Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

65. Borrelia & Leptospira Species

Sandra Chaparro MD

Jose G. Montoya MD

BORRELIA SPECIES

RELAPSING FEVER

Essentials of Diagnosis

  • The most common presentation is fever with rash, headache, shaking chills, myalgias, arthralgias, and—during the acute phase—hepatosplenomegaly.
  • Louse-borne relapsing fever (LBRF) is epidemic, caused by B. recurrentis, and characterized by one or two relapses.
  • Tick-borne relapsing fever (TBRF) is endemic, caused by several Borreliaspecies, and characterized by multiple clinical relapses.
  • Organisms can be visualized in blood smears of febrile patients, unlike other spirochetal pathogens, using dark-field microscopy or Giemsa or Wright stains.
  • Helical (3–10 spirals) spirochetes, 8–30 µm × 0.3 µm, motile (flagella).
  • Weil-Felix reaction: Proteus OX-K agglutinin titers are elevated (this is more common in LBRF).

General Considerations

The syndrome of relapsing fever consists of two clinical entities: epidemic relapsing fever caused by Borrelia recurrentis (LBRF) and transmitted by the human body louse and endemic relapsing fever caused by Borrelia spp. (TBRF) and transmitted by arthropods (Table 65-1).

  1. Epidemiology.
  2. Louse-borne epidemic relapsing fever (LBRF).This form of relapsing fever is transmitted person to person. Human body lice (Pediculus humanus corporis) ingest human blood infected with B recurrentis.The spirochetes multiply in the hemolymph of the lice. Humans become infected with B recurrentis when the fluids from a crushed louse contaminate mucous membranes or abrasions or other breaks in the skin. Humans are the only host for B recurrentis—its occurrence reflects socioeconomic and ecologic factors. Endemic foci are still observed in parts of Africa, South America, and the Far East.
  3. Tick-borne endemic relapsing fever (TBRF).TBRF is caused by ≥ 15 different types of Borreliaspp. and is transmitted to humans by ticks (Ornithodoros spp.). The spirochete is capable of invading all tissues of the tick. Infections in humans occur when saliva or excrement is released while the tick is feeding. The ticks are nocturnal feeders and are rarely noticed. The tick's bite does not cause pain, and feeding is completed after 5–20 min. Many rodents and small animals are reservoirs for Borrelia spp. The spirochete's geographic distribution and occurrence is determined by the biology of the tick. Ticks carrying Ornithodoros spp. are mostly found at altitudes of 1500–6000 feet and in humid, warm climates. TBRF has been reported in Africa, Asia, South America, and the western United States during the summer.
  4. Microbiology.Borreliaspp. belong to the family Treponemataceae. They are motile helical bacteria, 8–30 µm long, 0.2–0.5 µm wide, and with 3–10 loose spirals. Desiccation and UV light kill Borrelia spp. The generation time of these organisms is 18–26 h. They are not cultured in routine clinical laboratories but can be grown in chick embryos.
  5. Pathogenesis.After inoculation in humans from the tick or louse vector, an acute febrile illness ensues, accompanied by a spirochetemia. The bacteria are present in the bloodstream only during the febrile illness. During the afebrile period the bacteria are sequestered in internal organs such as the central nervous system (CNS), bone marrow, liver, and spleen. There is a cycle of antigenic variation with specific antibody responses that explains the relapses of the disease. Each remission is the result of mobilization, opsonization by antibodies produced against the variant strain, agglutination, and phagocytosis of the organism by antibodies produced against the variant strain. Borreliae can cross the placenta and produce abortion or severe infection in neonates.

Clinical Findings

  1. Signs and symptoms.LBRF and TBRF have similar signs and symptoms. The mean incubation period is 7 days (range, 2–18 days). Symptoms include sudden onset of fever, headache, photophobia, sweats, shaking chills, cough, nausea, vomiting, myalgias, and arthralgias (Box 65-1). Common findings include conjunctival suffusion, petechia, upper-quadrant abdominal tenderness, and hepatosplenomegaly. Other complications include gastrointestinal or CNS hemorrhage or both and myocarditis. A truncal rash at the end of the primary febrile episode with tachycardia is common. The fever may be accompanied by hypotension and shock. Fever can reappear with less intensity after 10 days. LBRF has usually a single or few relapses; TBRF has multiple relapses. Each successive relapse of TBRF is milder and of shorter duration. Each intervening afebrile period is longer than the previous one.

