David C. Tompkins MD1
Benjamin J. Luft MD, FACP2
1Associate Professor of Clinical Medicine, State University of New York at Stony Brook
2Professor and Chairman, Department of Medicine, State University of New York at Stony Brook
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Lyme disease is a vector-borne zoonosis caused by Borrelia burgdorferi, which is a thin, spiral, motile, extracellular bacterium belonging to the family Spirochaetaceae. The hallmark of infection is erythema migrans, an annular erythematous skin lesion that usually appears at the site of the tick bite.
In 1976, Steere and colleagues noted an association between erythema migrans and a cluster of patients with knee arthritis in Old Lyme, Connecticut; they called this syndrome Lyme arthritis.1 In the subsequent decade, these investigators defined the multisystem nature of the disease and modified its name to Lyme disease.
Isolation of the Lyme disease pathogen was not accomplished until 1981, when Burgdorfer and colleagues demonstrated a new spirochete inIxodes ticks collected on Shelter Island, New York.2 In 1982, spirochetes were identified in the midgut of the adult form of the deer tick I. dammini, and were named B. burgdorferi. Conclusive evidence that B. burgdorferi causes Lyme disease came in 1984, when B. burgdorferiwas cultured from the blood of patients with erythema migrans, from the rash itself, and from the cerebrospinal fluid of a patient with meningoencephalitis and a history of erythema migrans.
In the United States, surveillance for Lyme disease was begun by the Centers for Disease Control and Prevention (CDC) in 1982. Since that time, the number of reported cases has increased dramatically; nevertheless, as many as 90% of Lyme disease cases may be going unreported. Lyme disease has been reported in 49 of the 50 states, but most cases occur in the Northeast, the Midwest, and northern California. Nine states account for more than 90% of the nationally reported cases, with Connecticut leading the group. The other states are Rhode Island, New York, Pennsylvania, Delaware, New Jersey, Maryland, Massachusetts, and Wisconsin.3,4 The rising incidence of Lyme disease in the United States may be explained by multiple factors, including an increase in the numbers of ixodid ticks, the expansion of residential areas into previously rural woodlands (habitats favored by ixodid ticks and their hosts), an exploding deer population, and increased recognition.
The Lyme disease pathogen, B. burgdorferi, is maintained in and transmitted by ticks of the I. ricinus complex, including I. scapularis in the northeast and north central United States [see Figure 1], I. pacificus on the West Coast of the United States, I. ricinus in Europe, and I. persulcatus in Asia.5 In Europe, three genospecies of the B. burgdorferi sensu lato complex are pathogenic, including B. burgdorferi sensu stricto, B. garinii, and B. afzelii. B. burgdorferi is the only pathogenic species in North America. The varying relative distribution of these genospecies from region to region throughout Europe and Asia may account for the relative variability of disease syndromes associated with Lyme disease. In the United States, most patients have symptomatic illness,6,7 whereas in Europe most patients are asymptomatic.
Figure 1. Deer Tick
Ixodes scapularis, also known as deer tick or black-legged tick, is the vector of Lyme disease. Adult ticks are approximately 2.5 mm in size—about the size of a sesame seed.
In field studies in Connecticut and New York, B. burgdorferi has been found in 10% to 50% of nymphal and adult I. scapularis ticks.8,9Although B. burgdorferi has been demonstrated in mosquitoes and deer flies, only ticks of the I. ricinus complex seem to be important in the transmission of the spirochete to humans.10 An enzootic cycle of infection is maintained through passage of B. burgdorferi back and forth between ticks and their hosts. Infected nymphal ticks transmit B. burgdorferi to mice, which serve as a reservoir from which uninfected larvae may acquire infecting organisms. In this manner, a high rate of infection can be maintained in the tick population when the organism, ticks, mice, and deer are all present in the environment.
In temperate climatic zones, the seasonal variation of onset of Lyme disease is explained by the ecology of the predominant tick vectors. The ixodid tick has a three-stage life cycle (larva, nymph, and adult) that spans 2 years. Larvae hatch from fertilized eggs in late spring and feed once for 2 or more days in midsummer. Preferred hosts include a broad range of small mammals. The next spring they molt into nymphs and feed again for 3 or 4 days, with the same host range. After this second blood meal, the nymphs molt into adults. Adult I. scapularis organisms have a narrower host range, with a preference for deer. Mating occurs on deer, and the female deposits her eggs and the cycle begins anew.11 During their 2-year life cycle, ticks typically feed once during each of the three stages, usually the late summer for larval ticks, the following spring for nymphs, and autumn for the adults. I. scapularis nymphs appear to be the most important vector for transmission of B. burgdorferi. According to laboratory studies, a minimum of 36 to 48 hours of attachment of the tick is required for transmission. In the United States, most cases involving B. burgdorferi occur between May and August, which corresponds with increased outdoor human and nymphal tick activity.
The risk of infection in a given area depends largely on the density of the tick population, as well as on their feeding habits and animal hosts, which have evolved differently in different locations. In the northeastern and north central United States, I. scapularis ticks are abundant, and a highly efficient cycle of B. burgdorferi transmission occurs between immature larval and nymphal I. scapularis ticks and white-footed mice. This results in high rates of infection in nymphal ticks and a high frequency of Lyme disease in humans during the late spring and summer months.12,13 The proliferation of deer, which are the preferred host of the adult tick, was a major factor in the emergence of epidemic Lyme disease in the northeastern United States during the late 20th century.
Lyme disease is a progressive infectious disease with a wide array of clinical manifestations. In general, three stages of the illness can be distinguished: early localized disease, early disseminated disease, and persisting late disease.
