Tick-Borne Illnesses

Chapter 134


Tick-Borne Illnesses




Perspective


Ticks are hematophagous parasites of humans and animals, distributed worldwide. They transmit rickettsial, bacterial, spirochetal, viral, and protozoal diseases and cause disease by means of their own toxins (Table 134-1). As vectors of human disease, ticks rank second in importance only to mosquitoes. People who travel during the summer months may return from endemic areas with tick-borne disease. In addition, reports of infection acquired within urban areas emphasize the need to consider tick-borne illness even in the absence of a history of travel to high-risk areas. Tularemia (category A) and Q fever (category B) are now considered by the Centers for Disease Control and Prevention (CDC) to be significant threats during biologic warfare. For this reason, research involving ticks and their diseases has become increasingly important.



Reports on ticks, their feeding habits, and their possible relation to disease can be found from early history. Pliny (CE 77), in Historia Naturalis, referred to “an animal living on blood with its head always fixed and swelling, being one of the animals which has no exit [anus] for its food, it bursts with over-repletion and dies from actual nourishment.”1 Tick-borne illness was first recognized on the North American continent by Native Americans. According to legend, Shoshone men avoided the “evil spirits” that caused illness by sending only women into certain areas of the Rocky Mountain region known to be especially hazardous. The etiologic association of the tick vector with Rocky Mountain spotted fever (RMSF) was noted by missionaries and by early settlers, who named the affliction tick fever. Physicians in Idaho and Montana recorded the classic clinical descriptions of the disease in 1899.



Principles of Disease



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 an opisthosoma (abdomen)—instead of three. Identification of an arthropod as a tick and subsequent categorization into family and some genera are not difficult (Figs. 134-1 and 134-2). 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 more essential than species identification in assessing the risks of transmission of diseases. Blood-sucking 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) 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 genus Ornithodoros is the vector for relapsing fever. Ixodid ticks (hard bodied) include the genera Ixodes, Dermacentor, Amblyomma, and Rhipicephalus, which are those responsible for the remainder of human tick-borne diseases discussed in this chapter. These ticks need to form a new exocuticle (phase I of feeding) and thus feed slowly during the first 12 to 24 hours. Once it is fully formed, the new endocuticle allows rapid feeding (phase II) and significant engorgement.


In the capitulum of ticks, the sucking structure, consisting of the chelicerae, is surrounded by a sheath from which it protrudes during feeding. Sense organs on the capitulum, or podomeres, help locate a host by means of chemoreceptors. Hair, or setae, on the legs act as tactile and temperature receptors. A special sensory structure, Haller’s organ, is located on the first set of legs and is a humidity and olfactory receptor.


When a suitable location is found, adjacent cheliceral digits incise the skin, and the chelicerae and barbed hypostome are inserted. Two mechanisms prevent the tick from being removed from the skin: the barbed hypostome and a cement-like salivary secretion from the base of the hypostome, composed of lipoproteins and glycoproteins. This allows ixodid ticks to attach 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. The saliva injected during feeding contains many different substances. Both hard and soft ticks produce a histolytic secretion 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 E2, and prostacyclin (prostaglandin I2) 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. All infectious agents as well as 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. Likewise, a tick removed within a few hours after attachment is unlikely to transmit disease. The neurotoxins responsible for tick paralysis also are found in tick saliva.


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



Perspective


Lyme disease, the most common vector-borne disease in the United States, is a tick-borne illness caused by the spirochete Borrelia burgdorferi. The story of Lyme disease began in 1975, when health officials at Connecticut’s 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.2


Lyme disease occurs worldwide and has been reported on every continent except Antarctica.3 It now accounts for more than 95% of all reported cases of vector-borne illness in the United States. The actual overall 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.4


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. During 2000, a total of 17,730 cases of Lyme disease were reported from 44 states and the District of Columbia. Twelve states—Connecticut, Rhode Island, New Jersey, New York, Delaware, Pennsylvania, Massachusetts, Maryland, Wisconsin, Minnesota, New Hampshire, and Vermont—accounted for 95% of cases reported in the nation (Fig. 134-3).4



The principal tick vectors are I. scapularis in the Northeast and Midwest and Ixodes pacificus in the West. Nymphal Ixodes ticks satisfy all known epidemiologic requirements for the zoonosis as it exists in nature. There is no compelling evidence for alternative arthropod vectors of infection.