Table 65-1. Summary of relapsing fever syndromes1

 

TBRF

LBRF

Agent

Borrelia spp.

Borrelia recurrentis

Vector

Ornithodoros spp.

Pediculus humanus corporis

Reservoir

Rodents, small animals

Humans

Epidemiologic

Endemic

Epidemic

Distribution

Africa, Asia, South America, and western U.S. (during the summer)

Ethiopia, South America, Far East

1TBRF; tick-borne relapsing fever; LBRF; louse-borne relapsing fever

  1. Laboratory findings.LBRF and TBRF are established by the detection of the spirochetes in blood from febrile patients. Borreliaspp. can be detected in 70% of cases with dark-field microscopy, Giemsa-, Wright-, or acridine orange-stained preparations of blood smears or thick and thin smears. Serologies have limited value and are not standardized because of antigenic variation. Cross-reaction may occur with other spirochetes (5–10%). Welix-Felix agglutination of Proteus OX-K in convalescent-phase serum supports the diagnosis. Leukocytosis, mild normocytic anemia, and thrombocytopenia are common. There may also be an elevated sedimentation rate, increased prothrombin and partial thromboplastin times, and an increase in aspartate aminotransferase and bilirubin.

Differential Diagnoses

LBRF and TBRF may be confused with malaria, typhoid fever, hepatitis, leptospirosis, salmonellosis, infectious mononucleosis, viral respiratory infections, rat bite fever, Colorado tick fever, Rocky Mountain spotted fever, and dengue fever. Epidemiologic features and detection of spirochetemia can help to exclude these diagnoses.

Treatment

Relapsing fever responds to doxycycline, tetracycline, erythromycin, penicillin, and chloramphenicol (Box 65-2). One single dose of 500 mg of tetracycline (or erythromycin in children, pregnant patients, or patients with penicillin allergies) for LBRF and a 10-day course for TBRF are usually satisfactory. Antibiotic treatment can induce a Jarisch-Herxheimer reaction within 2 h; this reaction coincides with clearing of the spirochetes. This reaction is not prevented with corticosteroids.

BOX 65-1 Relapsing Fever in Children and Adults1

 

Acute

Relapse

More Common

· Fever

· Rash

· Headache

· Shaking chills

· Nausea, vomiting

· Myalgias

· Arthralgias

· Cough

· Conjunctival injection

· Petechia (more in LBRF)

· Hepatosplenomegaly

· Single relapse with LBRF

· Multiples relapses with TBRF

Less Common

· Nuchal rigidity (meningitis)

· Pulmonary rales, ronchi, pleuritic pain

· Lymphadenopathy

· Jaundice

· Gastrointestinal and CNS hemorrhage

· Myocarditis

· Rupture of the spleen

 

1LBRF, louse-borne relapsing fever; TBRF, tick-borne relapsing fever; CNS, central nervous system.

Prognosis

With appropriate therapy, mortality rates from relapsing fever are < 5%. In untreated patients the fatality rate for LBRF may reach 40%, and in TBRF is ≤ 5%.

Prevention

LBRF can be prevented with good personal hygiene, delousing procedures, and secondary prevention with case detection and treatment (Box 65-3). TBRF requires avoidance or elimination of the tick, using acaricides.

BOX 65-2 Treatment of Relapsing Fever in Children and Adults12

 

LBRF (single dose)

TBRF (7 day course)

First Choice

· Doxycycline 100 mg

· 100 mg at 12-h intervals

Second Choice

· Tetracycline 500 mg

· Erythromycin 500 mg

· Chloramphenicol 500 mg

· Penicillin G (procaine) 600, 000 IU

· 500 mg at 6-h intervals

· 500 mg at 6-h intervals

· 500 mg at 6-h intervals

· 600, 000 IU daily

Pediatric
Considerations3

· Erythromycin 40 mg/kg/day

· Penicilin G (procaine) 10, 000 IU/kg/day

· 40 mg/kg/day

· 10, 000 IU/kg/day

Penicillin
Allergic

· Tetracycline 500 mg

· Erythromycin 500 mg

· 500 mg at 6-h intervals

· 500 mg at 6-h intervals

1Antibiotic treatment can induce a Jarish-Herxheimer reaction within 2 h and coincides with clearing of the spirochetes.