Infection begins locally in the skin after a feeding tick inoculates B. burgdorferi. In most persons, the initial sign of infection is the development of erythema migrans.15 Even at this early phase of infection, the clinical expression of the disease is highly variable. Some persons are relatively asymptomatic, whereas others experience fever, arthralgias, myalgias, conjunctivitis, meningismus, or multifocal erythema migrans, and still others develop more dramatic signs of infection, including acute meningitis, myocarditis with or without conduction block, hepatitis, myositis, or frank arthritis. Up to 50% of infected persons will progress to symptomatic late disease if not treated during the acute phase of the infection. In the chronic phase of the illness, localized inflammatory processes may occur in one or more organ systems, particularly the nervous system and the musculoskeletal system.
The most common manifestation of early localized Lyme disease is erythema migrans, which occurs in up to 85% of patients and develops 3 to 30 days (typically within the first 7 to 10 days) after the bite. The lesion generally appears at the site of a tick bite and is frequently located around the knees, in the axilla, or in the groin.16
Erythema migrans usually begins as a red macule or papule, which expands over the course of days to weeks, presumably as the spirochetes spread centrifugally through the skin [see Figure 2]. Secondary cutaneous lesions may develop from hematogenous dissemination of spirochetes. Local symptoms include pruritus, tenderness, or paresthesias but are generally rare or absent in secondary lesions. Erythema migrans may also appear as a target lesion with variable degrees of central clearing and occasionally with vesicular or necrotic areas in the center.
Figure 2. Erythema Migrans Lesion
An erythema migrans lesion has enlarged over several days and now has a red border with clearing in the center.
In an observational cohort study in 10 endemic states, 118 patients with microbiologically confirmed erythema migrans presented a median of 3 days after symptom onset. Early erythema migrans commonly had homogeneous or central redness rather than peripheral erythema with partial central clearing. The most common associated symptoms were low-grade fever, headache, neck stiffness, arthralgia, myalgia, or fatigue.17 Subsequent episodes of erythema migrans have been reported in patients who received appropriate antimicrobial therapy for an initial episode, whereas primary failure of antibiotics is rare, occurring in only about 0.14% of patients.18
Borrelial lymphocytoma is an uncommon early manifestation of Lyme disease (occurring in approximately 5% of cases), occurring more often in children than in adults.19 It is a tumorlike nodule that typically appears on the ear lobe, nipple, or scrotum and is characterized by a dense lymphocytic infiltrate in the dermis or subcutaneous tissue.20 Borrelial lymphocytoma is usually caused by B. garinii and B. afzelii and is seen more frequently in Europe than in the United States. The lymphocytoma may occur with other manifestations of infection, such as meningitis, choroiditis, or arthritis. Histopathologically, lymphocytoma may be difficult to differentiate from lymphoma. IgG or IgM antibodies against B. burgdorferi are found in the serum of 80% of all patients with borrelial lymphocytoma. Direct detection of B. burgdorferi or specific DNA in lesional skin by culture or polymerase chain reaction is helpful to the diagnosis. In a study from Slovenia, 36 cases of borrelial lymphocytoma were detected during the period 1986 to 1990; patients were treated with antibiotic therapy, and all had complete recovery within an average of 3 weeks.21
Acrodermatitis Chronica Atrophicans
In European patients, especially elderly women with B. afzelii infection, a chronic, slowly progressive skin condition called acrodermatitis chronica atrophicans may develop on sun-exposed acral surfaces. The organism has been cultured from such lesions as long as 10 years after the onset of the disease.22 These lesions may be preceded by erythema migrans and may represent a late or chronic stage of infection. Early lesions have erythematous nodules or plaques with central clearing and involve the extensor areas of the extremities or joints. Later lesions become atrophic and poikilodermatous, resembling scleroderma or lichen sclerosus et atrophicus.
Within several weeks after the onset of Lyme disease, about 4% to 10% of untreated patients develop acute cardiac involvement—most commonly, fluctuating degrees of atrioventricular block; occasionally, acute myopericarditis or mild left ventricular dysfunction; and rarely, cardiomegaly or fatal pancarditis.23 Diffuse T wave changes, ST segment depression, and arrhythmias also are frequently observed. Patients may complain of dizziness, palpitations, dyspnea, chest pain, or syncope.24,25 Although temporary pacing is frequently required for complete heart block, permanent pacing is rarely needed.26 Recovery from the acute cardiac manifestations of Lyme disease is usually complete.
In Europe, B. burgdorferi has been isolated from endomyocardial biopsy samples from several patients with chronic dilated cardiomyopathy.27,28 However, this complication has not been observed in the United States.29 A study from the Netherlands noted improvement in left ventricular ejection fraction in eight of nine B. burgdorferi—seropositive patients with idiopathic dilated cardiomyopathy who were treated with antibiotics.30 Further studies are warranted to clarify the role of B. burgdorferi in acute and chronic heart failure.
