Introduction
Vector-borne infections include diseases caused by diverse pathogens (bacteria, viruses, parasites) that are transmitted to humans by a variety of vectors such as ticks, mosquitoes, lice, tsetse flies, sandflies, triatome bugs, blackflies, mites, and snails. Vectors are typically blood-sucking insects that ingest the pathogen from an infected host reservoir (human, animal, bird) and then transmit them to a susceptible human during their next bloody meal. Globally, infections caused by mosquitoes contribute to a significant burden of diseases, especially in tropical and subtropical regions. In the United States, tick-borne infections constitute the majority of the diseases transmitted by vectors. However, the unprecedented increase in global travel and trade over the past decades has resulted in a higher number of Americans at risk of travel-related mosquito-borne infections. It is important that primary care physicians are able to provide appropriate pretravel counseling and other preventive measures to their patients to reduce their risk of acquiring vector-borne infections during their travel outside the United States.
Tick-Borne Infections in the United States: Lyme Disease
Epidemiology
Lyme disease is the most common vector-borne infection reported in the United States, contributing to more than 60% of reported cases. The common vector-borne infections in the United States are listed in Table 15.1 . Lyme disease is caused by the spirochete Borrelia burgdorferi and transmitted by the Ixodes tick. In 1977, an investigation of a cluster of juvenile rheumatoid arthritis among children in Connecticut led to the recognition of Lyme disease. The Centers for Disease Control and Prevention (CDC) estimates that approximately 300,000 people in the United States acquire Lyme disease annually. , Almost all Lyme disease cases are reported from a dozen states in certain geographic regions of the United States, emphasizing the importance of environmental and ecologic factors in the transmission of vector-borne infections. The proportion of ticks infected with B. burgdorferi and other pathogens varies across different regions of the country. Climate change that enables ticks to expand their geographic home, an increase in deer population, and a rise in the number of homes near forested areas have all contributed to the rise in the number of Lyme disease cases in the United States. The causative pathogen— B. burgdorferi —is transmitted primarily by black-legged ticks, Ixodes scapularis, in the northeastern and upper Midwest regions, whereas Ixodes pacificus ticks are the predominant vectors for Lyme disease in northern California and Oregon. During its life cycle, I. scapularis goes through larval, nymph, and adult stages over a period of 2 years. The primary reservoir of B. burgdorferi is the white-legged mouse, from which the larval stage of I. scapularis ticks get infected after taking a bloody meal. Ticks do not fly, but quest on tall grass and get attached to the exposed skin of humans as they pass by. Once attached, the nymphs may go unnoticed by the human host, as they are very small and their bite is painless. If the tick is removed early, Lyme disease can be prevented, as it takes approximately 48 hours for transmission of the spirochete to occur. The nymphal stage of black-legged ticks is the most efficient in transmitting B. burgdorferi. The incidence of Lyme disease peaks in the summer months, corelating with the time period of peak activity of Ixodes nymphs. Adult female I. scapularis ticks feed on deer, and hence they are also called deer ticks. Even though deer is not a reservoir for B . burgdorferi, the deer population is important for survival of adult female I. scapularis ticks and hence for the transmission of Lyme disease.
| Vector-Borne Disease | Pathogen | Vector | Endemic Regions in United States |
|---|---|---|---|
| Lyme disease | Borrelia burgdorferi | Blacklegged deer tick (Ixodes scapularis , Ixodes pacificus) | Northeast, upper Midwest, northern California |
| Human granulocytic anaplasmosis | Anaplasma phagocytophilum | Blacklegged deer tick (Ixodes scapularis , Ixodes pacificus) | Northeast, upper Midwest |
| Babesiosis | Babesia microti | Blacklegged deer tick (Ixodes scapularis , Ixodes pacificus) | Northeast, upper Midwest |
| Human monocytic ehrlichiosis | Ehrlichia chaffeensis | Lone Star tick (Amblyomma americanum) , black-legged deer tick (Ixodes scapularis) | Southeast and southcentral United States |
| Rocky Mountain spotted fever | Rickettsia rickettsii | American dog tick (Dermacentor variabilis) , Rocky Mountain wood tick (Dermacentor andersoni) | Southcentral United States |
| West Nile virus infection | West Nile virus | Culex mosquito | All states in continental United States |
| Tularemia | Fransicella tularensis | American dog tick ( Dermacentor variabilis ) , Lone Star tick ( Amblyomma americanum ), deer flies ( Chrysops spp. ) | Southcentral United States |
| Powassan virus infection | Powassan virus (Flavivirus) | Black-legged deer tick (Ixodes scapularis) , Ixodes cookie, Ixodes marxi | Northeast, upper Midwest |
| Plague | Yersinia pestis | Rodent fleas | Rural Western United States |
Clinical Manifestations of Lyme Disease
Lyme disease can present with a variety of clinical symptoms and often involve multiple systems. The clinical presentations can be divided into three states: (1) early localized, (2) early disseminated, and (3) late Lyme disease. It should be noted that the clinical features may overlap between the three stages, and patients may also present with a late disease manifestation without previous history of early Lyme disease.