2LBRF, louse-borne relapsing fever: TBRF, tick-borne relapsing fever

3Tetracycline should be avoided in children <9 years of age.

LYME DISEASE

Essentials of Diagnosis

  • Most common in the northeastern, upper midwestern, and western parts of the United States.
  • Borrelia burgdorferiis the longest (20–30 µm) and narrowest (0.2–0.3 µm) spirochete member of the Borrelia genus and has the fewest flagella (7–11).
  • Erythema migrans (EM) is a red expanding lesion with central clearing that is commonly seen during the early stage of Lyme disease.
  • The most common systems affected are the skin (EM), the joints (arthritis), the CNS (facial palsy), and the heart (conduction defects).
  • Serology is not standardized; it is insensitive in early infection and does not distinguish active from inactive infection.
  • Grows in Barbour-Stoenner-Kelly medium from skin biopsy and other specimens.
  • Polymerase chain reaction (PCR) can be useful in synovial-fluid analysis. It has limited value with blood, cerebrospinal fluid (CSF), and urine.

BOX 65-3 Control of relapsing fever 1

 

LBRF

TBRF

Prophylactic Measures

· Good personal hygiene

· Delousing procedures

· Improving socioeconomic conditions (crowding, poverty, homelessness)

· Wear cloth to protect skin

· Avoid rodent- and tick-infested dwellings

· Pest control, repellents, acaricide

1LBRF, louse-borne relapsing fever; TBRF, tick-borne relapsing fever.

General Considerations

Lyme disease is a tick-borne illness caused by the spirochete B burgdorferi. Lyme disease can be divided into early disease (stage 1, EM), disseminated infection (stage 2), and late disease (stage 3, persistent infection). The first stage involves the skin, followed by stages 2 and 3, which often affect the skin, joints, CNS, and heart. However, any of the stages may fail to appear or may overlap with one another (Table 65-2).

  1. Epidemiology.Lyme disease is the most common vector-borne infection in the United States. In 1997, there were 12,801 cases reported in the United States. It is transmitted by ticks from the genus Ixodes. The Ixodes tick goes through a 2-year life cycle that is composed of three stages: larva, nymph, and adult. Tick larvae acquire the spirochete via a blood meal from an infected host. Both the nymph and female adult infect humans. A tick must be attached for at least 24 h to transmit the spirochete. Tick engorgement and attachment for ≥ 72 h are predictors of subsequent human infection. Ixodes ticks in the northeastern and midwestern United States belong to the Ixodes dammini (scapularis) species, in the western United States to Ixodes pacificus, in Europe to Ixodes ricinus, and in Asia to Ixodes persulcatus. Rodents and small mammals are the natural hosts of the larval and nymphal stages. The incidence of Lyme disease reflects a changing dynamic between the principal reservoir, the white-footed mouse, its food supply, and the suitability of its local habitat. Deer, horses, dogs, and other larger mammals and birds may be occasional hosts to the adult ticks. Most cases have their onset during summer and occur in association with hiking, camping, and residence in wooded, rural, or coastal areas.

Table 65-2. Clinical stages of Lyme disease in children and adults

Stage

Timing

Localized erythema chronicum migrans

Early infection

Disseminated infection

Within days or years

Persistent infection

Months to years

  1. Microbiology.Of spirochetes in the Borreliagenus, B burgdorferi is the longest (20–30 µm) and narrowest (0.2–0.3 µm), and has the fewest flagella (7–11). This organism can be grown from skin biopsy and other specimens on an artificial medium called Barbour-Stoenner-Kelly at 33°C. The B burgdorferisurface membrane is studded with lipoproteins called outer-surface proteins (OSPs) A, B, C, D, E, and F; other prominent flagellar antigens include flagellar protein, heat shock protein, and protoplasmic cylinder antigen. B burgdorferi is capable of altering its surface lipoproteins by recombining gene cassettes in a manner that resembles the mechanism of antigenic variation among the relapsing fever borreliae. The antigenic variability seen among different isolates has important implications for serologic tests and vaccine development. In the United States, most strains belong to the genomic group B burgdorferi sensu stricto, and in Europe most strains belong to the groups known as B garinii and B afzelii.
  2. Pathogenesis.After inoculation in the skin, B burgdorferireplicates within the dermis producing EM and spreads hematogenously to other organs. The organism has tropism for the skin, joints, heart and CNS. A rise in immunoglobulin M (IgM) is detected within 2–3 weeks after the onset of infection; an increase in IgG and IgA is established after 2–3 months of infection. Host genetic factors may determine the likelihood of tissue damage; for example, patients with human leukocyte antigens DR4 and DR2 may be more susceptible to chronic arthritis.

