laboratory studies are nonspecific, and such studies generally are not helpful in the diagnosis of Lyme disease. Abnormalities may include an elevated erythrocyte sedimentation rate, mild anemia, total white blood cell count in the normal range with a decreased absolute lymphocyte count, microhematuria, proteinuria, and mildly elevated hepatic transaminases. Cultures of blood, tissue, and body fluids (including CSF and synovial fluid) for B. burgdorferi and direct visualization techniques are difficult to perform properly and have such a low yield that they are not clinically useful.
Serologic testing measuring the host’s antibody response (for IgG and IgM) to B. burgdorferi is the most useful means of confirming a clinical diagnosis of Lyme disease, but is not without limitations. Results of serologic tests should be interpreted within the context of symptoms, considering the presumed stage of Lyme disease. These tests should be regarded only as adjuncts in the diagnostic process. Limitations of the tests’ performance and the interpretation of their findings often result in diagnostic confusion. False-negative and, especially, false-positive results are common. The antibody response to B. burgdorferi develops slowly. The peak of IgM titers appears between 3 and 6 weeks after the onset of illness. Earlier in the course of the illness, IgM titers may be negative. IgM antibody usually returns to nondiagnostic levels 4 to 6 weeks after the peak, but elevations may persist. IgG antibody may be detectable 2 months after exposure and peaks at approximately 12 months. Early antibiotic therapy may blunt or even abolish the antibody response.
A two-tier strategy is recommended for serologic testing—a sensitive enzyme immunoassay (EIA) followed by a Western blot (immunoblot). Positive or equivocal EIA results should be followed by a Western blot. If the EIA is negative, no further testing is necessary. Several Lyme disease serologic assays have recently been cleared by the Food and Drug Administration (FDA) allowing use of an EIA rather than Western blot as the second test in a Lyme disease testing algorithm. IgM and IgG immunoblots should be obtained if early disease is suspected. If late disease is suspected, IgG Western blot alone should be obtained. Criteria for positive Western immunoblotting (requiring the presence of bands at particular locations) have been adopted by the CDC.
About one-third of patients with early localized Lyme disease (erythema migrans) are seropositive at the time of presentation by the two-tier method. Patients with skin lesions typical of EM do not require confirmatory serologic testing, and the rash itself is sufficient for the diagnosis to be made. If the cause of the rash is uncertain, acute and convalescent phase serologic testing may be considered, with the convalescent sample drawn 2 to 4 weeks after the acute sample. In contrast to early localized disease, most patients with early disseminated Lyme disease or late Lyme disease are seropositive.
IgG (and occasionally IgM) antibody may persist for several years after adequate treatment and symptom resolution. Persistent seropositivity is not diagnostic of ongoing infection. Even an IgM response cannot be interpreted as a demonstration of recent infection or reinfection unless the appropriate clinical characteristics are present. IgG antibody that developed after natural infection does not always confer immunity against future infection by B. burgdorferi . Patients who are treated for EM may become reinfected; patients with Lyme arthritis, however, usually have high antibody titers to many spirochetal proteins and seem not to become reinfected. Thus, the expanded immune response of late disease appears to be protective against reinfection, at least in most patients, whereas the immature immune response of early disease does not.
False-positive enzyme-linked immunosorbent assay (ELISA) results are common. Serologic cross-reactivity can occur between B. burgdorferi and other spirochetes, most notably Treponema pallidum . False-positive results for Lyme disease also can occur with relapsing fever, gingivitis, leptospirosis, enteroviral and other viral illnesses, rickettsial diseases, autoimmune diseases, malaria, and subacute bacterial endocarditis. In addition, it is estimated that up to 5% of the normal population will test positive for Lyme disease by ELISA. Bayes theorem states that if the pretest likelihood of the disease is low, the positive predictive value is low: a positive test result is more likely to be a false-positive result. For this reason, screening serologic tests are not indicated in the absence of objective clinical evidence of Lyme disease.
Patients suspected of having acute Lyme neuroborreliosis should be evaluated with serologic tests and routine CSF examination, including cell counts and differential, protein, glucose, Gram stain, and culture. Most patients with neuroborreliosis have positive results on serum serologic testing, thereby making additional laboratory confirmation with CSF serology unnecessary. The PCR assay has low sensitivity when performed on CSF and is not routinely recommended. However, the PCR assay is superior to culture for detecting B. burgdorferi in synovial fluid and has a sensitivity of 73% and specificity of 99% in untreated Lyme arthritis.
