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Chapter 4 Tick-borne bacterial zoonoses.

Objectives

After completing this chapter, the learner should be able to

* Briefly describe the history of ticks and tick-borne diseases

* Describe basic tick biology

* Identify unique characteristics of ticks

* Differentiate between soft and hard ticks

* Describe methods of controlling ticks

* Describe protective measures veterinary professionals can take to prevent contracting tick-borne zoonoses

* Describe the causative agent of specific tick-borne bacterial zoonoses

* Identify the geographic distribution of tick-borne bacterial zoonoses

* Describe the transmission, clinical signs, and diagnostic procedures for tick-borne bacterial zoonoses

* Describe methods of controlling tick-borne bacterial zoonoses

Key Terms

capitulum

chelicera

festoons

horizontal transmission

hypostome

idiosoma

larva

molting

nymph

pedipalps

questing

scutum

transovarial transmission

transstadial transmission

vertical transmission

OVERVIEW

Ticks transmit a wide array of pathogens including bacteria, viruses, and parasites. Ticks typically transmit disease via a bite; however, direct contact, ingestion, aerosol exposure, transfusion, and maternal transmission can also occur. Ticks have been around in the same form for about 200 million years making them one of the oldest and most successful groups of arthropods. Greeks described ticks as pests and ticks are typically regarded in literature with disgust.

The discovery that ticks transmit disease preceded the discovery of mosquito-borne (malaria and yellow fever) and flea-borne (plague) diseases. In 1893, Smith and Kilbourne established ticks as the vector of Babesia bigemina, the protozoal agent that causes Texas cattle fever. In 1903, J. E. Dutton proved that ticks were vectors of human disease when he discovered the cause of endemic relapsing fever and its vector, the soft-tick Omithodoros moubata. In a short period of time, Dermacentor ticks were discovered as the vectors of Rocky Mountain spotted fever (RMSF) (H. T. Ricketts) and tularemia (R. R. Parker and E. Francis). An extensive list of tick-borne diseases now exists including viral encephalitides, hemorrhagic fevers, Colorado tick fever, Q fever, ehrlichiosis, anaplasmosis, and babesiosis.
Mosquitoes are the only arthropods that
transmit more disease than ticks.


TICKS

Causative Agent

Ticks are primitive, obligate, blood-sucking parasites that prey on every class of vertebrate (including mammals, birds, reptiles, and amphibians) in all parts of the world. Ticks are members of the Kingdom Animalia, phylum Arthropoda, subphylum Chelicerata, class Arachnida, and order Acarina. Ticks that transmit disease to animals and humans can be divided into two groups: the hard ticks (Ixodidae) (Figure 4-1) and the soft ticks (Argasidae). Table 4-1 characterizes these ticks. A third group of ticks, Nuttallielloidea, contains only the African species, Nuttalliella namaqua, and do not cause clinical disease. In contrast to other bloodsucking arthropods, ticks have long life cycles, consume large volumes of blood (up to 4 to 5 mL per tick), and produce large numbers of eggs.
Tick-killing compounds are sometimes
called acaridcides (from their order
name).


Epizootiology and Public Health Significance

Ticks are found in nearly every country throughout the world; however, only a few species are known to cause disease in humans and animals. Globally, tick-borne pathogens account for more than 100,000 human illnesses annually. Because humans are atypical hosts, tick-borne diseases are usually acute and severe. Examples of tick-borne diseases of humans include Lyme borreliosis, Crimean-Congo hemorrhagic fever (CCHF), ehrlichiosis, anaplasmosis, Q fever, babesiosis, tularemia, RMSF, Colorado tick fever, Russian spring summer encephalitis (TBE), and African tick typhus.

In animals, ticks can affect livestock production, cause irritation, and produce disease. Livestock production can be affected through blood loss (some ticks consume large amounts of blood that cause anemia); wounds that may cause pain, ulcerate, and lead to secondary infection (which can lower weight gain or milk production); and initiation of disease (including paralysis or infection). Wildlife may show signs of tick-borne disease or they may be asymptomatic and serve as a reservoir host for some diseases. Examples of tick-borne diseases of animals include Lyme disease, tick paralysis, tularemia, RMSF, hemobartonellosis, canine ehrlichiosis, Q fever, and cytauxzoonosis.
All ticks are epidermal parasites during
their larval, nymphal, and adult instars
(stages).


[FIGURE 4-1 OMITTED]

Identifying Ticks

All ticks have a general morphology consisting of two body regions: the capitulum (the cranial portion containing mouthparts) and the idiosoma (the caudal portion containing most internal organs and bearing the legs). Tick identification is based on characteristics of this morphologic scheme such as its shape, size, mouth parts, color, dorsal shield (scutum), and festoons (caudal abdominal markings). Figure 4-2 illustrates the parts of ticks.

* Mouthparts are found on the capitulum. Mouth parts of adult soft ticks are located on the ventral surface and are not visible dorsally. For adult hard ticks, mouth parts are visible dorsally and are either short (Dermacentor), long (Ixodes) or the longest (Amblyomma).

* The scutum is the dorsal plate or shield covering the cranial part of the body in female hard ticks and the entire dorsal surface in male hard ticks (the full scutum of male hard ticks limits the increase in size with engorgement). Soft ticks have a leathery or wrinkled appearance because they lack a scutum.

* Festoons are rectangular grooves seen on the caudal edge of some hard ticks and appear as a string of pearls. Dermacentor, Haemaphyalis, Rhipicephalus, Anocentor, and Amblyomma have festoons present, whereas Boophilus, Hyalomma, and Ixodes ticks do not. Soft ticks such as Omithodoros do not have festoons.

* In adult, nonengorged ticks, there are three major body shapes: teardrop, oval, and rounded. Both Dermacentor and Ixodes hard ticks have a teardrop shape that tapers at the mouthparts. Amblyomma hard ticks are more rounded. Omithodoros soft ticks have a characteristic full oval body shape.

* Size is commonly used to identify ticks, but is not as specific as other characteristics. In general, larvae and nymphs are significantly smaller than adult ticks and engorged adult ticks are significantly larger than nonengorged adults. Male ticks are often somewhat smaller than female ticks. Relative size of ticks from one species to another can also aide in tick identification (adult Dermacentor and Omithodoros are approximately the size of a sesame seed; adult Ixodes and adult male Amblyomma ticks are approximately one-half the size of a sesame seed; adult female Amblyomma ticks are larger than a sesame seed).

[FIGURE 4-2 OMITTED]

Tick Life Cycles

All ticks undergo four basic stages: egg, larva, nymph, and adult. These stages may take 6 weeks to 3 years to complete depending on the species of tick and environmental conditions, such as temperature (ticks in tropical regions have short life cycles, whereas ticks in cold climates have long life cycles) and host availability (some hard ticks can go several months without feeding). All stages except the egg require a blood meal from a host for transition to the next stage of development. Following emergence from the egg, ticks molt from one form to the next. Each stage between molts is called an instar and many times each instar will have a somewhat different body conformation. Ixodidae (hard ticks) have only one nymphal instar, whereas Argasidae (soft ticks) may have as many as five. Ticks are paurometabolous meaning that the immature stages resemble smaller forms of the adults.

Hard Ticks

Stages of Hard Ticks

Ixodidae (hard) ticks have three distinct life stages: larvae, nymphs, and adults. Only one blood meal is taken during each of the three life stages. After feeding the tick then drops off the host.

* Larvae emerge from the egg and have three pairs of legs (six legs total). Larvae obtain a blood meal from a vertebrate host and molt to the nymphal stage.

* Nymphs are the outcome of larvae molting and have four pairs of legs (eight legs total). Nymphs feed and molt to the next and final stage (adult).

* Adults are the outcome of nymph molting and also have four pairs of legs (eight legs total). After feeding, the adult female hard ticks lay one batch of thousands of eggs and then die.