Early Localized Lyme Disease
Patients with early localized Lyme disease usually present with a characteristic erythema migrans skin rash and may have accompanying constitutional symptoms, including fatigue, arthralgias, myalgias, headache, fever, and anorexia. Classic erythema migrans has a target-like or bull’s-eye appearance. The rash starts at the site of the tick bite, usually after 7 to 14 days, and then slowly expands over days with a zone of central clearing. Although the classic erythema migrans is considered diagnostic of early Lyme disease, it is seldom seen among patients when they present to their primary physicians. During the first few days of the rash, it is usually homogenously red or has central erythema. The rash is warm to the touch and may itch or burn rarely, but is not painful. Thorough body skin examination is important, as the rash is commonly found in “hidden” parts such as axilla, popliteal fossa, inguinal region, or belt line. Biopsy of the skin lesion is not needed, and it may show signs of vascular endothelial injury.
Diagnosis
Erythema migrans is present in approximately 80% of patients with early Lyme disease, despite only a small minority (around 25%) remembering a history of tick bite. , In the appropriate epidemiologic setting, early localized Lyme disease is diagnosed clinically based on erythema migrans skin rash. Patients may have mild, nonspecific abnormalities in total white blood cell count, erythrocyte sedimentation rate, red blood cell count, platelet and count, so these are not useful in making the clinical diagnosis. Abnormalities in hepatic transaminase levels, thrombocytopenia, and anemia may suggest the presence of coinfections transmitted by the same Ixodes tick bite, such as anaplasmosis or babesiosis. Serology is not a useful diagnostic tool in early Lyme disease and may be misleading, as false-negative results are quite common. Newer molecular methods may be helpful in identifying the coinfections.
Treatment
The important goals of antimicrobial therapy for early localized Lyme disease are to reduce the duration of clinical disease and lower the risk of subsequent occurrence of late Lyme disease manifestations. The first-line antibiotics include oral doxycycline, amoxicillin, and cefuroxime–axetil. Small randomized clinical trials conducted in the United States have shown that three first-line antibiotic regimens have equivalent efficacy in the treatment of early localized Lyme disease. Oral doxycycline, however, is the preferred antibiotic, given its activity against possible coinfecting pathogens such as Anaplasma phagocytophilum, Ehrlichia spp ., and Borrelia miyamotoi . Because of its effectiveness, oral doxycycline may also be used in children less than 8 years of age, as endorsed by the CDC and American Academy of Pediatrics. The preferred antibiotic regimens for different clinical presentations of Lyme disease are listed in Table 15.2 . Although most clinical trials used 21 days of antibiotic treatment, a shorter duration of treatment (10 to 14 days) appears to be equally effective. Many experts prefer shorter regimens (10 days of oral doxycycline or 14 days of oral amoxicillin) for the treatment of early localized Lyme disease. For pregnant women, doxycycline should be avoided due to potential adverse effects, and either a course of oral amoxicillin or cefuroxime–axetil is the preferred regimen. Macrolides such as azithromycin were noted to be not as effective as amoxicillin and are reserved only for patients who cannot tolerate any of the first-line antibiotic agents. Among patients treated with oral macrolides, chances of treatment failure, relapse, or progression to the late stage is significant, and close clinical monitoring is essential. Of note for primary care physicians is that first-generation oral cephalosporins such as cephalexin have no activity against B. burgdorferi and are not recommended for the treatment of Lyme disease. This is clinically relevant, as a common diagnostic dilemma faced by primary physicians in endemic regions is to differentiate between atypical homogenously erythematous early Lyme skin lesion and cellulitis. If it is difficult to separate the two entities, a reasonable approach might involve using oral cefuroxime–axetil that has activity against both B. burgdorferi and common pathogens involved in cellulitis.