Management
Prompt treatment of early disease can shorten the duration of symptoms and prevent progression to later stages of disease. Most manifestations of Lyme disease can be treated successfully with oral antibiotic therapy, with the exception of neurologic abnormalities, which usually require intravenous (IV) therapy. Treatment of Lyme disease is summarized in Table 123.4 .
TABLE 123.4
Treatment of Lyme Disease
Adapted from: New drugs for allergic conjunctivitis. Med Lett Drugs Ther . 2000;42:39-40; and Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis . 2006;43:1089-1134.
| Syndrome and Manifestation | Drug | Adult Dosage | Pediatric Dosage a |
|---|---|---|---|
| Early Lyme disease | Doxycycline b | 100 mg PO bid for 21 days | |
| or | |||
| Amoxicillin | 500 mg PO tid for 21 days | 50 mg/kg/day tid | |
| A lternative | |||
| Cefuroxime axetil | 500 mg PO bid for 21 days | 15 mg/kg/day bid (max dose of 250 mg bid) | |
| or | |||
| Erythromycin (less effective than doxycycline or amoxicillin) | 500 mg PO qid for 14–21 days | ||
| Neurologic disease | |||
|
With an isolated deficit, oral regimens for early disease, used for at least 28 days, may suffice. For a deficit associated with other neurologic manifestations, intravenous therapy is warranted (see below). | ||
|
Ceftriaxone | 2 g IV by single dose for 14–28 days | 75–100 mg/kg/day IV |
| Penicillin G | 20 million units daily in divided doses for 10–14 days | 300,000 units/kg/day IV | |
| A lternative | |||
| Chloramphenicol | 1 g IV qid for 10–21 days | ||
| Cardiac disease | |||
|
Doxycycline b | 100 mg PO bid | |
| or | |||
| Amoxicillin | 500 mg PO tid | 50 mg/kg/day tid | |
|
Ceftriaxone | 2 g IV daily by single dose for 14–21 days | 75–100 mg/kg/day IV |
| or | |||
| Penicillin G | 20 million units daily in divided doses every 4 hours for 14–21 days | 300,000 units/kg/day IV | |
| Arthritis | O ral | ||
| Doxycycline b | 100 mg PO bid for 30 days | ||
| or | |||
| Amoxicillin | 500 mg PO tid for 30 days | 50 mg/kg/day divided tid | |
| P arenteral | |||
| Ceftriaxone | 2 g IV by single dose for 14–21 days | 75–100 mg/kg/day IV | |
| or | |||
| Penicillin G | 20 million units daily in divided doses for 14–21 days | 300,000 units/kg/day IV | |
a Pediatric dosage should not exceed adult dosage.
b Tetracycline, 250 to 500 mg PO qid, may be substituted for doxycycline. Neither doxycycline nor any other tetracycline should be used for children younger than 8 years or for pregnant or lactating women.
c Regimens for radiculoneuropathy, peripheral neuropathy, and encephalitis are the same as those for meningitis.
d Oral regimens are reserved for mild cardiac involvement (see text).
Early Disease
Prompt antibiotic therapy is essential in early Lyme disease because it generally shortens the duration of the rash and associated symptoms and, more importantly, prevents later illness in most patients. Some patients with severe early disease, however, progress to later stages, despite appropriate antibiotic regimens.
The drug of choice for men, nonpregnant and nonlactating women, and children older than 8 years is doxycycline, 100 mg bid for 3 weeks. An advantage of doxycycline is that it also is effective for the treatment of human granulocytic anaplasmosis, which is transmitted by the same tick that transmits Lyme disease. Pregnant or lactating women and children younger than 8 years should receive amoxicillin, 500 mg three times daily orally (20 to 40 mg/kg/day in three doses for children). Cefuroxime axetil has been shown to be as effective as doxycycline and may be used in children of any age, but cephalexin is ineffective in Lyme disease.
Macrolide antibiotics are not recommended as first-line agents for therapy for early Lyme disease. They should be reserved for patients who cannot tolerate doxycycline, amoxicillin, and cefuroxime axetil. Macrolide regimens for adults include azithromycin, 500 mg orally daily for 7 to 10 days, erythromycin, 500 mg orally qid for 14 to 21 days, and clarithromycin, 500 mg orally bid for 14 to 21 days.