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 in nature, 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 the transmission of Lyme disease. It is not surprising that more than two thirds of patients with Lyme disease do not recall a tick bite, in view of the small size (1-2 mm) of nymphs (Fig. 134-4). The nymph feeds in the spring and summer, which correlates with a peak incidence of early Lyme disease occurring 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.




Principles of Disease


The spirochete B. 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, alternatively, with tick gut fluids periodically regurgitated during the feeding process.


After an incubation period that lasts several days to several weeks, spirochetemia develops, and Borrelia organisms may migrate outward in 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 manifestations. Although the exact roles of infecting spirochetes, spirochetal antigens, and host immune responses are unknown, it is likely that persistent live spirochetes are 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. Patients with chronic Lyme arthritis have an increased frequency of human leukocyte antigen (HLA) specificity, in particular for HLA-DR4 and, less often, 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 Figure 134-5.




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. After 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 skin and a resultant skin lesion, erythema migrans. Erythema migrans is the most characteristic clinical manifestation of Lyme disease and is recognized in 90% or more of patients. Erythema migrans may go unnoticed if the entire skin surface is not examined.5 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 that of 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 (Fig. 134-6).



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 apparently not in those who receive appropriate antibiotics.


Constitutional signs and symptoms commonly appear in early Lyme disease (Table 134-2). Malaise, fatigue, and lethargy are most common (seen in approximately 80% of patients) and may be severe. Fever typically is low grade and intermittent. Lymphadenopathy usually is regional in the distribution of erythema migrans 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.



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’s and Brudzinski’s 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,” this 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 erythema migrans appears to be approximately 10%.5 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 a variety of 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 meningitis, cranial neuropathies (usually Bell’s palsy), and radiculopathy 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’s and Brudzinski’s signs are absent and computed tomography 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 IgG or IgA) is present in 80 to 90% of patients. CSF polymerase chain reaction (PCR) assay results are positive in less than half of patients,6 probably reflecting the low number of organisms usually present in spinal fluid. Routine testing of CSF by PCR 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’s 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 the peripheral nerves may be involved in the form of thoracic sensory radiculitis, brachial plexitis, mononeuritis, and motor 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. 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. Estimates of the incidence of carditis in untreated patients who have Lyme disease range from 4 to 10%. 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, and ventricular impairment occur less often. In a review of 105 reported cases of Lyme carditis, 49% of cases were third-degree AV block, 16% were second-degree, and 12% were first-degree.7 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, block appears to be at or above the level of 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. 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.



Arthritis.: Although it is classically 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 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. 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 juxta-articular osteoporosis, cartilage loss, cortical or marginal bone erosions, and joint effusions.




Late Lyme Disease


The chronic phase of Lyme disease is characterized by arthritic and less commonly neurologic symptoms. Transition from a pattern of episodic inflammation in early disease to a more indolent persistent inflammation is observed over time. The term chronic (or late) Lyme disease is used to describe 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.8


Late neurologic complications include a wide variety of abnormalities of the central and peripheral nervous systems as well as 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 usually appear months to years after the onset of infection.


The most common late neurologic manifestation of Lyme disease is a chronic encephalopathy that is manifested as a mild to moderately severe impairment of memory and learning. Hypersomnolence and mild psychiatric disturbances (depression, irritability, or paranoia) also may develop.6


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 either 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. Computed tomography and magnetic resonance imaging may reveal multiple white matter lesions.9


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 as well as positive findings on serologic studies.