| Clinical Syndrome | Antibiotic Regimen for Adults |
|---|---|
| Early Lyme Disease | |
| Localized Erythema Migrans |
|
| Early Disseminated Disease | |
| Multiple Erythema Migrans |
|
| Early Lyme Carditis |
|
| Early Lyme Facial Nerve Palsy |
|
| Early Lyme Meningitis |
|
| Late Lyme Disease | |
| Late Lyme Arthritis |
|
| Late Lyme Central Nervous System Manifestations |
|
Most patients with early localized Lyme disease have complete resolution of symptoms with appropriate antibiotic therapy. However, a small percentage of patients may have persistent subjective symptoms like fatigue, headache, arthralgias, myalgias, and fatigue for several weeks to months after treatment. These patients require reassurance that these symptoms usually resolve spontaneously and do not need further antibiotics, as they do not have active infection. If symptoms persist beyond 6 months, patients are categorized as post–Lyme disease syndrome.
Early Disseminated Lyme Disease
Early disseminated Lyme disease is characterized by hematogenous spread of the spirochete to distant sites such as the skin, heart, and nervous system that present within a few weeks to months after the initial tick bite.
Multiple Erythema Migrans Lesions
The presence of multiple erythema migrans skin lesions is usually a sign of hematogenous dissemination rather than multiple concurrent tick bites ( Figs. 15.1 to 15.3 ). In one study, patients with spirochetemia were more likely to have multiple skin lesions and be symptomatic. In these patients, careful clinical evaluation is indicated to detect involvement of other systems such as the heart and nervous system. Oral doxycycline 100 mg twice daily for 21 days is the recommended antibiotic regimen for patients with multiple erythema migrans and without any evidence of Lyme meningitis or severe Lyme carditis requiring hospitalization. A significant proportion of patients with multiple erythema migrans lesions develop worsening of symptoms in the first 24 hours of antibiotic therapy due to an immune response to antigens released by dying spirochetes, called Jarisch–Herxheimer reaction.
Early Lyme Carditis
Lyme carditis occurs in approximately 1% to 10% of patients diagnosed with Lyme disease in the United States. Early Lyme carditis usually occurs within the first 2 months and may present alone or overlap with erythema migrans and/or early neurologic symptoms. The most common cardiac manifestation is the varying degrees of atrioventricular (AV) block due to dysfunction of the conduction system. Depending on the severity of cardiac involvement, patients may be asymptomatic or have symptoms such as palpitations, lightheadedness, or syncope. A report of three sudden cardiac deaths among otherwise healthy young adults and postmortem evidence of Lyme carditis raised the alarm of this potentially lethal presentation. Rarely patients may also develop mild forms of myopericarditis with nonspecific ST-T changes in the electrocardiogram (ECG) and usually without significant clinical symptoms. Lyme disease does not cause valvular endocarditis or aortitis.
Diagnosis
The CDC recommends two-tier serology testing: initial screening with enzyme-linked immunosorbent assay (ELISA) and confirmatory Western blot analysis for the diagnosis of Lyme carditis. Although serology may be negative during the early few weeks of infection, most patients would have developed a Lyme-specific antibody response by the time they present with symptoms of Lyme carditis. Positive two-tier serology testing in the appropriate epidemiologic risk factors and ECG findings is helpful in the diagnosis of Lyme carditis. Patients with negative Lyme serology are unlikely to have cardiac Lyme disease, and alternative diagnostic evaluation for cardiac conduction abnormalities should be pursued.