In the United States, arthritis is the predominant manifestation of disseminated B. burgdorferi infection, with about 60% of untreated patients developing joint manifestations, usually weeks to years after the initial infection. Months after the onset of illness, patients begin to have intermittent episodes of joint swelling and pain—primarily in the large joints and, occasionally, in the temporomandibular joint.23Musculoskeletal features include arthralgia; intermittent episodes of migratory arthritis, usually monoarthritis or asymmetrical oligoarthritis; and chronic arthritis, usually of the knees.31 Patients with Lyme arthritis usually have higher Borrelia-specific antibody titers than patients with any other manifestations of the illness, including late neurologic manifestations.32 In an observational cohort study of 15 patients with Lyme arthritis, fibromyalgia, or both, symptoms of Lyme arthritis resolved with antibiotic therapy, whereas symptoms of fibromyalgia persisted in 14 of 15 patients treated with antibiotic therapy.33
Although most patients respond favorably to antibiotic therapy, about 10% of adults and fewer than 5% of children with arthritis associated with Lyme disease develop inflammatory joint disease that persists for longer than 1 year, which may eventually lead to joint destruction. In about 10% of patients, particularly those with HLA-DRB1*0401 or related alleles, knee arthritis persists for months or even years.32Autoimmunity may develop within the inflammatory milieu of affected joints in these patients because of molecular mimicry between an immunodominant T cell epitope of the outer surface protein A (OspA) of B. burgdorferi and human lymphocyte function-associated antigen-1, an adhesion molecule that is highly expressed on T cells in synovium.34
Lyme disease is associated with both acute and chronic neurologic abnormalities, affecting both the central and peripheral nervous systems. All the neurologic syndromes associated with B. burgdorferi infection can occur without previous erythema migrans.35 Clinical data support the hypothesis that B. burgdorferi invades the nervous system early in the course of the infection. There is a high frequency of nonspecific complaints that may be referable to central nervous system involvement in patients with erythema migrans. In one series of 314 patients with erythema migrans, 64% had headache and 48% complained of a stiff neck.36 Additional evidence of early invasion of the nervous system is that within the first 3 months after infection, approximately 12% to 15% of patients experience acute meningitis, cranial neuritis, or painful radiculitis, alone or in combination.37
The distinguishing features of meningitis in Lyme disease are evident on CSF analysis: a mild CSF pleocytosis largely consisting of polymorphonuclear leukocytes or mononuclear cells, a modest elevation of the CSF protein level, and a normal CSF glucose level. Meningoencephalitis may be a prominent feature, manifesting as difficulty with memory and concentration and emotional lability.38 MRI abnormalities have been observed in more severely affected patients. In the absence of local antibody production, the diagnosis of chronicB. burgdorferi CNS infection is questionable, although this infection has been demonstrated to occur in rare cases.
Cranial neuropathies may occur with or without meningitis. Any cranial nerve may be affected by Lyme disease, but the seventh nerve (unilaterally and bilaterally) is by far the most frequently affected, with involvement in up to 10% of patients.38 Lyme disease may be responsible for approximately 25% of new-onset Bell palsy in an endemic area, with the palsy sometimes developing before positive serology for Lyme disease.39 Bell palsy in Lyme disease is presumably a peripheral neuropathy, given that no antibody has been found in the CSF of some patients who have been tested.
Lyme disease can cause a painful radiculitis that is manifested by neuropathic symptoms such as numbness, tingling, and burning. This radiculoneuropathy may affect the limbs or the trunk. Fifty percent of patients with this radiculitis have associated cranial nerve palsies. The peripheral nerve damage in Lyme disease is usually an axonopathy rather than a demyelinating syndrome.40
Acute or subacute myelitis can occur and is associated with spastic paraparesis and CSF pleocytosis.41 In rare cases, mononeuritis and a Guillain-Barré-like syndrome have been reported. Acute painful radiculoneuritis is the most striking early-stage neurologic syndrome. In the United States, a subtle form of Lyme encephalopathy, which seems to represent CNS infection, has been reported; it manifests predominantly with cognitive abnormalities. Less common neurologic manifestations include sudden sensorineural hearing loss, cerebellitis, intracranial aneurysm, and myelitis.
In patients in the United States, the diagnosis of Lyme disease is usually made on the basis of the characteristic clinical findings; a history of tick exposure in an area where the disease is endemic, and, except in patients with erythema migrans, an antibody response to B. burgdorferi by enzyme-linked immunosorbent assay (ELISA) and Western blot (immunoblot) testing, interpreted according to the criteria of the CDC and the Association of State and Territorial Public Health Laboratory Directors.42,43 In endemic areas, the presence of the characteristic rash is often appropriate to trigger initiation of antibiotic therapy without serologic confirmation. Also, antibiotic treatment of early localized disease may blunt the antibody response.
In patients presenting with erythema migrans, culture of the involved skin in Barbour-Stoenner-Kelly medium is virtually 100% specific and reasonably sensitive (57% to 86%) for B. burgdorferi.44 The yield from plasma samples is lower, and only occasionally have CSF samples in patients with meningitis yielded culture growth.
In patients with late-stage infection who develop arthritis, PCR testing is greatly superior to culture in the detection of B. burgdorferi in joint fluid.45 B. burgdorferi has not been isolated from the CSF of patients with chronic neuroborreliosis, and B. burgdorferi DNA has been detected in CSF samples in only a small number of such patients. The Lyme urine antigen test has provided grossly unreliable results and, therefore, should not be used to support the diagnosis of Lyme disease.46
Within 3 to 4 weeks after the onset of borrelial infection, an increase in the IgM response to one or more spirochetal antigens can be detected in most patients; the IgM response usually peaks after 6 to 8 weeks and then gradually declines. Humoral responses of IgM to other antigens gradually develop as the disease progresses. Although there are differences in antigenic responses between patients from North America and patients from Europe, antibodies against one or more of the major protein antigens (i.e., OspC [23 kd], 31 kd, 34 kd, 60 kd, or 66 kd) develop as the infection continues. Specific IgG and IgA responses gradually increase during the second and third months of infection and, once established, may remain detectable for years.
Some epitopes of antigenic components of B. burgdorferi, such as proteins with molecular masses of 41 kd and 60 kd, are common toTreponema pallidum, oral treponemes, and even Escherichia coli.47 Such cross-reactivity may result in a significant titer on ELISA screening (see below). False positive reactions have also been reported when sera from patients with juvenile rheumatoid arthritis, rheumatoid arthritis, systemic lupus erythematosus, infectious mononucleosis, or subacute bacterial endocarditis were analyzed for antibodies to B. burgdorferi.