Appearance of Hard Ticks

Hard ticks have mouthparts that are visible dorsally. In addition to the mouthparts, the capitulum contain chelicera (appendages on each side of the mouth) that pierce, tear, or grasp host tissues and protect the hypostome; pedipalps (a pair of jointed appendages) that aid feeding; a hypostome (ventral fusion of the pedipalps) that helps anchor the tick to the host; and a rostrum that extends dorsally over the mouth. When ticks find their host, the pedipalps grasp the skin, the chelicerae cut through the skin, and the hypostome enters the host's skin while feeding and its backward directed projections prevent easy removal of the attached tick.

Biology of Hard Ticks

Copulation in ticks occurs almost always on the host. In females, a blood meal is usually necessary for egg production. An engorged female tick will drop to the ground to deposit eggs in soil. From the many eggs (hundreds to tens of thousands) that are laid by female hard ticks emerge six-legged larvae.

Hard ticks seek hosts by a behavior called questing, a process by which ticks crawl up a piece of grass or perch on leaf edges with their front legs extended. Stimuli such as movement, odor, sweat, color, size, carbon dioxide, or heat can initiate questing. Questing occurs when ticks use extended front legs to climb on to a potential host that brushes against them. Upon finding a host, the tick feeds and then molts to an eight-legged nymph. When feeding the cuticle (outer surface) of hard ticks grows to accommodate the blood ingested. Female hard ticks can increase their size to a greater degree because their scutum only covers the cranial part of their bodies.

Molting in hard ticks can occur by a variety of different themes. Some ticks feed on only one host and molt through all three life stages on the same host. These ticks are called one-host ticks and an example is Boophilus spp. When a one-host tick becomes an adult, the female will drop off the host after feeding to lay her batch of eggs. Other ticks feed on two hosts during their lives and are called two-host ticks such as Rhipicephalus spp. Two-host ticks feed and stay on the first host during the larva and nymph life stages, then the nymph drops off and molts to an adult, and the adult attaches to a different host for its final blood meal. The adult female then drops off after feeding to lay eggs. Two-host ticks are adapted to feeding on a wide-range of hosts. Other ticks (incluing many hard ticks) feed on three hosts and are on a different host during each life stage. These ticks are called three-host ticks and examples include Dermacentor spp. and Ixodes spp. Three-host ticks drop off and reattach to a new host during each life stage. In all of the various types of host ticks, the engorged adult stage is terminal with the female dying after laying one batch of eggs and the male dying after he has reproduced. Figure 4-3 illustrates the types of tick host cycles.

Hard Tick Genera

There are three subfamilies of hard ticks within the Ixodidae family: Ixodinae (consisting of the single genus Ixodes), Amblyominae (containing the genera Amblyomma, Haemaphysalis, Aponomma, and Dermacentor), and Rhipicephalineae (containing the genera Rhipicephalus, Anocentor, Hyalomma, Boophilus, and Margaropus).

[FIGURE 4-3 OMITTED]

Ixodes ticks

There are over 200 species of Ixodes ticks worldwide and approximately 40 species are found in North America. All Ixodes ticks are three-host ticks that parasitize small mammals and are easily overlooked because of their small size. Examples include Ixodes scapularis, the blacklegged tick that is the primary vector of Lyme disease in the eastern and southcentral United States as well as a vector of Ehrlichia spp.; I. pacificus, the vector of Lyme disease and ehrlichosis in the western United States; and I. ricinus, I. persulcatus, and I. pavlovskyi, which transmit tick-borne encephalitis in Europe and Asia.
Ticks once known as I. dammini,
occurring in the northern and eastern
United States, are now considered the
same species as I. scapularis.


Amblyominae ticks

Types of Amblyominae ticks include Amblyomma spp., Haemaphysalis spp., Dermacentor spp., and Aponomma spp.

* Amblyomma spp. are restricted to tropical areas, appear to be one-host ticks, and contain approximately 100 species. The species of concern in the United States is A. americanum, the lone star tick, which is the vector for RMSF and tularemia.

* Dermacentor spp. are some of the most medically important ticks containing about 30 species with at least seven found in the United States. Dermacentor andersoni, the Rocky Mountain wood tick, is found in the western United States (west of the Rockies) and is the vector for tick paralysis, Powassan encephalitis virus, Colorado tick fever virus, tularemia, RMSF, and anaplasmosis. De. variabilis, the American dog tick, is found in the eastern United States (east of the Rockies) and isolated areas in the Pacific Northwest and is the principle vector of RMSF in the central and eastern United States. De. occidentalis, the Pacific Coast tick, is a vector of Colorado tick fever virus, RMSF, tularemia, and anaplasmosis. De. occidentalis also transmits chlamydial infection in cattle. De. albipictus, the horse tick or winter tick, is found in the northern United States and Canada and feeds on elk, moose, horses, and deer causing winter tick infestations.

* Haemaphysalis spp. are small ticks with about 150 species known worldwide. There are two species found in North America: Haemaphysalis leporispalustris, the rabbit tick which occasionally feeds on domestic animals and can serve as a vector of tularemia and RMSF in wildlife and H. cordeilis, the bird tick which is common on game fowl and may transmit diseases among these birds.

* Aponomma spp. parasitize reptiles, particularly in Asia and Africa. This genus of tick is not of medical or economic significance.

Rhipicephalinae ticks

Types of Rhipicephalinae ticks include Rhipicephalus spp., Anocentor spp., Hyalomma spp., Boophilus spp., and Margaropus spp. Rhipicephalus ticks contain approximately 60 species in areas of limited rainfall, show very little host specificity, and are typically two- or three-host ticks.

* Rhipicephalus sanguineus, the brown dog or kennel tick, is found in most of North America and is a three-host tick with all three stages feeding mainly on dogs. R. sanguineus transmits Rickettsia rickettsii (RSMF), Babesia canis, Rickettsia canis, Borrelia theileri, and Rickettsia connorii (in Europe and Africa).

* R. appendiculatus, the brown ear tick, transmits Theileria parva, a protozoan that causes East Coast Fever in cattle.

* Anocentor ticks have only one species, Anocentor nitens (the tropical horse tick), found in South America and parts of the southern United States. This tick transmits Babesia caballi, a protozoan blood parasite of horses.

* Hyalomma species are found in desert conditions where hosts are few and environmental conditions are extreme. Hyalomma ticks transmit CCHF, Dugbe virus, and occasionally West Nile virus, Babesia canis (transmitted by Hy. marginatum), Thogoto virus, swine poxvirus, and Theileria annulata (transmitted by H. anotolicum),

* Boophilus ticks are one-host ticks and consist of three species: Boo. annulatus, the American cattle tick which was once widespread in the southern United States and transmitted the protozoan Babesia bigemina, the causative agent of Texas cattle fever (also known as red-water disease); Boo. microplus, which affects cattle in Mexico, Africa, and Australia; and Boo. decoloratus, the blue tick that attacks cattle in Africa.

* Margaropus ticks contain four species that are rarely seen.

Soft Ticks

Stages of Soft Ticks

The life cycle of Argasidae (soft) ticks consists of three life stages: larvae, nymphs, and adults. Soft ticks feed several times during each life stage, females lay multiple small batches of eggs between blood meals throughout their lives, and most soft ticks have a multihost life cycle involving more than three hosts.

* Six-legged larvae emerge from the egg, take a blood meal from a host, and molt to the first nymphal stage. Depending on environmental conditions such as temperature and humidity, larvae will hatch from the eggs in anywhere from 2 weeks to several months.

* Eight-legged nymphs are the outcome of larval molting. Many soft ticks go through multiple nymphal stages, gradually increasing in size until the final molt to the adult stage. Each nymphal instar feeds separately, drops, and molts to the next stage.