A Jarisch-Herxheimer type of reaction may occur in the first 24 hours of antibiotic treatment, consisting of fever, chills, myalgias, headache, tachycardia, increased respiratory rate, and mild leukocytosis. Defervescence usually takes place within 12 to 24 hours. The pathogenesis of this reaction is controversial, but it probably is caused by the killing of spirochetes, with the release of pyrogens. The Jarisch-Herxheimer reaction occurs more commonly with penicillin and doxycycline than with erythromycin, probably because of their superior spirocheticidal activity.
Early Disseminated Infection
Neurologic Disease
For patients with relatively mild symptoms (e.g., solitary facial nerve palsy with normal findings on CSF examination), doxycycline or amoxicillin can be used in the same dosage as for early disease, but the duration of therapy should be extended to 28 days. The use of prednisone for facial nerve palsy from Lyme disease has been suggested but is not currently recommended.
Parenteral antibiotic therapy is required for patients with other objective neurologic abnormalities (e.g., meningitis or encephalitis, peripheral neuropathies, cranial neuritis other than facial nerve palsy) or evidence of the spirochete in the CSF. Ceftriaxone, 2 g/day IV for 14 days (75 to 100 mg/kg/day for pediatric patients), or penicillin G, 18 to 24 million units every 4 hours daily IV for 10 to 14 days, may be used. Ceftriaxone may be more effective than penicillin, and many experts recommend longer courses (e.g., up to 4 weeks). In cases of penicillin or cephalosporin allergy, oral doxycycline may be used for 28 days.
Cardiac Disease
Patients with mild cardiac conduction system involvement, such as a first-degree AV block with a PR interval less than 0.30 second, and no other significant symptoms usually can be treated safely on an outpatient basis with oral doxycycline or amoxicillin for 21 to 30 days. Patients with higher degrees of AV block, including first-degree block with a PR interval of more than 0.30 second or evidence of global ventricular impairment, should be hospitalized for cardiac monitoring and treatment with parenteral antibiotics. Penicillin G, 18 to 24 million units IV in 4 divided doses, or ceftriaxone, 2 g daily for 21 days (50 to 80 mg/kg/day for children), may be used.
The benefit of the adjuvant use of aspirin or prednisone in the treatment of Lyme carditis is uncertain and not currently recommended. Temporary cardiac pacing may be necessary in patients who have severe heart block with hemodynamic instability. The block generally resolves entirely with antibiotic treatment, so the recognition of Lyme carditis in young patients with unexplained heart block is critical for avoidance of unnecessary permanent pacemaker implantation.
Late Infection
Arthritis
In established Lyme arthritis, the response to antibiotic therapy may be delayed for several weeks or months. An oral regimen for 30 days, such as doxycycline, 100 mg orally bid, or amoxicillin, 500 mg tid, usually are effective and, for reasons of cost and convenience, may be selected as first-line therapy given on an outpatient basis before parenteral antibiotic therapy is considered. Persistent or recurrent joint swelling after recommended courses of antibiotic therapy can be treated with another 4-week course of oral antibiotics or with a 2- to 4-week course of IV ceftriaxone. A small percentage of patients with Lyme arthritis, particularly those with HLA-DR4 specificity or antibody reactivity with OspA, may have persistent joint inflammation, despite treatment with oral or IV antibiotics. Such patients often do not respond to any antibiotic therapy and may require arthroscopic synovectomy.
Neurologic Disease
Patients with late neurologic disease affecting the central or peripheral nervous system should be treated with ceftriaxone (2 g once daily IV for 2 to 4 weeks). Alternative parenteral therapy may include cefotaxime (2 g IV three times a day) or penicillin G (18–24 million units IV daily, given in divided doses every 4 hours). Response to treatment is usually slow and may be incomplete.
Lyme Disease and Pregnancy
Similar to the spirochetal agents of syphilis and relapsing fever, B. burgdorferi can be passed transplacentally. In rare cases, Lyme disease acquired during pregnancy may lead to infection of the fetus and possibly to stillbirth, but adverse effects on the fetus have not been documented conclusively. Counseling about the termination of a pregnancy because of maternal Lyme disease is unwarranted.
Lyme disease contracted during pregnancy can be treated and cured. Treatment of pregnant patients can be identical to that of nonpregnant patients with the same disease manifestations, except that doxycycline should be avoided. Most women give birth to normal infants despite documented Lyme borreliosis during their pregnancies.