BOX 65-4 Systems Affected in Lyme Disease (in Children and Adults)1

More Common

· Skin: Erythema chronicum migrans and acrodermititis chronica atrophicans

· Joints: Asymmetric monoarticular or oligoarticular arthritis

· CNS: Facial palsy, peripheral neuritis, encephalitis, cerebral vasculitis, and chronic encephalopathy

· Cardiac: AV blocks of various degrees

Less Common

· Eye: Conjuctivitis, keratitis, uveitis, retinitis, and optic neuritis

· Liver: Hepatitis

· Lung: Adult respiratory distress syndrome

· Congenital: Intrauterine fetal death, prematurity, cortical blindness, or no adverse outcome

1CNS, central nervous systems; AV, atreoventricular.

Clinical Findings

  1. Signs and symptoms.B burgdorferiinfection can involve the skin, musculoskeletal system, CNS, and cardiac tissues (Box 65-4).
  2. Skin.EM appears at the site of the tick bite 3–30 days after the bite and begins as a red macule or papule with areas of redness that expand with partial central clearing. The lesion often feels warm to hot; it may burn, prickle, or itch, and it is more common in the thigh, groin, and axilla. The lesion usually fades within 3–4 weeks (range, 1 day–14 months). The migratory nature of skin lesions most likely represents spirochetemia with secondary seeding of the skin rather than multiple tick bites. EM may be accompanied by fatigue, fever, chills, achiness, headache, and lymphadenopathy. It can also present with CNS and liver involvement. Multiple annular secondary lesions tend to be smaller and less migratory and to lack indurated centers. Acrodermatitis chronica atrophicans lesions follow years after EM. There is usually bluish-red discoloration, and then the lesion becomes sclerotic or atrophic. This condition has been associated with elevated antibodies to B burgdorferi and usually responds to antibiotic therapy; it is seen primarily in elderly women in Europe.
  1. Musculoskeletal system.Joint symptoms are the second most common clinical manifestation after EM. These symptoms may begin 5–6 weeks (range, 1 week to 2 years) after the bite, and they include, at one end of the spectrum, subjective joint pain, and at the other, arthritis or chronic erosive synovitis. The arthritis is usually of sudden onset, monoarticular or oligoarticular, and migratory. The knee is the most frequently involved joint, followed by the shoulder, elbow, temporomandibular joint, ankle, wrist, and hip. Initially, recurrent attacks of arthritis are common, but their frequency decreases by 10–20% each year. During recurrences, usually more joints are involved than in the initial episode. These attacks last ~ 1 week, with intervals of 1 week to 2 years between attacks. Joint fluid leukocyte counts range from 500 to 110,000 cells/mm3. Of all patients with Lyme disease, ~ 10% develop a severe chronic erosive arthritis often associated with IgG antibody response to OSPs A and B of the organism and with human leukocyte antigen DR4.
  2. CNS.Neurologic abnormalities begin within 4 weeks (range, 2–11 weeks) after the tick bite. The most common symptoms are headache, stiff neck, photophobia, facial palsy, and peripheral nerve paresthesias. CSF findings are similar to those seen in viral meningitis with lymphocytic pleocytosis of ~ 100 cells/mm3and elevated protein levels. Cranial nerve VII is the most frequently involved; unilateral or bilateral facial palsies occur in 11% of patients, and these findings can be seen in 50% of patients with meningitis. Other cranial nerves, particularly III, IV, V, and VIII, are less often involved. Months to years after the initial infection, patients may have chronic encephalopathy (manifested by memory impairment, mood changes, sleep disturbances, and difficulty with concentration), polyneuropathy, or, less commonly, leukoencephalitis. These patients may present with neuropsychiatric symptoms, focal CNS disease, or severe fatigue. However, it is often difficult to establish B burgdorferi as the etiologic agent in patients who present with fatigue or psychiatric manifestations.