* Eight-legged adults are the outcome of nymphal molting. The time to completion of the entire life cycle is generally much longer than that of hard ticks and can last over several years because they can survive for many years without a blood meal. Adults do not molt.

Appearance of Soft Ticks

Like hard ticks, soft ticks have two body regions: the capitulum and the idiosoma. Unlike hard ticks, soft ticks have mouthparts that are not readily visible dorsally because their capitulum in the nymph and adult stages lies in a depression (called a camerostome) that has a dorsal wall (called a hood) that extends over the capitulum (Figure 4-4). In soft ticks, the idiosoma has a sac-like shape. Soft ticks do not have a scutum (protective covering) on the dorsum of the body, and the exoskeleton is leathery and rough in texture.

[FIGURE 4-4 OMITTED]

Biology of Soft Ticks

Some soft ticks seek hosts by questing; however, the majority of soft ticks are nest parasites. Most soft ticks feed repeatedly and rest off the host between meals. Soft ticks usually feed on one type of animal during their lifetime and when not on the host they tend to stay near the habitats of the host animal (examples include soil, burrows, nests, and crevices). Soft ticks feed for short periods of time on their hosts (ranging from several minutes to days, depending on life stage, host type, and tick species). The nymph and adult stages feed rapidly (usually 30 to 60 minutes), whereas the larvae may feed rapidly or may require days to fully engorge. The feeding behavior of many soft ticks resembles that of fleas because the ticks reside in the host's environment and feed rapidly when the host returns. The cuticle (outer surface) of soft ticks expands, but does not grow to accommodate the large volume of blood ingested (which may be 5 to 10 times their unfed body weight). Adult females lay eggs in these hiding places several times between feedings. Some adult female soft ticks will feed several times and lay 20 to 50 eggs after each meal compared to adult female hard ticks that feed only once and lay one large batch of eggs, often containing as many as 10,000 or more eggs.
Ticks feed only on the blood of
vertebrates.

Soft ticks feed rapidly and leave their
host after engorging. Hard ticks secrete
a cement-like substance that helps
secure them to the host for longer
feeding times. This substance dissolves
after feeding is complete.


Soft Tick Genera

There is one family of soft ticks (Argasidae) that contains five genera: Argas, Omithodoros, Otobius, Nothoaspis, and Antricola.

Argas ticks

Argas ticks parasitize birds and bats and may occasionally bite humans without transmitting disease. Examples in this group include Argas persicus (the fowl tick), Ar. reflexus (the pigeon tick found in the Near and Middle East, Europe, and Russia), and Ar. cooleyi (found in cliff swallows in the United States).

Omithodoros ticks

There are over 100 species of Omithodoros ticks that parasitize mammals.

* Omithodoros hermsi is found in the Rocky Mountain and Pacific Coast states of the United States and is the vector of Borrelia recurrentis, the causative agent of relapsing fever.

* O. cariaeceus is found from Mexico to the Oregon coast and produces a painful bite in people.

* O. moubata is found in Africa and is primarily a parasite of warthogs.

Otobius ticks

Otobius ticks are called spinose ear ticks because the nymph stage has a spiny covering and they typically feed in the folds of the external auditory canal.

* Otobius megnini is found in the warmer parts of the United States, feeding mainly on cattle. Heavy infestations can effect production in livestock. Ot. megnini can also infest horses, sheep, goats, antelope, mule deer, dogs, and humans. This tick can be the vector for Q-fever, tularemia, Colorado tick fever, and RMSF.

* Ot. lagophilus is found in western North America and the larvae and nymphs feed on the faces of rabbits.

Nothoaspis and Antricola ticks

Ticks in these genera are found in cave-dwelling bats in North and Central America and are of limited medical and economic importance.

Transmission

Tick bites may cause local reaction, possible infection, or tick paralysis. The outcome of a tick bite depends on the species of tick, life stage of the tick, presence or absence of an infectious agent, and host factors such as immune status, age, and duration of tick attachment. Two important factors that affect the outcome of a tick bite are attachment time and tick stage. Infectious agents can be transmitted to the host via infected saliva only after there is sufficient attachment time to the host. An engorged tick signifies longer attachment time and increased risk of disease transmission. I. scapularis usually requires undisturbed attachment and feeding for approximately 24 to 52 hours before the spirochete Borrelia burgdorferi can be transmitted and cause Lyme disease. Omithodoros spp. requires less than one hour of attachment time, usually at night, to transmit the Borrelia spirochete causing relapsing fever. De. andersoni usually requires 5 to 7 days of attachment time before tick paralysis occurs. The stage of tick development (larva versus nymph versus adult) also affects disease transmission. I. scapularis nymphs are more likely to transmit Lyme disease than adult ticks. Table 4-2 summarizes different diseases transmitted from ticks.

Types of Transmission

The cycle of tick-borne disease agents require a vertebrate host that develops a level of infection so that the infectious agent can be passed on to a feeding tick, a tick that acquires the agent and is able to pass the agent to another host, and adequate numbers of vertebrate hosts that are susceptible to tick-borne infection. The transmission of tick-borne agents can follow several different mechanisms including

* horizontal transmission: transfer of the agent from tick to susceptible host usually through the saliva of the tick when it is feeding, but may occur by inoculation or inhalation of aerosolized agents from dried tick feces,

* vertical transmission: transfer of the agent from one tick generation to another tick generation,

* transovarial transmission: transfer of the agent from the female to her eggs so that hatched larvae are infected (this is a type of vertical transmission),

* transstadial transmission: transfer of the agent from one tick life stage (instar) through molting to the next instar.

Management and Control

Tick surveillence involves the use of chemical agents and management techniques to control both the parasitic and nonparasitic stages of the tick.

Management techniques to control ticks include

* keeping grass and weeds cut short to discourage tick infestation (by allowing sunlight and heat to penetrate an area that is detrimental to tick survival) and tick transfer to a host,

* controlling moisture because lack of moisture is detrimental to ticks,

* using predators to reduce tick populations,

* selective grazing of livestock to remove the favorable habitat for ticks,

* manually removing of ticks when present in low numbers (making sure mouthparts are not broken or left embedding in the host) (Figure 4-5),

* rotating pasture to control the nonparasitic stages of ticks, and

* potentially using animal breeds that are resistant to some tick species. Chemical control of ticks includes

* appropriate use of pesticides or acaricides on animals and their environments keeping in mind that some species of ticks have become resistant to the recommended levels of some insecticides. Chemicals that have historically been used to control ticks include organophosphates, carbamates, pyrethrins, synthetic pyrethroids, formamidines, fipronil, and selamectin.

* appropriate application of chemicals which may include solutions, emulsions, or suspensions that are applied as dips, impregnated tags, sprays, spot-ons, washes, pour-ons, or dusting.

[FIGURE 4-5 OMITTED]

Summary

Ticks transmit a variety of pathogens and typically transmit disease through a bite. Ticks are obligate, blood-sucking parasites that attack all vertebrates in all parts of the world. Ticks that cause disease to animals and humans are either hard ticks (Ixodidae) or soft ticks (Argasidae). Ticks have a general morphology consisting of two body regions: the capitulum (cranial portion) and the idiosoma (caudal portion). The capitulum has the mouthparts and the idosoma contains most internal organs and bears the legs. All ticks undergo four basic stages: egg, larva, nymph, and adult. There are three subfamilies of hard ticks: Ixodinae (consisting of the single genus Ixodes), Amblyominae (containing the genera Amblyomma, Haemaphysalis, Aponomma, and Dermacentor), and Rhipicephalineae (containing the genera Rhipicephalus, Anocentor, Hyalomma, Boophilus, and Margaropus). There is one family of soft ticks that contains five genera: Argas, Omithodoros, Otobius, Nothoaspis, and Antricola. Tick-borne disease can be transmitted horizontally, vertically, transovarially, and transstadially. Tick control can be accomplished through management and chemical means.