Serodiagnostic tests are insensitive during the first several weeks of infection. In the United States, only about 20% to 30% of patients have positive responses, usually of the IgM isotype, during this period.48 By convalescence, 2 to 4 weeks later, about 70% to 80% of treated patients have seroreactivity. After 1 month, the majority of patients with active infection have IgG antibody responses. In persons who have been ill for longer than 1 month, a positive IgM test result by itself is likely to be false positive; therefore, such a response should not be used to support the diagnosis in this setting.49 In patients with acute neuroborreliosis, especially those with meningitis, the intrathecal production of IgM, IgG, or IgA antibody against B. burgdorferi may often be demonstrated by antibody-capture enzyme immunoassay, but this test is less often positive in patients with chronic neuroborreliosis.50
Two-step serologic testing
Immunofluorescence assays (IFAs) and ELISAs are the two most commonly used methods for the detection of antibodies to B. burgdorferi. ELISAs are more sensitive than IFAs and offer the advantage of easier screening of large numbers of samples. Although B. burgdorferiantibody tests are potentially useful and constantly improving, they have limited sensitivity (primarily in early disease) and specificity, and they have not yet been standardized.51 These limitations have led to erroneous diagnoses and may have contributed to fundamental misunderstandings of Lyme disease. Therefore, a straightforward two-step serologic approach has been proposed by the CDC [see Figure 3]: a positive or equivocal first test, usually an ELISA or indirect IFA, is followed by an immunoblot test on the same serum sample, which can detect IgM and IgG antibodies to individual B. burgdorferi antigens.42,52
Figure 3. Diagnosis of Lyme Disease
Diagnosis of Lyme disease. (ELISA—enzyme-linked immunosorbent assay; IFA—immunofluorescence assay)
The following two criteria are used for interpretation of the immunoblot test:
If the immunoblot test result is negative, the reactive ELISA or IFA result was very probably false positive. Neither ELISA nor immunoblot testing permits detection of fourfold rises in antibody titer (seroconversion).
Some patients lack diagnostic serum levels of specific antibodies but have neurologic involvement and, as a result, have diagnostic levels of antibody in their CSF, because B. burgdorferi organisms reaching this immunologically privileged site remain viable and induce a local immune response.53,54 Intrathecal production of antibody against B. burgdorferi may be demonstrated by using the following formula:
If the ratio is greater than 1, localized production of anti-Borrelia antibodies has occurred.
After antibiotic treatment, antibody titers fall slowly, but IgG and even IgM responses may persist for many years after treatment. Thus, even an IgM response cannot be interpreted as a demonstration of recent infection or reinfection unless the appropriate clinical characteristics are present.
New serologic tests
An ELISA has been developed on the basis of a conserved immunodominant portion (C6) of the B. burgdorferi variable surface antigen (VlsE).55 This assay can be used in vaccinated and unvaccinated patients. The C6 Lyme ELISA is important because it detects both IgM and IgG antibodies in patients with Lyme disease but not in uninfected vaccine recipients.56 This assay, when used together with an assay for another immunodominant antigen from OspC, may have the same level of specificity and sensitivity as the two-step approach (see above).57
The primary goals of therapy for Lyme disease are the control of inflammation and the eradication of the infection. Lyme disease is most responsive to antibiotics early in the course of the disease: erythema migrans typically resolves promptly and later-stage disease is prevented.58,59 Early localized infection that is limited to a single skin lesion, with mild or no systemic symptoms, is uniformly responsive to short-course oral therapy with a number of agents [see Table 1]. Of the antibiotics studied to date, the most effective agents for this stage of disease have been amoxicillin, 500 mg three times a day; doxycycline, 100 mg twice daily; and cefuroxime axetil, 500 mg twice a day. Each of these agents is taken for 14 to 21 days.60 An advantage of doxycycline is its efficacy against human granulocytic ehrlichiosis, a possible coinfection. Amoxicillin should be used in children and pregnant women. About 10% of patients with early-stage Lyme disease experience a Jarisch-Herxheimer reaction (higher fever, redder rash, or greater pain) during the first 24 hours of antibiotic therapy. Patients should be warned of the reaction; if it occurs, the symptoms may be treated with anti-inflammatory agents such as aspirin. Although carditis resolves spontaneously, patients who have atrioventricular nodal block with a PR interval greater than 0.3 second should receive an intravenous regimen as at least part of the antibiotic course (e.g., ceftriaxone, 2 g/day, or penicillin G, 20 million units in four divided doses a day) for 14 to 21 days. Cardiac monitoring is recommended, but the insertion of a permanent pacemaker is not necessary.61
Table 1 Antibiotic Therapy for Lyme Disease
Isolated facial palsies resolve completely or almost completely in nearly all patients. Patients who have facial palsy should undergo a careful neurologic evaluation, including a lumbar puncture and CSF examination. If facial palsy is the only clinical abnormality and CSF findings are normal, current practice is to administer oral antibiotics for 21 to 30 days. Most experts prefer a 30-day course of treatment, however, because of the late neurologic relapses that occasionally occur after shorter courses of therapy. Patients with evidence of active neuroborreliosis should receive a 2- to 4-week course of intravenous ceftriaxone or penicillin G.
Arthritis does not always respond to antibiotic therapy.62 About 10% of patients in the United States have persistent joint inflammation for months or even several years after 2 months or more of oral antibiotic therapy or 1 month or more of intravenous antibiotic therapy.62Patients who have persistent arthritis despite appropriate treatment and negative PCR test results of joint fluid may be treated with anti-inflammatory agents or arthroscopic synovectomy.