  3. Cardiac tissue.Cardiac involvement begins within 5 weeks (range, 3–21 weeks) after the bite, in ~ 5–10% of patients. Such abnormalities usually consist of atrioventricular block (first degree, Wenckebach, or complete heart block) and can last for 3 days–6 weeks. Some patients can present with myopericarditis, pericardial effusion, and chronic cardiomyopathy.
  4. Other clinical findings.Other unusual manifestations include ophthalmologic involvement (conjunctivitis, keratitis, uveitis, choroiditis, retinal detachments, and optic neuritis), hepatitis, myositis, dermatomyositis, eosinophilic lymphadenitis, and adult respiratory distress syndrome.
  5. Congenital infection.Maternal-fetal transmission of B burgdorferihas been reported with adverse fetal and neonatal outcome in a few cases (congenital heart disease, encephalitis, cortical blindness, intrauterine fetal death, and premature birth). Of note, a prospective study found no association between congenital malformation and infection by B burgdorferi. Despite the fact that there is no definitive proof that B burgdorferi causes fetal damage or an adverse outcome in the offspring, prompt diagnosis in the mother and treatment should be emphasized.
  6. Laboratory findings.The diagnosis of Lyme disease is made on clinical findings, epidemiologic features, and an elevated antibody response to B burgdorferi.The available laboratory tests (with the exception of a positive culture from an EM lesion) can be unreliable. Serologic testing only should be undertaken when clinical and epidemiologic features suggest Lyme disease as the diagnosis. Most patients with B burgdorferi are found to have detectable antibodies when tested with enzyme-linked immunosorbent assay (60–70% within 2–4 weeks of infection and 90% by the disseminated and persistent stages). However, serologic tests lack standardization, their accuracy is often unsubstantiated, and false-positive results are common. IgM antibody appears 2–4 weeks after the EM lesion, peaks at 6–8 weeks, and declines after 4–6 months. IgG antibody appears 6–8 weeks after the EM lesion, peaks at 4–6 months, and remains at low levels despite antibiotic therapy. A fourfold rise in antibody titer would be suggestive of recent infection. Western blot analysis is used to confirm results obtained by enzyme-linked immunosorbent assay. The finding that a patient has significant amounts of anti-B burgdorferi–specific antibodies can be interpreted only in the context of the clinical setting. Demonstrating that a patient has an immune response against this organism does not mean that the patient is actively infected or that any symptoms are necessarily related to B burgdorferi infection. Detection of spirochetal DNA by PCR is useful in synovial fluid (75–85% of sensitivity). However, the sensitivity of PCR in CSF, blood, or urine samples has not been well established.

Differential Diagnosis

Lyme disease mimics many different diseases (Table 65-3). The EM lesion may be confused with streptococcal cellulitis, erythema multiforme (the latter lesions tend to be smaller, urticarial, or vesicular and may occur on mucosal surfaces), and erythema marginatum (these lesions are smaller and migrate rapidly in minutes to hours). Lyme arthritis can be distinguished from other rheumatoid diseases, such as acute rheumatic fever, based on the EM lesion and the brief episode of synovitis. The chronic form of Lyme arthritis may resemble pauciarticular juvenile rheumatoid arthritis, psoriatic arthritis, Reiter's syndrome, and reactive arthritis caused by members of the Salmonella, Shigella, Campylobacter, and Yersinia genera. This form of arthritis may also be associated with rubella, hepatitis B, or echoviruses. The aseptic meningitis in Lyme disease may resemble enteroviral, leptospiral, or early tuberculous meningitis. It is important to consider sarcoidosis, Behçet's disease, and multiple sclerosis when the disease becomes chronic.