LYME DISEASE

Overview

Lyme disease, also known as Lyme borreliosis, borreliosis, Bannworth's syndrome, tick-borne meningopolyneuritis, erythema chronicum migrans (EM), and Steere's disease, was first discovered in 1975, but many manifestations of this disease had been previously described. In Europe, a red, slowly expanding rash associated with tick bites known as erythema chronicum migrans or EM was first described at the beginning of the 20th century. The signs of neurological disease and the association of Lyme disease with Ixodes ticks (commonly referred to as blacklegged ticks or deer ticks) were recognized by the mid-1930s and were attributed to a disease called tick-borne meningoencephalitis. In the 1940s, a similar tick-borne illness was described that began with EM and developed into multisystem illness. In the late 1940s, spirochete-like structures were observed in skin lesions.

In the United States, Lyme disease was not recognized until 1975, when a geographic cluster of childhood arthritis cases occurred in Lyme, Connecticut. The epidemic of arthritis in these children in Connecticut along with seasonal onset of signs and onsets of arthritis within the same families in different years prompted Dr. Allen Steere from Yale to investigate this disease phenomenon. It was determined that the patients in the United States had what was known as EM, which in turn led to the recognition that Lyme arthritis was one manifestation of the same tick-borne condition known in Europe.

Lyme disease is caused by the spirochete bacteria Borrelia burgdorferi and is the most common tick-borne disease in the United States. In 1982, Willy Burgdorfer, a Montana bacteriologist, identified a spirochete in the midgut of adult Ixodes scapularis ticks as the cause of Lyme disease. In 1984 spirochetes were cultured from the blood of patients with EM and from cerebrospinal fluid (CSF) of a patient with meningoencephalitis and EM. Different strains of the bacteria are now recognized, which explains why the clinical manifestations of Lyme disease are different in the United States and Europe.

The emergence of Lyme disease in the United States is likely a result of the explosion of deer and tick populations with the reforestation of the northeast, as well as the increased contact between ticks and humans as people moved into deer habitats. By the early 1800s, many parts of the eastern United States had been cleared of trees for use in lumber products or for development of farmland. The virgin forest was replaced with fields or low brush, and many animals such as deer and their predators normally found in these regions had disappeared. By the mid-1800s, agriculture moved westward and abandoned farmland in the eastern United States. In time trees and brush that were different than the original forest began to grow in this region. Deer returned to the eastern United States by the early 1900s, but their predators did not, and deer populations reached record levels by the end of the 1900s. Deer are the preferred hosts of the adult I. scapularis; humans and other animals are accidental hosts.

[FIGURE 4-6 OMITTED]

Bo. burgdorferi is found in white-footed mice and does not cause disease signs in affected mice. White-footed mice are also the preferred feeding site of the larva and nymph stages of I. scapularis (Figure 4-6), the blacklegged or deer tick, which may contain Bo. burgdorferi bacteria. These juvenile stages of the I. scapularis consume mouse blood and become infected with the spirochete. The nymph stage of the I. scapularis will then feed on almost any type of vertebrate, which may include humans and other animals, thus spreading the spirochete. Lyme disease is now endemic in some areas of the United States including parts of the east coast and Midwestern states such as Wisconsin and Minnesota where deer and human interaction is common.
The use of the common term deer tick
has fallen out of favor when describing
I. scapularis because many types of ticks
feed on deer making it an imprecise term.


Causative Agent

Bacteria belonging to the genus Borrelia are spirochetes composed of 3 to 10 loose coils and are vigorously motile by means of flagella (Figure 4-7). Borrelia bacteria are longer and more loosely coiled than the other spirochetes and stain well with Giemsa stain. Bo. burgdorferi is the longest and narrowest species of Borrelia and it has fewer flagella. Bo. burgdorferi spirochetes are fastidious, microaerophilic bacteria that grow best at 33[degrees]C to 34[degrees]C in broth called Barbour-Stoenner-Kelly medium. This bacterium grows slowly, with a doubling time of 12 to 24 hours.

[FIGURE 4-7 OMITTED]

A variety of Borrelia spp. cause disease including:

* Bo. burgdorferi causes disease in the United States and Europe and has been subdivided into multiple species including three that cause human disease. Bo. burgdorferi sensu lato (broad sense) refers to the group of related Borrelia organisms as a whole, whereas Bo. burgdorferi sensu stricto (strict sense) is the specific strain of bacteria associated with classical Lyme disease. Antigenic variation among sensu stricto isolates has been documented making vaccine development challenging. Bo. burgdorferi has lipoproteins on its surface termed outer surface proteins (Osp). The North American Bo. burgdorferi has two major Osp: Osp A and Osp B. When the surface structure of the spirochete changes (termed host-adaptation), the production of Osp A and Osp B is turned off and the production of another outer surface protein, Osp C, is often turned on.

* Bo. garinii and Bo. afzelii are genospecies associated primarily with neurologic Lyme disease and chronic skin disease in Europe and Asia.

* Bo. lonestari is the cause of southern tick-associated rash syndrome in the United States. There are other nonpathogenic strains of Borrelia found in the United States, Europe, and Asia.

Epizootiology and Public Health Significance

Lyme disease is the most common tick-borne disease reported in the United States. Cases of Lyme disease have been increasing in most parts of the country since the 1980s. In 1982 there were 497 cases of Lyme disease reported in 11 states. From 1993 to 1997, an average of 12,451 cases of human cases of Lyme disease were reported to the Centers for Disease Control and Prevention (CDC) annually; 17,730 human cases were reported in 2000; and 23,763 human cases were reported to the CDC in 2002. A national surveillance program was initiated in 1982 and more than 157,000 cases have been reported to health authorities in the United States since that time. The overall incidence rate of reported cases in the United States is approximately 7 per 100,000 people (it is believed to be underreported).
Ticks must be attached to a host for 24
to 52 hours before transmission of Bo.
burgdorferi can occur because time is
required for bacteria to migrate from the
midgut of the tick to its salivary glands.
During this time the surface structure of
the spirochete changes in response to
cues from the host and the blood meal.


Lyme disease has been reported in 49 states and the District of Columbia (Figure 4-8). It has a distinctive geographic concentration in the northeastern, upper Midwest, and Pacific coastal regions of the United States. It is a reportable disease throughout the United States, but the actual incidence is likely to be much higher in endemic areas where not all cases are reported or early disease may have been treated without antibody testing. Approximately 90% of cases were reported in the Northeast (the states between Maryland and Maine), 8% from the upper Midwest (mainly Wisconsin and Minnesota), and 2% from the Pacific coast (northern California and Oregon in particular). Lyme disease occurs in geographically limited areas and the incidence in endemic areas may reach 1% to 3% per year. People of all ages and both genders are equally susceptible, although the highest rates are in children aged 0 to 14 years, and in persons 30 years of age and older. Although Lyme disease has been reported from 49 states and the District of Columbia, the significant risk of infection is found in only about 100 counties in 12 states located along the northeastern and mid-Atlantic seaboard and in the upper Midwest region, and in a few counties in northern California. In the Northeast and Midwest, the white-footed mouse is the major reservoir host and I. scapularis is the primary tick vector. In the Pacific coast region, the dusky-footed wood rat is the major reservoir host and I. pacificus is the major tick vector. Lyme disease is also seen in Europe, Soviet Union, China, Japan, Southeast Asia, South Africa, Australia, and Canada.

[FIGURE 4-8 OMITTED]

People who live or work in residential areas surrounded by tick-infested woods or overgrown brush are the most at-risk group of contracting Lyme disease. People who work or play in their yard, participate in recreational activities such as hiking, camping, fishing and hunting, or engage in outdoor occupations, such as landscaping, forestry, and wildlife and parks management in endemic areas may also be at greater risk of contracting Lyme disease. Most cases of Lyme disease occur in the late spring and summer when the tiny nymphs are most active and human outdoor activity is greatest.
Areas in the United States with
I. scapularis report the highest incidence
of Lyme disease cases. Principal vectors
of Lyme disease are I. scapularis in the
northeast and upper-Midwest states
and I. pacificus along the west coast of
the United States. Although I. scapularis
is widely distributed in the southern
United States, it is not an established
vector of Lyme disease in that area.