Despite receiving appropriate treatment for Lyme disease, a small percentage of patients continue to have subjective symptoms—primarily, musculoskeletal pain, neurocognitive difficulties, or fatigue—that may last for years. This disabling syndrome, which is sometimes called chronic Lyme disease, is similar to chronic fatigue syndrome or fibromyalgia.64 In a large study, however, pain and fatigue were no more common in Lyme disease patients than in age-matched control subjects who had not had the disease.65 In a study of patients with post-Lyme disease syndrome who received either intravenous ceftriaxone for 30 days, followed by oral doxycycline for 60 days, or intravenous and oral placebo preparations for the same duration, there were no significant differences between the two study arms in the percentage of patients who said that their symptoms had improved, gotten worse, or stayed the same.66 There is no evidence that treatment of asymptomatic seropositive patients is beneficial.
Primary prevention strategies will help reduce the number of Lyme disease cases, and some strategies may also prevent other tick-borne illnesses, including babesiosis and human granulocytic ehrlichiosis in the United States and tick-borne encephalitis in Europe. The first line of defense is avoidance of tick-infested habitats when possible; use of personal protective measures (e.g., repellents and protective clothing) in tick-infested habitats and checking for and removing attached ticks; and modifications of landscapes in or near residential areas. Tick control (burning or removing vegetation, acaricide use, and deer elimination) reduces I. scapularis populations by up to 94%, and acaricide application to wildlife decreases nymphal I. scapularis populations by up to 83%. Transmission of borrelial infection requires a period of 24 to 72 hours of tick attachment. Therefore, removal of ticks within 24 hours will usually prevent infection. If an engorged tick is found, a single 200 mg dose of doxycycline administered within 72 hours is effective at preventing the development of Lyme disease.67 A vaccine for Lyme disease (LYMErix), consisting of recombinant OspA and approved by the Food and Drug Administration for persons 15 to 70 years of age, was introduced in the United States in 1998 but was withdrawn from the market in 2002 because of low sales.
Leptospirosis is a worldwide zoonosis acquired by contact with infected animals or by exposure to contaminated soil or freshwater. A variety of animals can be chronically infected and shed viable organisms that can persist in the environment, leading to human infection. The importance of environmental and occupational exposure is reflected by several of the synonyms for this disease: rice-field fever, cane-cutter fever, swamp fever, and mud fever. Clinically, leptospirosis can range from asymptomatic infection to severe multisystem disease with significant mortality. Leptospirosis cases are often undiagnosed because of the protean manifestations of infection, lack of awareness by clinicians, and limited diagnostic tools.68
The genus Leptospira consists of tightly coiled spirochetes that are thin (0.1 µm) and vary in length from 6 to 20 µm [see Figure 4].Leptospira can be cultured on artificial media, but initial cultures may take weeks to grow.69
Figure 4. Leptospira spirochetes
(a) A scanning electron micrograph reveals numerous corkscrew-shaped Leptospira spirochetes atop a 0.1 µm polycarbonate filter. (b)Leptospira spirochetes are visible on a photomicrograph of a liver smear, using a silver-staining technique, taken from a patient with a fatal case of leptospirosis.
In the past, the genus Leptospira was divided into two species, the pathogenic L. interrogans and the nonpathogenic L. biflexa, on the basis of serologic reactivity to the lipopolysaccharide O antigen. A large number of serovars have been identified within each of these species. The classification of the genus Leptospira has undergone extensive reorganization with the application of DNA-relatedness techniques. Thirteen named species and four unnamed genomospecies are now recognized.70 The complete genetic sequence of L. interrogans serovar lai has been determined.71
A wide variety of mammals can become infected with Leptospira and serve as reservoir hosts. Particularly important in human infection are rodents, livestock, and pets.72,73 Animals are often infected early in life and develop persistent infection of the proximal renal tubules. Infected animals are frequently asymptomatic and shed viable spirochetes in the urine for extended periods, contaminating water and soil.Leptospira can persist in a warm, moist environment for several weeks—a fact that correlates with the higher incidence of human infection in tropical areas, particularly during the rainy season. In temperate regions, where survival of the organism in the environment is limited by temperature, the incidence of leptospirosis is seasonal, peaking in the summer and early fall. In the United States, the greatest number of cases have been reported in Hawaii, but cases occur throughout the country. Studies have demonstrated leptospiruria in 41 of 500 healthy dogs in Kansas and 35% of Texas cattle.74,75
Human infection can result from direct contact with urine or tissues of infected animals; such exposure occurs in veterinarians, dairy workers, hunters, and animal handlers. The more common exposure is to contaminated water and soil.76 Outbreaks of leptospirosis have been reported related to ecotourism and adventure sporting events.77,78
Leptospires enter the body through minor cuts and abrasions, mucous membranes, and conjunctiva and by inhalation of infected aerosols. Infection spreads throughout the body via the bloodstream. Motility and the ability to migrate through tissues are felt to be important to the pathogenesis of Leptospira, allowing the spirochete to establish initial infection and to disseminate to sites of end-organ damage.71 A variety of hemolysins and phospholipases and a sphingomyelinase have been identified and may have a role in the ability of this organism to move through tissues. The mechanism by which Leptospira causes tissue damage is not fully understood, but a systemic vasculitis may facilitate migration of the organism into a variety of tissues, accounting for the broad spectrum of clinical illness.79 In addition, the host immune response is felt to contribute to tissue damage and the clinical severity of disease.80 In animals with experimental infections that mimic the more severe icteric Weil disease and hemorrhagic syndromes, the livers and kidneys demonstrate large numbers of leptospires and associated tissue inflammation. Several leptospiral proteins have been identified with homology to host proteins important in hemostasis, which may activate hemolytic pathways and contribute to the hemorrhagic complications seen in severe disease.81
Infection with Leptospira can result in a spectrum of clinical manifestations. Asymptomatic infection is not uncommon, and subclinical or very mild disease that does not lead to medical attention has been reported in several studies.82,83 When symptomatic, leptospirosis has classically been described as a biphasic illness, with a self-limited septicemic phase followed (although not invariably) by an immune phase. Symptoms of infection develop after an incubation period of 2 to 20 days (mean, 10 days). Illness begins abruptly with high fevers, chills, rigors, headache, myalgias, abdominal pain, nausea, vomiting, diarrhea, and cough. Conjunctival suffusion and muscle tenderness, particularly of the calf and lumbar areas, have been cited as distinctive examination findings. Less common physical findings include lymphadenopathy, splenomegaly, and hepatomegaly.84 The acute illness lasts 5 to 7 days. Leptospira can be recovered from the blood and cerebrospinal fluid during the first week of illness, although symptoms of meningitis are not prominent.