Table 65-3. Differential diagnosis of Lyme disease1

Stage

Clinical manifestation

Other diagnoses

Localized Infection

· Erythema chronicum migrans

· Streptococcal cellulitis

· Erythema multiforme

· Erythema marginatum

· Tinea corporis (ringworm)

· Nummular eczema

· Granuloma annulare

Disseminated Infection

· 7th nerve palsy

· Idiopathic Bell palsy

· CNS tumor

· Myocarditis (viral and other etiologies)

· Acute rheumatic fever

· Carditis

· Endocarditis

· Meningitis

· Viral meningitis

· Parameningeal infections

· Postinfectious meningoencephalitis

· Leptospiral meningitis

· Tuberculous meningitis

· Listeria partially treated

· Bacterial (pyogenic) meningitis

· Subacute (to chronic) meningitis

· Arthritis

· Acute rheumatic fever

· Malignant effusion

· Post-traumatic effusion

· Hemophilia

· Pyogenic arthritis

Persistent Infection

· Arthritis

· Juvenile rheumatoid arthritis

· Henoch-Schönlein purpura

· Serum sickness

· Collagen vascular disease

· Psoriatic arthritis

· Postinfectious arthritis

· Beh¸et's disease

· Chronic fatigue syndrome

1CNS, Central nervous system.

Treatment

Early disease responds readily to several oral agents (such as doxycycline, amoxicillin, or cefuroxime), which are usually prescribed for 2–3 weeks (Box 65-5). There are few published, controlled trials that compare different regimens for late Lyme disease. Intravenous therapy, usually ceftriaxone or penicillin, is used for 2–3 weeks for late Lyme disease.

  1. Erythema migrans.In EM, oral antibiotic therapy with doxycycline shortens the duration of the rash and prevents the development of late sequelae. Amoxicillin is also effective and preferred for children under 9 years of age and in pregnant or lactating women.
  2. Musculoskeletal disease.Treatment for one month with oral doxycycline or amoxicillin is usually effective. For refractory cases, intravenous therapy with ceftriaxone or penicillin G, and arthroscopic synovectomy may lead to clinical improvement. Analgesics such as acetaminophen or nonsteroidal anti-inflammatory agents should be used in patients with symptomatic arthritis.
  3. Neurologic disease.Patients with facial nerve palsy alone can be treated with oral doxycycline or amoxicillin. Intravenous penicillin G, ceftriaxone, or cefotaxime is effective for meningitis, cranial or peripheral neuropathies, encephalitis, or other late neurologic complications.
  4. Cardiac disease.Patients with cardiac atrioventricular block can be treated with doxycycline or amoxicillin if the PR interval is < 0.3 s. For those patients with more severe cardiac involvement, intravenous ceftriaxone or penicillin should be considered. High-degree atrioventricular block may require temporary pacing.

BOX 65-5 Treatment of Lyme Disease in Children and Adults

 

Oral Therapy

Intravenous therapy

First Choice

· Doxycycline, 100 mg twice per day

· Amoxicillin, 500 mg three times per day

· Ceftriaxone, 2000 mg daily

Second Choice

· Clarithromycin, 500 mg twice per day

· Azithromycin, 500 mg daily

· Cefuroxime, 500 mg twice per day

· Cefotaxime, 2000 mg at 8-h intervals

· Penicillin G, 5 million IU at 6-h intervals

Pediatric Considerations1

· Amoxicillin, 50 mg/kg/day

· Ceftriaxone, 75 mg/kg/day

· Penicillin G, 300, 000 IU/kg/day

Penicillin Allergic

· Clarithromycin, 500 mg twice per day

· Azithromycin, 500 mg daily

· Doxycycline, 100 mg twice per day

· Azithromycin, 500 mg daily

1Tetracycline should be avoided in children < 9 years of age.

Prognosis

Most patients treated promptly with an appropriate antibiotic have an uncomplicated course. True failures are rare, and in most cases re-treatment or prolonged treatment is the result of misdiagnosis and misinterpretation of serologic results rather than inadequate therapy.