Transmission

For Lyme disease to exist in an area, three closely related elements must be present: Bo. burgdorferi bacteria, Ixodes ticks, and mammals such as mice and deer that provide a blood meal for the ticks through their various life stages. Ticks, small rodents, and other vertebrate animals all serve as natural reservoirs (bacteria can live and grow within these hosts without causing them disease) for the spirochete. Bo. burgdorferi is transmitted by the Ixodidae (I. scapularis or blacklegged ticks) family of ticks known as the I. ricinus complex. This complex consists of 14 closely related tick species that are nearly identical in their appearance. The important vectors of human Lyme disease consist of four ticks that bite humans: I. scapularis (in northeastern and north-central United States), I. pacificus (in the western United States), I. ricinus (the sheep tick in Europe), and I. persulcatus (in Asia). Ticks of the I. ricinus complex have larva, nymph, and adult stages and feed once during each of the three stages of their usual two-year cycle; therefore, these ticks require 2 years to complete their life cycle and must feed on three independent hosts during this cycle (Figure 4-9). The 2-year cycle includes:

* Adult female ticks lay eggs on the ground in early spring.

* By summer, eggs hatch into larvae and feed only once. Larvae feed on mice, other small mammals, deer, and birds in the late summer and early fall. The tick larvae first become infected by feeding on these animals especially rodents (white-footed mice are the preferred reservoir hosts) which are hosts for Bo. burgdorferi. These hosts do not develop immune responses to the bacteria nor do they develop organ damage and they allow Bo. burgdorferi to replicate to a sufficient level to be infectious for subsequently feeding ticks.

* Larvae molt into nymphs by fall, and they are dormant (inactive) until the next spring. This period of inactivity is sometimes referred to as overwinter. In

* In late spring and early summer, nymphs feed only once on rodents (white-footed mice are the main reservoir host), small mammals, birds, and humans.

* Nymphs molt into adults in the fall.

* In the fall and early spring, adult ticks feed and mate on large mammals (especially deer which are the preferred host) and bite humans. The adult female ticks will then drop off these animals and begin laying eggs in spring.

[FIGURE 4-9 OMITTED]

The nymph stage is responsible for disease transmission to humans; Bo. burgdorferi is not directly transmitted from animals to humans. The nymphs and adults obtain their blood meals by feeding on larger mammals. Deer are the preferred feeding hosts; other mammals such as dogs, horses, cattle, and people are accidental hosts of these ticks. Deer are not involved in maintaining Bo. burgdorferi; their role is to maintain the ticks. Ticks only crawl (they do not fly or jump) and can attach to any part of an animal's body but often crawl to the more hidden areas such as the groin or axilla (armpit) to feed. There is minimal transovarial transmission of Bo. burgdorferi in ticks, so each tick must be infected by feeding on an infected host. Bo. burgdorferi can be transmitted transstadially from larvae to nymph to adult. There is some evidence of in utero transmission of Bo. burgdorferi in dogs, which is important because there have been cases of adverse fetal outcomes in women who were infected with Bo. burgdorferi during pregnancy (neonatal deaths).

Ixodes ticks are found in temperate regions with high humidity at ground level. In the eastern United States, ticks are associated with the deciduous forest and habitat containing leaf litter that provides a moist cover from wind, snow, and other elements. In the upper Midwestern states, these ticks are generally found in heavily wooded areas often surrounded by land cleared for agriculture. On the Pacific Coast, the habitats are more diverse and ticks have been found in forest, north coastal scrub, high brush, and open grassland areas. Coastal tick populations prefer areas of high rainfall, but ticks are also found at inland locations.
Risk of infection with Borrelia bacteria
depends on the density of ticks, their
feeding habits, and their animal hosts.


A tick must be attached to an animal for 24 to 52 hours to transmit the bacterium because of the life cycle of Bo. burgdorferi in ticks (peak transmission occurs between 48 and 52 hours). In previously infected ticks (nymphs and adults), only small numbers of bacteria are present until the tick feeds. Once the tick begins feeding, bacteria multiply in the midgut of the tick. The bacteria then migrate to the tick's salivary glands after 2 to 3 days. From the salivary gland they can be injected into the animal by the tick when it finishes its feeding. Without this multiplication of bacteria in the midgut, ticks are rarely able to pass on enough organisms to cause infection. Bo. burgdorferi bacteria persist in infected I. scapularis ticks from stage to stage (transstadially).

Pathogenesis

Following tick transmission of Bo. burgdorferi, the spirochete replicates in the skin at the site of the bite. After a few days to weeks, the spirochete is disseminated via the blood to a variety of sites such as joints, blood vessels, and connective tissues of the heart by binding to a number of host-cell receptors. Once in organs the spirochete can elicit a vigorous inflammatory reaction that causes carditis, arthritis, vasculitis, and dermatitis. Within a few weeks, the immune system can clear the organism from infected organs and blood causing disease signs to resolve. Despite this intense immune response, some spirochetes can survive for years in some organ systems causing recurrent bouts of disease.
By harboring infected ticks, domestic
animals may increase the chances for
human exposure to Lyme disease.


Once Bo. burgdorferi bacteria gets into a host, one of the following events can occur:

* Animals clear the infection, do not develop clinical signs, and become seropo sitive

* Bo. burgdorferi disseminates throughout the body and produces clinical signs related to the invasion of bacteria into a particular organ system

* Bo. burgdorferi causes an immune response leading to clinical signs in various organs, without evidence of bacterial invasion

Clinical Signs in Animals

Lyme disease in animals is seen throughout the active tick season, but is most often diagnosed in late spring and fall when nymphs are more active, rather than during summer. Clinical signs in animals vary with the species involved:

* Dogs. In the initial or acute stage of Lyme disease dogs typically present with an abrupt onset of fever, anorexia, lethargy, and lameness that usually occurs in one or two joints and may be shifting (Figure 4-10). In the secondary or chronic stage of Lyme disease dogs may present with chronic, intermittent arthritis, heart conditions (such as pericarditis, endocarditis, and conduction disturbances), neurologic conditions (such as behavioral changes and seizures), and renal conditions (such as glomerulonephritis and protein-losing nephropathies). Rheumatoid arthritis may occur secondary to Bo. burgdorferi infection.

* Horses. In horses Lyme disease causes arthropathy, uveitis, and encephalitis.

* Cattle. In cattle Lyme disease causes arthropathy, cutaneous lesions, and multisystemic disease.

* Cats. Cats do not produce consistent clinical signs and pathologic lesions when naturally-exposed to Bo. burgdorferi.

[FIGURE 4-10 OMITTED]

Clinical Signs in Humans

In humans Lyme disease represents itself in three stages as follows:

* Early local disease (previously called stage 1 or localized): the most notable lesion in this stage is an erythema migrans (EM) (previously referred to as erythema "chronicum" migrans or ECM) which is also known as the bull's-eye rash (Figure 4-11). The rash is an expanding, red skin lesion that develops at the site of a tick bite. Other clinical signs in this stage include fever, lethargy, joint and muscle pain, and headaches.

* Early disseminated disease (previously called stage 2 or disseminated): this stage occurs weeks to months after initial infection producing clinical signs such as multiple smaller EM-like lesions on various parts of the body (apparently as a result of spread of the bacterium through the skin without additional tick bites). Other clinical signs in this stage include fatigue, neurologic disease (especially meningitis and facial nerve paralysis), myocarditis, and arthropathy without joint effusion.