The septicemic phase may be followed by a period of improvement in symptoms and absence of fever lasting several days. The onset of the immune phase of illness coincides with the development of specific antibody to Leptospira and the clearance of organisms from the blood and CSF. Leptospires remain detectable in the kidney, urine (leptospiruria), and aqueous humor for several weeks. The immune phase of leptospirosis is often more severe than the septicemic phase and is potentially fatal. The immune phase lasts 4 to 30 days and is characterized by aseptic meningitis, uveitis, iritis, rash, hemorrhagic pneumonitis, and hepatic and renal involvement.71,84,85,86,87,88Mortality in patients with severe disease results from multiorgan failure and pulmonary hemorrhage.
The septicemic and immune phases of leptospirosis are illustrated by the meningeal findings. Early in infection, patients often have severe retro-orbital headaches and photophobia. CSF studies reveal a neutrophilic pleocytosis, with counts ranging from 10 to 1,000 cells/µl.Leptospira can often be demonstrated in the CSF by culture and PCR. During the immune phase of illness, approximately 25% of patients will develop an aseptic meningitis characterized by headache, vomiting, and signs of meningeal irritation. CSF analysis reveals a lymphocytic pleocytosis, and Leptospira can no longer be isolated.
Acute renal failure is reported in 16% to 40% of cases and is associated with tubular necrosis and interstitial nephritis. Jaundice develops in approximately 40% of patients and does not seem to result from hepatocellular damage but, rather, from cholestasis.84 Serum bilirubin levels may be very elevated (usually to less than 20 mg/dl), with more moderate elevations in transaminase concentrations (less than 200 IU/L) and mild elevation of the alkaline phosphatase level.89 Bilirubin levels may take days to weeks to normalize. Pulmonary involvement occurs in up to 70% of cases, and symptoms may range from cough, dyspnea, and hemoptysis to respiratory failure. Severe hemorrhagic pneumonitis and acute pulmonary distress syndrome may occur in the absence of hepatic and renal failure.90 Radiographs reveal patchy alveolar infiltrates that may progress to large areas of consolidation that are thought to represent pulmonary hemorrhage. Significant pulmonary involvement is a poor prognostic sign and is associated with increased mortality.84
Weil disease is the most severe form of Leptospira infection, with a mortality of up to 40%. It may develop during the immune phase of a biphasic illness or progress directly from the acute phase without the characteristic brief improvement in symptoms to fulminant illness. Weil disease is characterized by high fevers and the rapid onset of liver failure, acute renal failure, hemorrhagic pneumonitis, cardiac arrhythmias, and circulatory collapse.71,91
General Laboratory Studies
During the initial septicemic phase of illness, results of routine laboratory tests are not specific; the neutrophil count may be normal or elevated. During the immune phase of illness, the laboratory values are consistent with the specific end-organ dysfunction. Liver dysfunction is often characterized by markedly elevated serum bilirubin levels with less pronounced increases in serum transaminase and alkaline phosphatase levels. Renal function can deteriorate rapidly, with evidence of interstitial nephritis on biopsy. Renal injury may be compounded by associated hypovolemia. In patients with evidence of meningitis, CSF assays reveal a neutrophilic pleocytosis early and, later, a lymphocytic pleocytosis (usually below 500 cells/µl); modest elevation in protein levels (50 to 100 mg/ml); and a normal glucose level.
Specific Laboratory Studies
Leptospirosis can be diagnosed in three ways: by the direct demonstration of organisms in blood, urine, or tissues; by culture; or serologically.
Dark-field microscopy of blood or urine and silver staining of infected tissues have been used to directly visualize leptospires, but both techniques have limited sensitivity and specificity.92 Approximately 104 leptospires/ml are necessary for one cell/field to be visible by dark-field microscopy.93 Immunostaining has been shown to enhance the ability to directly demonstrate leptospires in tissue; however, the reagents are not commercially available.94,95
Leptospira grows slowly in the laboratory, which can limit the utility of culture for diagnosis. Leptospira can be isolated from a variety of body fluids using commercially available semisolid, albumin-polysorbate media. Antibiotic use may limit the sensitivity of culture, and the timing of specimen collection is important. During the first 7 to 10 days of illness, the spirochete can be recovered from blood, particularly during periods of fever, and from CSF. The culture media should be inoculated with several drops of the patient's blood or CSF at the bedside. Alternatively, blood specimens can be collected in heparin or sodium oxalate (citrate anticoagulation is inhibitory); these should be inoculated within 24 hours. Recovery of leptospires from the urine begins after the first week of illness, and as with blood and CSF, inoculation of media should be done promptly (in less than 1 hour after collection). The cultures are incubated at 30° C and are not reported as negative until after a minimum of 6 to 8 weeks. Identification at the species level is available from a few reference laboratories.