Treatment
Symptomatic patients and those with a high degree AV block require close monitoring with cardiac telemetry, as the degree of AV conduction block can fluctuate rapidly. Intravenous (IV) ceftriaxone 2 g daily in adults is the preferred initial regimen for symptomatic patients and those with first-degree AV block with a PR interval more than 300 milliseconds or second- or third-degree AV block. A third-generation cephalosporin (IV cefotaxime) or IV penicillin G are acceptable alternative regimens, and desensitization should be considered for patients with a history of severe immunoglobulin E (IgE)–mediated anaphylaxis to penicillin. Consultation with a cardiac electrophysiologist is helpful, as patients may require implantation of a temporary pacemaker. It is reasonable to continue an IV antibiotic until the high-degree AV block has resolved and then transition to one of the oral antibiotics (oral doxycycline, amoxicillin, cefuroxime axetil) to complete a total of a 21- to 28-day course. With appropriate antibiotic therapy, complete AV block usually improves within a week, and hence, patients do not need permanent pacemaker placement. Minor conduction abnormalities may last up to 6 weeks before resolution.
Early Lyme Neurologic Manifestations
Patients with early disseminated Lyme disease involving the nervous system may present with lymphocytic meningitis, facial nerve palsy, or motor or sensory radiculoneuropathy. Early neurologic symptoms typically occur weeks to several months after the tick bite. A high degree of clinical suspicion is important for diagnosis, as these may be the only and first symptoms of Lyme disease. Abrupt onset of facial nerve palsy is the most common neurologic manifestation of early disseminated Lyme disease. Lyme disease is one of the very few causes of bilateral facial nerve palsies. In endemic regions, Lyme neuritis may constitute up to a quarter of all facial nerve palsies during the summer season. Other cranial nerves may rarely be involved. Severe radicular pain involving one or more dermatomes may be a presentation of Lyme radiculoneuritis involving peripheral nerves. Patients may also rarely present with acute brachial and/or lumbosacral plexopathies.
Early dissemination of spirochetes to the meninges can result in lymphocytic meningitis that may mimic viral meningitis with symptoms of headache, fever, neck stiffness, and photosensitivity. Signs of meningeal irritation may also accompany other clinical manifestations of early Lyme disease, such as erythema migrans, Lyme carditis, facial nerve palsy, or peripheral neuropathy.
Diagnosis
Two-tier serology testing with initial ELISA followed by confirmatory Western blot is the recommended initial test. A positive or equivocal ELISA result should be followed by confirmatory Western blot. If serology is negative, the likelihood of early disseminated Lyme disease affecting the nervous system is very low. Cerebrospinal fluid (CSF) analysis in patients with Lyme meningitis shows lymphocytic pleocytosis (a few hundred lymphocytes per microliter), moderate protein elevation, and relatively normal glucose level. The sensitivity of CSF Lyme antibodies is unclear, and negative CSF antibodies do not eliminate central nervous system (CNS) Lyme disease. Similarly, CSF polymerase chain reaction (PCR) for B. burgdorferi has variable sensitivity and specificity, limiting its utility in clinical diagnosis. Magnetic resonance imaging (MRI) of the brain is usually normal, as brain parenchymal infection is uncommon. In patients with suspected peripheral neuropathy, electromyography and nerve conduction studies are indicated to evaluate the type and distribution of peripheral nerve damage.
Treatment
Patients with isolated facial nerve palsy or peripheral neuropathy may be treated with oral doxycycline 100 mg twice daily for 14 to 28 days. Oral amoxicillin and cefuroxime–axetil have not been tested for this clinical entity. Antimicrobial therapy does not usually accelerate clinical resolution of facial nerve palsy, but helps prevent other complications from disseminated Lyme disease. If there is concurrent meningitis with CSF abnormalities, IV ceftriaxone is recommended. Glucocorticoids have not been shown to be a beneficial adjunctive therapy in patients with Lyme facial nerve palsy. For patients with Lyme lymphocytic meningitis or encephalomyelitis, IV ceftriaxone 2 g daily for 21 to 28 days is the preferred regimen. Some patients may have persistent nonspecific neurologic symptoms such as fatigue and cognitive or memory difficulties for several weeks to months, despite appropriate antimicrobial therapy and microbiologic cure.