* Late disseminated disease (previously called stage 3 or persistent): this stage occurs months to years after initial infection and is characterized by chronic arthritis and/or encephalopathy (sleep disturbances, fatigue, personality changes).
In humans Lyme disease is a multistage,
multisystem disease that is categorized
into early localized, early disseminated,
and late disseminated stages.


[FIGURE 4-11 OMITTED]

Diagnosis in Animals

Pathology associated with Lyme disease is a result of the host's immune response to the spirochetes. Skin lesions on histological examination consist of perivascular infiltrates of lymphocytes and macrophages. In disseminated infection, all infected tissues show an infiltration of lymphocytes, macrophages, and plasma cells. Vasculitis may be seen at multiple sites. Bo. burgdorferi can be visualized in tissue sections stained with Warthin-Strarry silver stain and in blood and CSF stained with acridine orange or Giemsa stain.
People contract Lyme disease from ticks
in the nymph stage 85% of the time
(spring to summer) and the adult stage
15% of the time (fall).


Bo. burgdorferi is difficult to culture, but may be cultured from ticks or vertebrate hosts using BSK (Barbour-Stoenner-Kelly) broth that has been incubated at 33[degrees]C for 6 weeks or longer. Weekly samples are taken from the broth and examined by darkfield microscopy for the presence of spirochetes. BSK agar with 1.3% agarose produces slow-growing colonies.

Serologic tests for Lyme dis-ease include immunofluorescent assay (IFA), enzyme-linked immunoabsorbant assay (ELISA), and Western blot tests that detect antibody production to Bo. burgdorferi. ELISA tests serve as rapid screening methods because they are quick, reproducible, and less expensive; however, false positive rates are high making confirmatory tests necessary (Figure 4-12). A combination of ELISA screening and immunoblot confirmation is recommended for the diagnosis of Lyme disease. Some other problems exist with serologic testing of this spirochete. Studies have shown that the rate of positive serology tests in enzootic areas is higher than the prevalence of clinical disease. Addtionally, IgM cannot be used as an indicator of recent infection because IgM titers remain elevated in dogs for long periods of time after infection. Antibody titers also tend to remain elevated after antibiotic treatment making tracking of the progress of treatment difficult. Polymerase chain reaction (PCR)-based diagnostic testing is becoming more widely available and has been performed on urine and serum samples.

[FIGURE 4-12 OMITTED]

Diagnosis in Humans

The diagnosis of Lyme disease in people is based primarily on clinical findings and known exposure with serologic testing providing supportive diagnostic information. The most widely used tests for identifying Lyme disease in people are antibody detection tests. The current recommendation from the CDC is for a two-step testing process. In the first step, patients with symptoms consistent with Lyme disease are tested with an ELISA or an IFA test. The second step is to confirm positive tests with the more specific Western blot (WB) test (Figure 4-13). Patients with early disseminated or late disseminated disease usually have strong serologic reactivity and demonstrate banding patterns diagnostic for Bo. burgdorferi. Because antibodies may persist for months or years following successfully treated or untreated infection (they are believed to be re-exposed to new borrelial antigens), positive antibody test results alone cannot be used as an indicator of active disease. Patients that are not treated continue to produce IgM antibodies long after the initial infection, thus patients may have both IgM and IgG antibodies at the same time making the correlation between antibody type and length of exposure invalid. Antibody testing in patients with erythema migrans is not indicated because the rash may develop before antibodies are produced and the test results could be misinterpreted.

[FIGURE 4-13 OMITTED]

PCR has been used to amplify genomic DNA of Bo. burgdorferi in skin, blood, CSF, and synovial fluid, but PCR has not been standardized for the diagnosis of Lyme disease.

Treatment in Animals

Treatment of Bo. burgdorferi infection in dogs consists of doxycycline or amoxicillin (in young animals in which tetracycline products are contra-indicated or in dogs that are not eating). Both treatments are done for 30 days to completely clear all of the Bo. burgdorferi organisms from the body (Bo. burgdorferi can persist in skin, CNS, and joint and connective tissues).

Prophylactic treatment with antibiotics in animals that are bitten by an I. scapularis tick is controversial. In enzootic areas, treating all dogs that are found to have been bitten by an I. scapularis tick is questionable, because the tick must be attached to the animal for greater than 24 hours to transmit the spirochete.

Animals showing signs of lameness may be treated concurrently with nonsteroidal anti-inflammatory drugs; corticosteroids should not be used because they decrease both the humoral and cell-mediated immune response to the spirochete. Animals with carditis may exhibit bradycardia (abnormally slow heart rate) making medical treatment with cardiac drugs and pacemakers necessary. Lyme nephritis may require fluid therapy and supportive medical therapy in addition to antibiotics. Seizures observed in animals with neuroborreliosis should be treated with anticonvulsants.

Treatment in Humans

Lyme disease in human adults is treated with oral doxycycline for 30 days because, with long-term exposure, accurately pinpointing the date of infection is not always possible. A 30-day course of antibiotics also reduces the number of patients who relapse after the shorter courses of antibiotics. Children and pregnant women are treated with amoxicillin or cephalosporin antibiotics as a result of the side effects of doxycycline use during growth.

Management and Control in Animals

In enzootic regions, regular examination of animals for ticks should be performed daily since transmission of Bo. burgdorferi requires a minimum 24- to 52-hour feeding time. Tick collars, spot-on products, sprays, baths, and dips should be used to eliminate ticks from animals or prevent their attachment. Environmental control, such as cutting brush and mowing grass more frequently, may alter the environment ticks thrive in and minimize their ability to parasitize small mammals that serve as the reservoir for the spirochete and a host for immature ticks.

Vaccination is also recommended for dogs that are at increased risk of contracting Lyme disease. Both a whole-cell, killed bacterin and a recombinant vaccine containing only the Osp A (outer-surface protein) from Bo. burgdorferi are available. The whole-cell bacterin induces antibodies against a wide variety of spirochete antigens including Osp A and Osp B. These antibodies are directed against antigens on the spirochete in the tick midgut; other antibodies may also be present in this vaccine to act against spirochetes present in the tick salivary glands and in the host. The recombinant vaccine is only effective against Osp A and must kill all spirochetes within the tick before the down regulation of Osp A occurs. If the antibodies are ingested by ticks during the early stages of feeding and then inactivate Bo. burgdorferi within the gut of the tick, transmission to the host is blocked. Because there is substantial genetic and antigenic variation among Bo. burgdorferi isolates multivalent vaccines may be needed to provide protection against a wide range of geographically distinct strains. In North America and Europe, at least five seroprotection groups of Bo. burgdorferi have been identified.

Management and Control in Humans

In humans, just like animals, deterrence and prevention of Lyme disease is emphasized. Several recommendations to reduce the risk of tick bite include:

* Avoidance of ticks and tick-infested areas.

* Alteration of the tick habitat. Back yard patios, decks, and grassy areas that are mowed regularly are less likely to have ticks present. Areas around ornamental plantings and gardens are more hospitable for mice and ticks. The highest concentration of ticks is found in wooded areas.

* If tick-infested areas cannot be avoided, application of repellents containing DEET (N, N-diethylmetatoluamide) or permethrin will deter ticks. Permethrin can only be applied on clothing and DEET may cause side effects with frequent, long-term use (especially in children).

* Performance of tick checks after potential exposure to ticks. The groin, axilla, and hairline should be inspected particularly well.

* The Lyme disease vaccine for humans is no longer available (it was introduced to the market in 1998 and was withdrawn from the market in 2002).

* Some physicians advocate the use of prophylactic antibiotics if an I. scapularis tick bite is observed. If the attached tick is removed quickly, no other treatment should be necessary. If an engorged nymphal stage of the I. scapularis is found, a single dose of doxycycline may be given if the tick is found within 72 hours of the bite.
Larva and nymph stages of Ixodes ticks
attach to birds and may be the primary
means by which infected ticks are
spread from one area to another (thus
potentially spreading disease from one
area to another).