Prophylaxis

Routine use of antimicrobial prophylaxis after a tick bite is not recommended. However, some experts recommend amoxicillin for pregnant women who remove an engorged deer tick after exposure in an endemic area. Persons who develop a rash or illness within a month after a tick bite should seek prompt medical attention. Strategies to prevent Lyme disease include avoiding tick habitats, wearing protective clothing, using repellents to avoid tick attachment, promptly removing attached ticks, and using community measures to reduce tick abundance (Box 65-6). The Lyme vaccine is made from recombinant OSP-A of B burgdorferi. Antibodies produced in response to the vaccine destroy spirochetes in the gut of the engorged tick before they can be transmitted. It is indicated for use in adults, in three doses intramuscularly at 0, 1, and 12 months. Ideally the third dose should be given in March because the tick season in the Northeast and upper Midwest usually begins in April. The efficacy of the vaccine has been reported to be 76% after the third dose; however, the long-term safety, timing of booster doses, and cost effectiveness are unknown. Use of this vaccine should be limited to persons with frequent or prolonged exposure to tick habitats in endemic areas.

LEPTOSPIRA SPECIES

Essentials of Diagnosis

  • The most severe forms of leptospirosis commonly present with liver and renal involvement.
  • Transmission occurs by indirect contact with an infected animal.
  • Predisposing factors include occupational exposure (veterinarians and farmers) and recreational exposure (campers and swimmers).
  • These organisms can be detected by dark-field examination, silver or fluorescent antibody stains, or PCR. Tween 80-albumin is the best medium for culture.
  • Motile spirochete, 0.1 × 6–20 µm, with hooked end.
  • Isolation from any clinical specimen or seroconversion or fourfold increase in antibody titers is diagnostic.

BOX 65-6 Control of Lyme disease

Prophylactic Measures

· Doxycycline, 100 mg twice per day by mouth

· Amoxicillin, 500 mg at 8-h intervals per 10 days by mouth

· Vaccine in high-risk workers and persons living or visiting endemic areas

Isolation Precautions

· Wear cloth to protect skin

· Repellents, insecticides

· Check for ticks every 24 h

BOX 65-7 Leptospirosis in Children and Adults

More Common

Anicteric

· Septic phase: (3–7 d) Fever, headache, myalgias, abdominal pain, nausea, vomiting

· Immune phase: (0 d–1 mo) Lower fever, intense headache, aseptic meningitis, conjuctival injection, uveitis, hepatosplenomegaly, pulmonary involvement, skin rashes

Less Common

Icteric

· Septic phase: (3–7 d)

· Imune phase: (10–30 d) Jaundice, renal dysfunction, vasculitis, pulmonary hemorrhage, myocarditis

General Considerations

Leptospirosis is caused by multiple species of Leptospira and is characterized by two different forms of disease. There is a mild form (anicteric) and a severe form (icteric, also known as Weil's syndrome) of leptospirosis.

BOX 65-8 Treatment of Leptospirosis in Children and Adults

 

Anicteric

Icteric

First Choice

· Ampicillin, 500 mg four times daily by mouth

· Amoxicillin, 500 mg four times daily by mouth

· Doxycycline, 100 mg four times daily by mouth

· Penicillin G, 1.5 million IU four times daily intravenously

· Ampicillin, 1000 mg four times daily intravenously

· Amoxicillin, 1000 mg four times daily intravenously

Second Choice

· Tetracycline, 2000 mg/day by mouth

· Erythromycin, 2 500 mg four times daily intravenously

Pediatric
Considerations1

· Ampicillin, 50 mg/kg/day by mouth

· Amoxicillin, 50 mg/kg/day by mouth

· Penicillin G, 6–8 million IU/m2 day intravenously

· Erythromycin, 2 50 mg/kg/day intravenously

Penicillin Allergic

· Doxycycline, 100 mg four times daily by mouth

· Erythromycin, 2 500 mg four times daily intravenously

1Tetracycline should be avoided in children < 9 years of age.
2 Erythromycin is active in in-vitro and animal models but no human clinical data is available.