Vaccination
No vaccine against Lyme disease is currently available in the United States. The LYMErix vaccine (SmithKline Pharmaceuticals, Philadelphia), initially licensed in 1999, was withdrawn from the market in 2002. The vaccine, directed against the outer surface protein A of B. burgdorferi (OspA), was apparently safe but required repeated doses for optimal protection. Ongoing questions about its safety and cost-effectiveness dampened demand for the vaccine.
A history of vaccination with the previously licensed vaccine should not change the approach to management. Because protective immunity produced by the vaccine is short-lived, it is unlikely that previous vaccination will provide any residual protective effect. Vaccination may cause a persistently positive ELISA result but a negative Western blot result.
Prophylaxis and Asymptomatic Tick Bites
A well-designed trial found that a dose of doxycycline given within 72 hours after a bite by a deer tick ( I. scapularis ) effectively prevented Lyme disease. A single 200-mg dose of doxycycline therefore should be considered for adult patients and children 8 years of age and older (4 mg/kg, up to a maximum dose of 200 mg) when all the following criteria are met: (1) the tick is an adult or nymphal I. scapularis ; (2) the tick has been attached for 36 hours or more, as indicated by certainty of the time of exposure or degree of engorgement; (3) prophylaxis can be started within 72 hours after tick removal; (4) the local rate of infection of these ticks with B. burgdorferi is 20% or greater; and (5) doxycycline is not contraindicated. B. burgdorferi infects 20% or more of ticks in highly endemic areas such as New England, parts of the Mid-Atlantic region, and parts of Minnesota and Wisconsin. Most other areas of the United States do not have infection rates high enough to warrant prophylaxis.
The efficacy of single-dose doxycycline in patients who present more than 72 hours after removing a tick is unknown. In children, the dosing and efficacy of prophylactic treatment have not been evaluated. The effectiveness of doxycycline for preventing other infections transmitted by I. scapularis ticks (e.g., babesiosis, human granulocytic anaplasmosis) is unknown and should not be assumed. Other antimicrobial agents effective for treating Lyme disease (e.g., amoxicillin) and even other regimens of doxycycline (e.g., 100 mg bid) have unknown efficacy for Lyme disease prophylaxis. Anyone who has been bitten by a tick should be instructed to seek medical evaluation if symptoms of tickborne illness develop.
Southern Tick-Associated Rash Illness
A rash similar to erythema migrans (EM) has been described in humans following bites of the lone star tick, Amblyomma americanum, found from central Texas and Oklahoma eastward across the southern states and along the Atlantic coast as far north as Maine. The rash may be accompanied by fatigue, fever, headache, muscle and joint pains. This condition has been named southern tick-associated rash illness (STARI). The cause of STARI is not known.
STARI is diagnosed based on symptoms, geographic location, and possibility of tick bite. Because the cause of STARI is unknown, no diagnostic blood tests are available.
It is not known whether antibiotic treatment is necessary or beneficial for patients with STARI. Because STARI resembles early Lyme disease, patients are often treated with oral antibiotics.
Relapsing Fever
Relapsing fever is caused by bacteria of the Borrelia species, order Spirochaetales. Human Borrelia infections occur worldwide, and all are associated with arthropod vectors. The epidemic (louseborne) form of relapsing fever is caused solely by Borrelia recurrentis and is found mostly in Africa, where mortality rates can reach 70% with outbreaks. The endemic form, tickborne relapsing fever (TBRF), is caused by a group of closely related Borrelia species, their names derived from the species names of Ornithodoros tick vectors that carry them. The more common species in North America are Borrelia hermsii, Borrelia turicatae, and Borrelia parkeri . B. burgdorferi has been recognized as the causative agent of the third and most recently described borrelial disease, Lyme disease.
TBRF is maintained in an animal reservoir consisting primarily of wild rodents, including squirrels, mice, rats, chipmunks, and rabbits. It is found predominantly at altitudes of 2000 to 7000 feet in coniferous forest habitats. The tick vectors are argasids (soft ticks) belonging to several species of the genus Ornithodoros, which routinely reside in the nests and burrows of their mammalian hosts. Ticks acquire the infection by feeding on a spirochetemic rodent. The borreliae remain viable in the ticks for several years and can be passed transovarially to the next generation. In addition, soft ticks—unlike hard ticks—can survive up to 10 years, making removal of all infested nests imperative. Two unique characteristics make this genus a significant reservoir and vector. These soft ticks feed for brief periods (15–20 minutes), usually at night, and their painless bite generally is unnoticed by the sleeping victim. Transmission occurs by injection of infected saliva through the bite site or intact skin. Less common modes of transmission (e.g., venipuncture equipment in injection drug users) have been reported.