Summary

Lyme disease is an important infectious disease in North America, Europe, and Asia. The causative agent of Lyme disease is the spirochete Bo. burgdorferi that has now been subdivided into multiple species. This spirochete exists in nature in enzootic cycles involving ticks of the I. ricinus complex and a wide range of animal hosts. A tick must be attached to an animal for 24 to 52 hours to transmit the bacterium because of the life cycle of Bo. burgdorferi in ticks (peak transmission occurs between 48-52 hours). Lyme disease in animals is seen throughout the active tick season, but is most often diagnosed in late spring and fall when nymphs are more active, rather than during summer. In dogs, the initial or acute stage of Lyme disease typically presents with an abrupt onset of fever, anorexia, lethargy, and lameness that usually occurs in one or two joints and may be shifting. In the secondary or chronic stage dogs may present with chronic, intermittent arthritis, heart conditions, neurologic conditions, and renal conditions. In horses Lyme disease causes arthropathy, uveitis, and encephalitis, whereas in cattle Lyme disease causes arthropathy, cutaneous lesions, and multisystemic disease. Cats do not produce consistent clinical signs and pathologic lesions when naturally-exposed to Bo. burgdorferi. In humans, Lyme disease represents itself in three stages. The first stage (early local disease) produces erythema migrans (bull's-eye rash); the second stage (early disseminated disease) presents with fatigue, neurologic disease, myocarditis, and arthropathy; the final stage (late disseminated disease) is characterized by chronic arthritis, and/or encephalopathy.

Bo. burgdorferi is difficult to culture, but may be cultured from ticks or vertebrate hosts using BSK (Barbour-Stoenner-Kelly) broth that has been incubated at 33[degrees]C for 6 weeks or longer. Serologic tests for Lyme disease include IFA, ELISA, and Western blot tests that detect antibody production to Bo. burgdorferi. Treatment of Bo. burgdorferi infection consists of doxycycline or amoxicillin. In enzootic regions, regular examination of animals for ticks; preventative products such as tick collars, spot-on products, sprays, baths, and dips; environmental control; and vaccination in dogs are important in prevention of Lyme disease.

RELAPSING FEVER

Overview

Relapsing fever, more accurately known as either tick-borne relapsing fever (TBRF) or louse-borne relapsing fever (LBRF), is an arthropod-borne infection caused by several species of spirochetes in the genus Borrelia. TBRF is usually zoonotic and is endemic on most continents, each with its own species of Borrelia (for example, Bo. hermsii in North America and Bo. duttonii in Africa). LBRT is found in developing countries (Africa, China, and Peru mainly) and is caused by Bo. recurrentis and is spread from person to person by human lice.

In 1843 in Edinburgh, Scotland, the name relapsing fever was given to this disease by Craigie and Henderson, who described a human epidemic fever, with a characteristic pattern of acute fever followed by remission and relapse. Relapsing fever is believed to have been described by Hippocrates in the 4th century B.C. The German physician Otto Obermeier first discovered highly motile threadlike spirochetes as the cause of an epidemic of relapsing fever in Berlin in 1868. Gregor Munch first suggested that relapsing fever was transmitted by the bite of arthropods such as lice, fleas and bugs in 1878. The theory of lice being one of the vectors of relapsing fever was confirmed by the French microbiologists Sergent and Foley in 1910.

TBRF is transmitted by the soft tick of the genus Omithodoros and occurs in Africa, Spain, Saudi Arabia, Asia, and certain areas in the western United States and Canada (it is endemic in the higher elevations and coniferous forests of the western United States and southern British Columbia). From 1903 to 1905, British physicians Joseph Dutton and John Todd in the Congo, and independently Ross and Milne in Uganda, identified the spirochete responsible for "human tick disease." Both Dutton and Todd contracted the disease during their work. Dutton died of the disease and the causative agent of East African relapsing fever (Bo. duttonii) is named after him. In 1904, German microbiologist Robert Koch was called to East Africa to investigate fever in cattle and learned that Europeans traveling into the interior regions of Africa had been suffering recurrent fever as well. Koch unknowingly confirmed the vector role of the soft tick Omithodoros and demonstrated that spirochetes were transmitted to eggs (transovarial transmission) from infected female ticks. In the United States, TBRF is caused by the soft tick Omithodoros hermsii (a rodent tick) and was first reported in North America from gold miners near Denver in 1915.

The causative agent of LBRF (Bo. recurrentis) was first observed in the blood of patients during an outbreak of the disease in Berlin, Germany, in 1868; however, it was not until 1907 that the human body louse (Pediculus humanus) was determined to transmit the spirochete. Bo. recurrentis has no wild animal reservoir and is transmitted solely among humans by the human body louse. In the 19th century, outbreaks of LBRF occurred in the British Isles, Europe, and the United States. More recently, LBRF has been recorded only in northeastern and central Africa, especially Ethiopia, Somalia, and Sudan, where infestations of human body lice are prevalent. Some authorities believe the Yellow Plague of Europe starting around A.D. 550, which halved the European population, was a result of LBRF.

Causative Agent

Relapsing fever is caused by many different species of the spirochete Borrelia. These spirochetes are morphologically indistinguishable from each other and are motile, slightly staining gram-negative, and have between 3 and 10 loose coils. Borrelia spp. are able to avoid immune destruction by undergoing antigenic variation (periodically changing surface antigens to avoid recognition by antibodies). Antigenic variation usually results from gene conversions or gene rearrangements in the deoxyribonucleic acid (DNA) of the bacterium. These variants express a unique variable major protein (Vmp), which occurs in two classes: the variable large proteins (Vlps) and the variable small proteins (Vsps). In each phase of bacteremia a population of one serotype predominates. After Borrelia spp. invade the body, bacteria multiply in tissues and cause a fever until the onset of an immune response. Bacteria levels drop because of antibody mediated phagocytosis and the fever resolves. In time an antigenically distinct mutated Borrelia spp. appears in the infected individual, multiplies, and reappears in the blood causing another febrile attack. The immune system is stimulated and responds to the new antigenic variant, but the cycle of antigenic variation continues producing a new set of antibodies in the host.

* TBRF, also known as endemic relapsing fever, may be caused by over 20 Borrelia species. The nomenclature used when naming these species of Borrelia often mimics the name of the tick vector (e.g., Bo. turicatae infecting Or. turicatae, Bo. hermsii in Or. hermsii). In the mountains of California, Utah, Arizona, New Mexico, Colorado, Oregon, and Washington, infections are usually caused by Bo. hermsi. In Africa, the main species are Bo. duttonii and Bo. crocidura. Borrelia spirochetes in ticks affect the salivary glands and transmission occurs when the tick feeds on new hosts. Small mammals such as rodents, chipmunks, tree squirrels, bats, and rabbits are hosts for the spirochete, whereas ticks serve as the reservoir and are able to pass the bacterium transovarially. Lizards have also been known to be hosts for Borrelia bacteria.

* LBRF, also known as epidemic relapsing fever, is the more severe form of relapsing fever and is caused by the spirochete Bo. recurrentis. LBRF is transmitted by body lice (Pediculus humanus corporis), and to a limited extent the head louse (Pediculus humanus capitis). Humans are most likely the only reservoir with lice being unable to transmit it transovarially to its progeny. Bo. recurrentis does not invade the salivary or genital glands of the louse; therefore, transmission is not from the bite or the saliva of the louse but rather by inoculation of hemolymph from a crushed louse through conjunctiva, broken skin, or scratched through intact skin.
Soft ticks feed for short periods of time
(15 to 20 minutes), so infection occurs in
minutes, in contrast to hard ticks (such
as those that cause Lyme disease) that
feed for days, where infection requires
several hours.