Diagnostic Strategies


The diagnosis of Lyme disease should be considered on the basis of clinical and epidemiologic features. Identification of the disorder often is difficult, especially in the early stage. A history of tick bite is elicited in only approximately one third of cases. Erythema migrans is present in most patients and, in endemic areas, is considered diagnostic. Isolated late symptoms may emerge months after the initial infection, however, and the patient may not recall the rash. The disease should be considered in patients who live in or have visited an endemic area and who present during the summer months with nonspecific symptoms suggesting a viral illness or meningitis. In addition, the development of monarticular arthritis, multiple neurologic abnormalities, or heart block in previously healthy patients should raise the suspicion of Lyme disease.


Results of routine laboratory studies are nonspecific, and such studies generally are not helpful in 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 increased alanine transferase level. 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.10


Serologic testing is the most practical and useful means of confirming a clinical diagnosis of Lyme disease, but it is not without limitations. Results of serologic tests should be interpreted cautiously within the clinical context, and such tests should be regarded as only adjuncts in the diagnostic process. Current serologic tests measure host antibody response (for both IgG and IgM) to B. burgdorferi. Problems with the performance of these tests and interpretation of 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-linked immunosorbent assay (ELISA) followed by a Western blot (immunoblot). Positive or equivocal ELISA results should be followed by a Western blot. If the ELISA is negative, no further testing is necessary.


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.10


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 erythema migrans 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 developed after natural infection does not always confer immunity against future infection by B. burgdorferi. Patients who are treated for erythema migrans may become reinfected; patients with Lyme arthritis, however, usually have high antibody titers to many spirochetal proteins and seem not to become reinfected.11


False-positive 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.12


Patients suspected of having acute Lyme neuroborreliosis should be evaluated with serologic tests and routine CSF examination. Paired serum and CSF samples should be obtained to evaluate for intrathecal production of antibody, although most patients with neuroborreliosis have positive results on serum serologic testing, thereby making additional laboratory confirmation with CSF serology unnecessary.12 PCR has low sensitivity when it is performed on CSF and is not routinely recommended.6 PCR assay is superior to culture for the detection of B. burgdorferi in synovial fluid and has a sensitivity of 73% and specificity of 99% in untreated Lyme arthritis.13



Differential Considerations


Although Lyme disease is manifested in many ways, each stage has characteristic clinical findings that are helpful in narrowing the scope of a differential diagnosis that at first may seem overwhelmingly broad. Early Lyme disease (erythema migrans and associated constitutional symptoms) may be easily confused with a variety of other diseases, especially if the characteristic rash of erythema migrans 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.


The rash of erythema migrans 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. 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; erythema migrans 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 erythema migrans and has a predilection for the extensor surfaces of the legs. Erythema marginatum of acute rheumatic fever also is in the differential diagnosis for erythema migrans; the Lyme disease rash differs in comprising generally fewer, larger, less evanescent lesions that migrate more slowly. Atypical erythema migrans manifesting as a urticarial rash may suggest hepatitis B infection or serum sickness. Other cutaneous entities in the differential diagnosis for erythema migrans include cellulitis, fungal infection, fixed drug eruptions, plant dermatitis, and insect or spider bites. Lyme disease should be considered in a patient with any 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 erythema migrans, 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’s palsy of other 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 asymmetrical, oligoarticular, and episodic. In contrast to patients with rheumatoid arthritis, those with Lyme arthritis rarely have symmetrical polyarthritis, morning stiffness, a positive result on rheumatoid factor assay, or subcutaneous nodules. Lyme arthritis commonly is 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 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 both 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.



Management


Prompt treatment of early disease can shorten the duration of symptoms and prevent progression to later stages of disease. Most of the various manifestations of Lyme disease can be treated successfully with oral antibiotic therapy, with the exception of neurologic abnormalities, which usually require intravenous therapy. Treatment of Lyme disease is summarized in Table 134-3.