The mainstay for the diagnosis of leptospirosis has been by serology, using a microscopic agglutination test (MAT).96 The end point is the highest dilution of serum in which 50% agglutination occurs. The MAT uses live organisms, which are coincubated with the patient's serum and examined by dark-field microscopy for agglutination. A fourfold rise in paired titers or a single titer of greater than 1:800 in a patient with an appropriate history supports the diagnosis. Many patients will have a negative test result during the acute illness, and seroconversion may be delayed as long as 30 days after the onset of clinical illness. The MAT is technically complex to perform and to interpret. In addition, live cultures must be maintained for all the serovars required as antigens.
Because of the complexity of the MAT, rapid screening tests for leptospiral antibody have been developed. IgM antibody becomes detectable during the first week of illness and is more sensitive than MAT when the first specimen is taken early in the illness. Commercially available IgM dipstick assays have been shown to perform well.97,98
An attractive method to confirm a diagnosis of leptospirosis is PCR, which is more sensitive than culture and is particularly useful in early infection, before significant antibody titers develop. Leptospira DNA has been amplified from blood, urine, and various tissues.94,99 However, the PCR test is currently limited to research laboratories.
Antibiotic therapy does not appear to have a clear advantage over placebo for treatment of leptospirosis but does tend to reduce mortality, duration of fever, length of hospitalization, and extent of leptospiruria.100 Most practitioners treat patients with severe disease with parenteral penicillin (1.5 million units every 6 hours), ampicillin (1 g every 6 hours), or ceftriaxone (1 g daily), each for 7 days. Mild infections can be treated with oral doxycycline (100 mg every 12 hours), ampicillin, or amoxicillin. Jarisch-Herxheimer reactions have been reported after treatment with penicillin and ampicillin.101,102
Prevention of leptospirosis can be achieved by limiting high-risk exposure with appropriate protective measures. These include not swimming in potentially contaminated freshwater, wearing rubber gloves and goggles when handling animals, and not walking barefoot. Weekly doxycycline prophylaxis has been shown to be effective at preventing symptomatic infection in persons at high risk for exposure.103
Relapsing fever, caused by spirochetes of the Borrelia genus, is a febrile illness characterized by recurrent episodes of fever and septicemia separated by afebrile periods. Two forms of the disease are recognized: louse-borne and tick-borne.
Louse-borne relapsing fever (LBRF) is caused by infection with B. recurrentis. This spirochete is transmitted from person to person by the human body louse (Pediculus humanus), and humans are the only known reservoir for this organism.104 LBRF usually occurs in epidemics that are associated with social catastrophes, such as war and famine, which foster the conditions (e.g., crowding and poor hygiene) that allow lice to flourish and spread from person to person. In addition, LBRF is endemic in areas of central and eastern Africa and Peru.105Humans become infected by crushing the lice, which releases the spirochetes and permits them to penetrate the skin or mucous membranes.
Tick-borne relapsing fever (TBRF) is caused by at least 15 different species of Borrelia, each of which is associated with a distinct member of the soft ticks of the genus Ornithodoros. In contrast to Dermacentor and Ixodes ticks, which are teardrop shaped with mouth parts visible dorsally, Ornithodoros ticks have an oval body shape and mouth parts located on the ventral surface (not visible dorsally) [see Figure 5]. Adult Ornithodoros ticks are about the size of a sesame seed. Animal reservoirs for these Borrelia species include rodents and small animals, such as squirrels, rabbits, chipmunks, owls, and lizards. Ornithodoros ticks are obligate blood feeders that typically inhabit caves, decaying wood, rodent burrows, and animal shelters. Their bite often goes undetected because they feed rapidly (over 5 to 20 minutes) at night and have a painless bite.106 Infection of humans occurs when the tick releases saliva or excrement during feeding. TBRF has been reported worldwide, with the exception of Antarctica, Australia, and certain areas in the southwestern Pacific. Most cases in the United States occur west of the Mississippi River, particularly in the mountain and high-desert areas.107 Human infection occurs with activity that brings the person into the tick's environment (e.g., camping and cave exploration).
Figure 5. Soft Tick
Ornithodorus, or soft tick, is the vector of the Borrelia species that causes tick-borne relapsing fever. Adult ticks are approximately 2.5 mm in size—about the size of a sesame seed.
After entering the bloodstream, Borrelia spirochetes multiply and can reach levels of 105 to 108 organisms/µl. These periods of spirochetemia are associated with fever and systemic symptoms. With the development of a specific antibody response, the spirochetes are cleared from the blood, becoming sequestered in internal organs, and patients become asymptomatic. In response to immune pressure, theBorrelia organisms undergo modifications of their outer-surface proteins that allow the spirochetes to reemerge into the circulation; reemergence results in recurrence of symptoms.108 This process of antigenic variation in response to specific antibody formation can occur for a number of cycles and is responsible for the relapsing course of clinical disease. The number of febrile relapses is higher for tick-borne infection than for louse-borne infection.
The incubation period of relapsing fever can range from 4 to 18 days and averages about 1 week. In both TBRF and LBRF, illness begins with the abrupt onset of fevers (usually above 39° C [102.2° F]), rigors, myalgias, arthralgias, and severe headache.107,109 Physical findings include conjunctival suffusion, petechiae, abdominal tenderness with hepatosplenomegaly, and altered sensorium. A truncal rash that can be petechial, macular, or papular is common during the primary febrile episode. Almost a third of patients develop neurologic complications, including meningitis, cranial nerve palsies, coma, and seizures.