Late Lyme Disease
During the early stage of Lyme infection, spirochetes may disseminate hematogenously to different distant sites such as the joints, nervous system, and heart. Appropriate antibiotic therapy given during the early stage of Lyme disease is curative and prevents progression to late Lyme disease. Late Lyme disease develops in a significant proportion of patients who did not receive first-line antibiotic therapy for their early Lyme disease. However, in some patients, late Lyme disease may present even without any clinically significant manifestation of early Lyme disease. Late symptoms usually develop several months to a few years after the tick bite and predominantly involve the joints and/or the nervous system.
Late Lyme Arthritis
Most patients with late Lyme disease present with arthritis involving the knee, usually several months to years after the initial tick bite. Patients usually do not recall a tick bite and may not have experienced clinically apparent early Lyme disease. Among patients with potential exposure to ticks, clinical evaluation of arthritis should include the possibility of late Lyme arthritis. Monoarthritis involving the knee joint is the most common clinical syndrome, but other large joints such as the shoulder, ankle, and wrist may be infected. Patients usually have a large swollen joint that is warm to the touch and minimal pain. Systemic symptoms such as fever, chills, and night sweats are usually absent, and Lyme arthritis may mimic mechanical injury/arthritis. In children, asymmetric oligoarticular Lyme arthritis may resemble juvenile rheumatoid arthritis.
Diagnosis
Synovial fluid analysis usually has an elevated white blood count in the range of 10,000 to 25,000 cells per microliter, consistent with inflammatory arthritis. Two-tier Lyme serology using CDC criteria is the established initial test for the evaluation of patients with suspected Lyme arthritis. Because Lyme arthritis is a late clinical manifestation, the sensitivity of two-tier serology testing is high and has a high negative predictive value. Another fact to remember is that Lyme serology may remain positive for years, even after successful antibiotic treatment for Lyme arthritis. A persistently positive Lyme serology does not mean active/chronic infection and does not necessitate a longer course of antibiotic therapy. Synovial fluid PCR for B. burgdorferi can be tested to help in the diagnosis of Lyme arthritis, but has not been validated for widespread clinical use.
Treatment
Infectious Diseases Society of America (IDSA) guidelines recommend 28 days of oral doxycycline 100 mg twice daily or amoxicillin 500 mg three times daily or cefuroxime–axetil 500 mg twice daily for treatment of Lyme arthritis without concomitant neurologic manifestations. In some patients, clinical resolution may be slow or incomplete with the first course of antibiotics and may require another 28 days of oral antibiotic therapy. For patients who had very minimal or no improvement with the oral regimen, IV ceftriaxone 2 g daily for 14 to 28 days is recommended. Intraarticular steroid injections should be avoided, as they may adversely affect the resolution of Lyme arthritis. If active synovitis persists despite 2 to 3 months of antibiotics, patients might benefit from disease-modifying antirheumatic drugs (DMARDs) used in the treatment of chronic inflammatory arthritis, as the ongoing inflammation is thought to be due to retained spirochetal antigens or autoimmunity triggered by initial infection. In antibiotic-refractory Lyme arthritis, further prolonged antibiotic therapy is of little use, as there is no evidence of active spirochetal infection.
Late Lyme Neurologic Disease
The most common late neurologic syndrome is Lyme encephalopathy that can present with nonspecific symptoms such as fatigue, cognitive slowing, or memory difficulties. Because the symptoms are nonspecific, it is important to identify patients with true Lyme encephalopathy due to active infection. CSF analysis and brain MRI are indicated, and IV ceftriaxone 2 g daily for 21 to 28 days is recommended for those with objective findings. In the absence of objective evidence of active brain infection, presence of nonspecific symptoms alone does not suggest late Lyme disease, and prolonged IV antibiotics have not been helpful. Other uncommon neurologic symptoms associated with late Lyme disease include mononeuritis multiplex, sensory axonal peripheral neuropathy, and encephalomyelitis.