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 important, 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 twice daily for 3 weeks.3 An advantage of doxycycline is that it also is effective for 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 orally (20 to 40 mg/kg per 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.14


Macrolide antibiotics are not recommended as first-line agents for therapy for early Lyme disease.14 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 days3; erythromycin, 500 mg orally four times daily for 14 to 21 days; and clarithromycin, 500 mg orally twice daily 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 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.


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, parenteral antibiotic therapy is required. Ceftriaxone, 2 g/day intravenously for 14 days (75 to 100 mg/kg/day for pediatric patients), or penicillin G, 18 to 24 million units daily intravenously for 10 to 14 days, may be used.14 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 for 28 days may be used.



Cardiac Disease.: Patients with mild cardiac conduction system involvement (first-degree AV block with a PR interval of 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.14 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. Either penicillin G, 18 to 24 million units intravenously, or ceftriaxone, 2 g daily for 21 days (50 to 80 mg/kg/day for children), may be used.


The benefit of adjuvant use of aspirin or prednisone in the treatment of Lyme carditis is uncertain. Temporary cardiac pacing may be necessary in patients who have severe heart block with hemodynamic instability. The block generally resolves completely 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.3 Thirty-day oral regimens, such as doxycycline, 100 mg orally twice daily, or amoxicillin, 500 mg three times daily, usually are effective and, for reasons of cost and convenience, may be selected as first-line therapy given on an outpatient basis before use of parenteral antibiotic therapy is considered.14 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 intravenous ceftriaxone.3 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 either oral or intravenous antibiotics. Such patients often do not respond to any antibiotic therapy and may require arthroscopic synovectomy.





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 and efficacious but required multiple and repeated doses for optimal protection. Ongoing questions about its safety and cost-effectiveness dampened demand for the vaccine.15


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


Although previous expert consensus has recommended that persons bitten by deer ticks (I. scapularis) should not routinely receive antimicrobial chemoprophylaxis,3 this recommendation should be modified in accordance with the findings of a well-designed trial in which a single 200-mg dose of doxycycline given within 72 hours after tick bite effectively prevented Lyme disease.15 A single 200-mg dose of doxycycline 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 of 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 the 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. Infection rates of 20% or greater of ticks with B. burgdorferi generally are reported from 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.3


The efficacy of single-dose doxycycline in patients who present more than 72 hours after removal of a tick is unknown. In children, dosing and efficacy of prophylactic treatment have not been evaluated. The effectiveness of doxycycline for the prevention of other infections transmitted by I. scapularis ticks (e.g., babesiosis, human granulocytic anaplasmosis) is unknown and should not be assumed.15 Other antimicrobial agents that are effective for the treatment of Lyme disease (e.g., amoxicillin) and even other regimens of doxycycline (e.g., 100 mg twice daily) have unknown efficacy for Lyme disease prophylaxis.


Bites from Dermacentor variabilis and Amblyomma americanum do not require prophylactic treatment. Any patient who has been bitten by a tick should be instructed to seek medical evaluation if symptoms of tick-borne illness develop.



Relapsing Fever




Principles of Disease


Tick-borne relapsing fever 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.16 The tick vectors are argasids 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; thus the tick is a major reservoir and vector. These soft ticks feed for brief periods (15-120 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., by way of venipuncture equipment in injection drug users) have been reported.


In the United States, relapsing fever occurs primarily in the western Mountain and Pacific states, including Montana, Wyoming, Nevada, Colorado, California, and Washington. Persons who come in contact with infected ticks from wild rodents are at greatest risk. Outbreaks have been reported among groups of persons sleeping overnight in hunting cabins inhabited by wild rodents.16,17


In tick-borne relapsing fever, the initial febrile episode lasts 3 days. This is followed by an asymptomatic period of variable duration, usually approximately 7 days, during which 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 tick-borne relapsing fever, 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, 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.18

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Jul 26, 2016 | Posted by in ANESTHESIA | Comments Off on Tick-Borne Illnesses

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