The primary febrile episode is unremitting until it terminates abruptly after 3 to 6 days. After a period of well-being lasting 7 to 10 days, symptoms recur. Each relapse is usually shorter in duration and less severe in intensity. LBRF often is associated with a single relapse, whereas TBRF often is associated with multiple symptomatic relapses.
Mortality from relapsing fever ranges from 2% to 40% and is higher with LBRF. Death is often from complications of myocarditis, with associated arrhythmias, hepatic failure, and cerebral hemorrhage.
The febrile periods of illness are associated with high-level spirochetemia, and dark-field microscopy or Giemsa or Wright staining of blood smears can directly demonstrate Borrelia [see Figure 6]. Detection of spirochetes is improved with lysed thick smears or acridine orange staining.110,111 Spirochetes are rarely seen on blood smears obtained when the patient is afebrile. Culture is difficult and not readily available. Serology is of limited value, in part because of the antigenic variability of the organisms. Currently available assays target antigens common to other spirochetes and bacteria and do not have a high sensitivity. Serologic tests for both syphilis and Lyme disease may be positive.112
Figure 6. Peripheral Blood from Relapsing Fever Patient
In this thin Wright stain of peripheral blood from a patient in the febrile stage of relapsing fever, several spirochetes can be seen.
The Borrelia species that cause relapsing fever are susceptible in vitro to penicillins, tetracyclines, macrolides, cephalosporins, and chloramphenicol.113 LBRF can be successfully treated with a single oral dose of 500 mg of tetracycline. Young children and pregnant women may be treated with a single dose of erythromycin (500 mg).114 TBRF requires a 5- to 10-day course of antibiotics; shorter courses of treatment are associated with a higher rate of treatment failures. Tetracycline and erythromycin are felt to be equally effective. In patients with meningitis or encephalitis, a 14-day course of parenteral penicillin G, ceftriaxone, or cefotaxime is generally used. Jarisch-Herxheimer reactions are common within the first several hours after initiating antibiotic therapy and may be severe, with rigors, high fever, and hypotension. For this reason, it is recommended that all patients be kept under observation for several hours after the first dose of antibiotics.
Rat-bite fever is a systemic febrile illness that results from infection with Streptobacillus moniliformis in North America and Europe and withSpirillum minus in Asia. These bacteria are transmitted to humans by the bite of a rat or other small rodent. Illnesses from the two organisms are similar, but each has unique clinical features [see Table 2].
Table 2 Characteristics of Rat-Bite Fever
STREPTOBACILLUS MONILIFORMIS INFECTION
The usual incubation period after a rodent bite is less than 10 days (range, 1 to 22 days). Onset of illness is abrupt, with fever, chills, headache, vomiting, and severe migratory arthralgias and myalgias.116 In contrast to S. minus infection, ulceration at the initial bite site and regional lymphadenopathy are usually absent with S. moniliformis infection. Within several days after the onset of the fever, a nonpruritic, maculopapular, petechial, vesicular or pustular rash develops on the extremities, with involvement of the palms and soles. An asymmetrical polyarthritis occurs in a significant number of patients; frank septic arthritis may develop. The large joints are most commonly involved (i.e., knees, ankles, wrists, shoulders, and hips).117
Fever associated with S. moniliformis infection tends to subside after several days, even without specific therapy. The other clinical manifestations usually resolve over the next several weeks. Rare, potentially fatal complications include cardiac involvement (e.g., endocarditis, myocarditis, and pericarditis), meningitis, pneumonia, and abscesses in a variety of solid organs. Two cases of fulminant sepsis and death in previously healthy persons have been reported.118
SPIRILLUM MINUS INFECTION
The original rat bite heals promptly, but 1 to 4 weeks later, the site of the bite becomes swollen, indurated, and painful, and it may ulcerate. In contrast to S. moniliformis infection, S. minus infection usually includes regional lymphadenitis. Headache, fever, chills, and malaise accompany the formation of the ulcer.121 A sparse, dusky-red maculopapular rash appears on the trunk and extremities in many cases. The severe arthritis and myalgias seen in S. moniliformis infection are rare in disease caused by S. minus.
Symptoms of S. minus infection subside after a few days but recur several days later. Without specific antibiotic therapy, fevers lasting 3 to 4 days recur at regular intervals between afebrile periods lasting 3 to 9 days. This relapsing course can persist for several months; in rare instances, fever relapses have occurred for a year or more. More serious complications include endocarditis, myocarditis, meningitis, conjunctivitis, hepatitis, and pleural effusions. Mortality without antibiotic therapy ranges from 6% to 10%.
Leukocytosis is often present with S. minus, and up to 50% of patients will have a false positive test for syphilis. S. minus cannot be grown on artificial media. Initial diagnosis relies on visualization of spirochetes in blood, exudates, or lymph node tissue on culture staining or dark-field microscopy. Intraperitoneal inoculation of mice has been used to establish the diagnosis.121,122 No specific serologic test is available.
Both S. moniliformis and S. minus infections are effectively treated with penicillin given for 10 to 14 days.123 Initial therapy for severely ill patients should be parenteral, but once the patient becomes stable, the course may be completed with oral penicillin or ampicillin. A Jarisch-Herxheimer reaction has been reported with initial therapy for S. minus infection. Oral tetracycline is appropriate for penicillin-allergic patients.
Figure 1 CDC/Jim Gathany.
Figure 4a CDC/Janice Carr.
Editors: Dale, David C.; Federman, Daniel D.