  1. Epidemiology.Leptospirosis is a zoonosis of worldwide distribution and is especially common in tropical regions. Rodents, dogs, cats, other wild mammals, fish, and birds are important reservoirs. The bacteria can live in the renal tubules of dogs for long periods of time. Transmission to humans occurs by indirect contact with urine, blood, or tissue of an infected animal (eg, by veterinarians or farmers); human-to-human transmission is rare. It can be contracted during recreational activities involving water. Leptospirosis has been reported during the summer and autumn months in the southern and western United States and especially in Hawaii.
  2. Microbiology.Leptospires are spirochetes belonging to the genus Leptospira, which is composed of two species: L interrogansand L biflexa. The pathogenic leptospires belong to the first species and are divided into 200 serotypes that have major antigens in common and are combined into 23 serogroups. Leptospires are motile spirochetes, 0.1 µm wide, 6–20 µm long, and with hooked ends.
  3. Pathogenesis.The bacteria enter the abraded skin or mucous membranes and spread by blood to multiple organs including liver (liver disease occurs in severe cases due to hepatocellular dysfunction including decreased production of clotting factors and albumin, and reduced esterification of cholesterol), kidneys (renal failure due to tubular damage by immune complexes, hypoxemia, or direct toxic effect of the leptospires), CNS (in the first week, the leptospira can be found in the CSF, but no meningitis is seen until the serum antibody appears), eye (can produce chronic or recurrent uveitis), muscle (changes include cytoplasmic vacuoles and polymorphonuclear leukocyte infiltration), and blood vessels (vasculitis, capillary injury, and hemolysis are characteristic features).

Clinical Findings

  1. Signs and symptoms.Leptospirosis has an incubation period of 1–2 weeks. Among infected patients who develop leptospirosis, 90% have the anicteric form, and 10% have the icteric form. There are two phases—septic and immune. The septic phase lasts 4–7 days and consists of a flulike syndrome; during this phase leptospiras can be found in the bloodstream. The immune phase lasts 4–30 days and consists of aseptic meningitis, uveitis, iritis, rash, and hepatic and renal involvement. During this phase, leptospiras can be found in urine and aqueous humor (Box 65-7).
  2. Anicteric leptospirosis.The septic phase is characterized by fever, headache, myalgias, abdominal pain, nausea, and vomiting. The immune phase consists of less prominent fever, intense headache, aseptic meningitis, conjunctival suffusion, uveitis, hepatosplenomegaly, pulmonary involvement, and skin rashes.
  3. Icteric leptospirosis.The septic phase resembles that of the anicteric leptospirosis. The most prominent manifestation during the immune phase is hepatorenal dysfunction with hemorrhagic diathesis.
  4. Laboratory findings.Laboratory findings in anicteric leptospirosis include normal leukocyte counts with neutrophilia and elevated ESR and CSF protein. Pulmonary and myocardial involvement; high bilirubin levels; increases in alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase, creatinine, and blood urea nitrogen; and thrombocytopenia are commonly found in icteric leptospirosis. The diagnosis is made by isolation of the organism from any clinical specimen or seroconversion or fourfold increase in antibody titer. The bacteria can be isolated from blood or CSF during the first 10 days. Tween 80-albumin medium is preferred, and multiple cultures should be performed. The organisms can also be detected by dark-field examination, PCR, silver stains of body fluids or fluorescent antibody stains of tissue. Leptospira-specific antibodies can be detected by macroscopic agglutination with killed antigen, microscopic agglutination with live antigen (more specific) and enzyme-linked immunosorbent assay. Agglutinins appear after 6–12 days, and peak titers are reached in 3–4 weeks. Cross-reaction is common with other spirochetal diseases.

BOX 65-9 Control of leptospirosis

Prophylactic Measures

· Doxycycline 200 mg once a week

Isolation Precautions

· Effective rat control

· Avoidance of infected urine and tissues from animals

· Vaccination of animals

Differential Diagnoses

Differential diagnoses include dengue, dengue fever, hemorrhagic fever, LBRF, TBRF, and other diseases caused by arthropod-borne and rodent-borne pathogens.

Complications

Aseptic meningitis is the most common complication in the anicteric cases. Renal failure, liver damage, pulmonary hemorrhage, vasculitis, and myocarditis are less common but are the usual causes of death.

Treatment

Penicillin G or doxycycline are effective even when treatment is delayed (Box 65-8). Penicillin G or ampicillin should be used in severely ill patients. In less severely ill patients, an oral dose of ampicillin, doxycycline, or amoxicillin can be used.

Prognosis

In the absence of jaundice, the disease is rarely fatal. The mortality rate in icteric patients under 30 years of age is 5%; in the elderly the rate is 30–40%.

Prevention

Doxycycline can prevent infection (Box 65-9). However, prevention is problematic because exposure is difficult to predict. Effective rat control and avoidance of infected urine and known contaminated water sources are important preventive measures.

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