Post–Lyme Disease Syndrome
Although the majority of patients with early Lyme disease have resolution of clinical symptoms with appropriate antibiotic therapy, approximately 5% to 15% of patients have persistent symptoms such as fatigue, musculoskeletal pain, and cognitive and/or memory difficulties. If symptoms persist for more than 6 months, patients may have post–Lyme disease syndrome. The risk factors, pathogenesis, and biologic mechanisms that contribute to persistent symptoms are still unclear, and scientific research to answer these important questions is sorely needed. Microbiologic treatment failure with current first-line antibiotic regimens is very rare, and no resistant strains of B. burgdorferi have been described so far. An alternative term— chronic Lyme disease —which may inaccurately imply chronic persistent infection, has been used by some physicians and patient advocacy groups who have supported longer courses of antibiotics for these patients. However, available current scientific evidence does not support the hypothesis of persistent bacterial infection, and current guidelines from IDSA and American Association of Neurology (AAN) do not recommend additional longer courses of antibiotics for persistent subjective symptoms. , Randomized controlled trials have shown that longer courses of antibiotics did not improve the subjective symptoms. Alternatively, prolonged antibiotics have been reported to have caused serious adverse reactions, including anaphylaxis, catheter-related bloodstream infections, and severe Clostridium difficile infections. Patients with persistent symptoms should be thoroughly evaluated for other alternative medical conditions such as fibromyalgia, underlying malignancy, and depression.
Lyme Disease Acquired in Europe
Lyme disease in Europe can be caused by B. afzelli and B. garinii in addition to B. burgdorferi , the predominant strain in the United States. Certain skin presentations such as borrelial lymphocytoma, acrodermatitis, chronic atrophicans, and morphea-like lesions are seen only among patients who acquired the infection in Europe during their travel. Infections due to B. garinii in Europe have also been associated with rare late neurologic manifestations, including chronic encephalomyelitis, cranial neuropathy, and cognitive impairment.
Coinfections Associated with Lyme Disease
The I. scapularis ticks prevalent in the Northeastern and Midwestern parts of United States may also carry other pathogens such as Anaplasma phagocytophilum and Babesia microti. Approximately up to a third of patients with Lyme disease in these regions have coinfections. ,
Human Granulocytic Anaplasmosis
Anaplasmosis is an infection of human granulocytes with obligate intracellular bacteria, namely Anaplasma phagocytophilum. Around 3% to 15% of patients infected with B. burgdorferi can also have A. phagocytophilum infection transmitted by the same tick bite. White-footed mice are the primary reservoir in the endemic regions. In patients diagnosed with Lyme disease, the presence of leukopenia, thrombocytopenia, and mild-to-moderate elevation in hepatic transaminases suggests coinfection with anaplasmosis. Leukopenia is a common feature and may be either due to lymphopenia or neutropenia, depending on the stage of infection. If untreated, patients may progress to severe disease with multiorgan dysfunction and septic shock physiology. Fortunately, oral doxycycline commonly used for the treatment of Lyme disease is effective against A. phagocytophilum. The other first-line Lyme antibiotics (amoxicillin and cefuroxime) are not effective, and persistent fever beyond 48 hours should prompt evaluation for coinfections. In endemic regions, febrile illness associated with leukopenia and thrombocytopenia with mild elevation of hepatic transaminases during summer or spring are highly suggestive of human granulocytic anaplasmosis (HGA), and prompt antibiotic treatment should be initiated without waiting for confirmatory diagnostic evaluation. Peripheral blood smear may show intracellular inclusions in the granulocyte but lack sensitivity ( Fig. 15.4 ). It takes 2 to 3 weeks for the development of specific antibodies against the infecting organism. Initial ELISA or indirect fluorescent antibody (IFA) test may be negative. A fourfold rise in titer between acute and convalescent IFA is diagnostic of infection. Some laboratories may also offer PCR-based molecular tests for the detection of coinfections. Oral doxycycline 100 mg twice daily for 10 days is the recommended regimen for adults ( Table 15.3 ). Potential benefits of doxycycline exceed the risk of dental staining, and the American Academy of Pediatrics (AAP) recommends its use for patients less than 8 years of age. The use of tetracycline in pregnant women has been associated with maternal hepatotoxicity and adverse effects on fetal bone and teeth development. However, the benefits of doxycycline use outweigh risks for the treatment of HGA in pregnant women.