In the United States, TBRF occurs primarily in the western Mountain and Pacific states, including Montana, Wyoming, Nevada, Colorado, California, and Washington. Between 1990 and 2011, the CDC received 504 reports of TBRF. The groups most commonly affected were males and people between the ages of 10 to 14 and 40 to 44 years. Of all reported cases, 70% were collectively from California, Washington, and Colorado. Most cases involved visitors to those states. Although TBRF is not nationally reportable, it was reported in 12 states in 2011. Outbreaks have been reported among groups of persons sleeping overnight in hunting cabins inhabited by wild rodents. In Texas, most cases were reported in the winter months among people who had been exploring caves.
Clinical Features
In TBRF, the initial febrile episode lasts 3 days. This is followed by an asymptomatic period of variable duration, usually, approximately 7 days. During this time, patients generally feel better and may return to their usual daily activity levels under the assumption that they have recovered from another viral illness. Relapse then occurs, with symptoms that mimic those of the original illness. With TBRF, this cycle repeats itself three to five times. Each successive relapse usually is less severe. Relapse is caused by the spirochete’s unique ability to undergo antigenic variation within the body of the infected host. Each successive antigenic variation is cleared from the bloodstream by specific host antibodies, and a characteristic relapsing febrile course results.
Clinical illness is manifested in two classic stages as each fever episode resolves. The first stage is called the chill phase (high fevers with reported temperatures of up to 106.7°F (41.5°C), mental status changes, tachycardia, and tachypnea), lasting approximately 30 minutes, followed by a flush phase (rapid temperature decrease, sweats, and hypotension), which can be confused with a Jarisch-Herxheimer reaction.
After a postbite incubation period of 4 to 18 days, during which time the host concentration of spirochetes increases, fever of abrupt onset occurs, often accompanied by shaking chills, headache, arthralgias, myalgias, nausea, and vomiting. On occasion, a pruritic eschar may be noted at the site of the tick bite, but this usually is absent by the onset of clinical symptoms. Consequently, the nonspecific nature of the clinical presentation may lead to misdiagnosis of the disease as a viral illness. The patient’s temperature is high, and generalized muscle weakness and lethargy are common. Hepatomegaly, splenomegaly, and jaundice are sometimes seen. Neurologic involvement is less common but can be manifested as delirium, nuchal rigidity, peripheral neuropathy, or pupillary abnormalities. Uveitis, iritis, and other cranial neuropathies can present acutely or, rarely, as long-term sequelae. A macular or petechial rash, more apparent on the trunk than on the extremities, may be present. There is evidence that febrile illness caused by relapsing fever might cause Plasmodium vivax malaria relapse.
Severe cases of TBRF resulting in acute respiratory distress syndrome (ARDS) in California and Nevada near the Lake Tahoe area and in the state of Washington prompted a comprehensive epidemiologic investigation of cases in those areas during a 10-year period. This study showed that ARDS may be more common than was previously suspected. Reported occurrence rates for Jarisch-Herxheimer reaction varied between 6% and 21%, 16% for hypoxia, 8% for elevated liver function test values, and 6% for ARDS; 46% of patients with TBRF required hospitalization.
Differential Diagnoses
On initial presentation, the differential diagnosis is extensive; however, it narrows with the occurrence of relapse. A history of possible soft tick exposure together with recurrent fever should suggest the diagnosis. Other conditions that initially may be considered include malaria, typhus, dengue, yellow fever, Colorado tick fever, and tularemia. Careful examination of blood smears, together with clinical data and other laboratory tests, aid in making the correct diagnosis.
A recently discovered Borrelia species, phylogenetically related to those responsible for relapsing fever, is now known to cause a new tickborne illness called Borrelia miyamotoi disease (BMD). It has been found in the Upper Midwest, mid-Atlantic, and Northeast states and tends to occur in late summer months as opposed to Lyme disease, which tends to occur in midsummer. Caused by the spirochete of the same name, BMD resembles Lyme disease and human granulocytic anaplasmosis (HGA), but the vectors consist of several species of the hard tick genus Ixodes. Headache, fever, and myalgias are the most common symptoms and tend to be more severe than those associated with Lyme or HGA. Diagnosis can be made using blood PCR samples and antibody titers. Giemsa-stained acute blood smears may reveal spirochetemia. Lab tests often show leukopenia, thrombocytopenia, and elevated liver enzymes. Both amoxicillin and doxycycline are effective treatments. ,
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