Epizootiology and Public Health Significance

TBRF or endemic relapsing fever has worldwide distribution and is endemic in most of Africa. Few cases of TBRF are reported in the United States; those reported are typically seen in the late spring and summer in the western mountainous states and the high deserts and plains of the Southwest, south into Texas, and northwest into Washington. Cases may appear in clusters where people are in contact with rodents on which the ticks feed (such as infested camp sites). The mortality rate of people with TBRF who are treated is less than 1%. A poor prognosis is given to people with signs of severe jaundice, severe change in mental status, and severe bleeding. The number of TBRF cases peak in the summer months. TBRF has been reported in 15 states: Arizona, California, Colorado, Idaho, Kansas, Montana, Nevada, New Mexico, Ohio, Oklahoma, Oregon, Texas, Utah, Washington, and Wyoming. TBRF was removed from the list of nationally notifiable conditions in 1987; however, 11 states require TBRF to be reported to their State Health Departments (Arizona, California, Colorado, Idaho, Nevada, New Mexico, Oregon, Texas, Utah, Washington, and Wyoming).

LBRF or epidemic relapsing fever is found in areas of overcrowding, war, and poverty. Currently LBRF is found in Africa, China, and Peru. Epidemic relapsing fever has not been reported in the United States since 1906. Mortality rates from LBRF vary from 30% to 70% in untreated patients with the mortality rate decreasing to about 5% with treatment.

Transmission

TBRF

In the United States, TBRF results from infection by Bo. hermsii and Bo. turicatae. The disease is transmitted to humans principally by the bites of the infected ticks Or. hermsii and Or. turicata (possibly also by Or. parkeri and Or. rudis) (Figure 4-14). These ticks inhabit the burrows and nests of rodents in southern British Columbia, Washington, Idaho, Oregon, California, Nevada, Colorado, and the northern regions of Arizona and New Mexico. The reservoir hosts are typically rodents (squirrels, mice, and chipmunks) and the natural infection cycle of Borrelia occurs without producing apparent disease in these animals. Other animals that may serve as reservoir hosts are pigs, goats, sheep, rabbits, bats, opossums, armadillos, foxes, cats, and dogs.
Cabins and camping areas are attractive
nesting sites for rodents potentially
infected with Borrelia, and may be areas
where cluster outbreaks occur.


[FIGURE 4-14 OMITTED]

Humans are incidental hosts of TBRF when bitten by an infected tick. Omithodoros ticks are night feeders and their bites often go unnoticed. Direct transmission from human to human is rare.

LBRF

LBRF is transmitted from person to person by the body louse (Pediculus humanus corporis) and less commonly the head louse (Pediculus humanus capitis) (Figure 4-15). Lice only become infected with Bo. recurrentis through a blood meal; there is not transovarial transmission. Infection in humans occurs when the lice are crushed and their infected hemolymph invades the human through nonintact surfaces. Infection does not occur from the louse bite. Transmission may also occur from person to person via infected blood by needle-stick injury, blood transfusion, conjunctiva, and broken skin. There are no animal reservoirs for LBRF.

[FIGURE 4-15 OMITTED]

Pathogenesis

Regardless of transmission, once the spirochete gets into the body a spirochetemia develops in about 3 to 18 days (average is 7 to 8 days). Spirochete levels in blood may reach 500,000 per milliliter; however, clinical signs do not develop during the incubation period. The spirochete then invades the endothelium of many body systems producing fever, headache, fatigue, a low-grade disseminated intravascular coagulation (DIC), and thrombocytopenia (low numbers of clotting cells). As antibodies are produced, the spirochetes are cleared from the blood (many times undetectable in 24 to 48 hours). At this time the person becomes susceptible to other serotypes. The waxing and waning relapses occur as a result of shifting of outer surface proteins of the Borrelia bacterium that allows a new clone to avoid antibody destruction. The person will clinically improve until the new clone multiplies in sufficient quantities to cause another relapse. In time, recovery is because of the development of antibodies to all or most serotypes during the course of infection or to a rise of cross-protective antibodies. TBRF tends to produce more relapses (average of three) compared to LBRF (often just one).

Clinical Signs in Animals

Animals such as rodents (mice, rats, hamsters, and chipmunks), rabbits, and domestic animals (pigs, horses, and cattle) can serve as reservoirs for TBRF, but do not show clinical signs of disease.
Omithodoros ticks can live for 10 to 20
years and can survive without a blood
meal for several years.


Clinical Signs in Humans

After an incubation of 2 to 12 days (usually 7 to 8 days), affected people develop acute high fever and chills. A 2- to 3-inch itchy black scab may develop at the site of the tick bite, but typically the bite goes unnoticed (Figure 4-16). Other signs include headache, muscle and joint pain, rapid pulse, weakness, anorexia, and weight loss. In TBRF, multiple episodes of fever occur that may last up to 3 to 4 days in this form of relapsing fever and the person may remain free of fever for up to 2 weeks prior to a relapse. In LBRF, the initial episode usually lasts 5 to 7 days and is usually followed by a single, milder episode. In both forms, the fever may end in "crisis," which consists of shaking chills, followed by intense sweating, decreased temperature, and hypotension (low blood pressure) that results in death in up to 10% of individuals.

[FIGURE 4-16 OMITTED]

After several cycles of fever, some people may develop central nervous system signs such as seizures, stupor, and coma. The Borrelia spirochete may also invade heart and liver tissues, causing myocarditis (inflammation of the heart muscle) and hepatitis (resulting in jaundice). Diffuse bleeding and pneumonia are other complications of this illness.

Diagnosis in Animals

Relapsing fever is only diagnosed in animals for experimental purposes and would be similar to those methods used in humans.

Diagnosis in Humans

Diagnosis of relapsing fever is confirmed by microscopy of a blood smear stained with Giemsa or Wright stain taken from a patient during a febrile episode (70% of people will show spirochetes in their blood during the febrile period). Multiple thick and thin smears should be examined. The spirochete is not found in the blood between relapses. Actively motile spirochetes may be seen in an unstained drop of blood when viewed using phase-contrast or darkfield microscopy. Culture of Borrelia should be done on BSK II medium in a microaerophilic atmosphere at 30[degrees]C to 35[degrees]C for 6 weeks. PCR, IFA, and ELISA tests have been developed for diagnosing relapsing fevers but are not used routinely. The IFA and ELISA tests have approximately a 10% false-positive rate. Injection of blood from infected humans into laboratory animals followed by examination of the laboratory animal's blood sometimes is useful in diagnosing this disease (xenodiagnosis).

Treatment in Animals

Animals are not treated for relapsing fever.

Treatment in Humans

Both forms of relapsing fever can be treated with tetracycline for 10 days. The development of a Jarisch-Herxheimer reaction (apprehension, diaphoresis (sweating), fever, tachycardia, and tachypnea especially with LBRF) can occur with tetracycline treatment; therefore, treatment should be started in a hospital setting. Erythromycin can be used for the treatment of pregnant women and children. Antipyretics are used to reduce fever. Poor prognostic signs include severe jaundice, severe change in mental status, severe bleeding, and prolonged QT interval on electrocardiogram (ECG). Tick or louse removal is imperative.

Management and Control in Animals

Tick control in pet animals and livestock may control the spread of TBRF in an area. LBRF is not found in animals.

Management and Control in Humans

Tick and rodent control is essential for preventing TBRF. Ways to control ticks include:

* Wearing proper clothing.

* Using tick repellent with DEET (use with caution on children and do not apply to infants younger than the age of 2).

* Changing and washing all bedding before use, especially in endemic areas.

* Removing existing ticks promptly and properly by grasping them close to the skin with tweezers. Avoid crushing the tick's body. Ways to control rodents include:

* Checking sleeping areas for evidence of rodents when camping (finding holes in the floor or walls, shredded material from mattresses, and rodent droppings on counters or in cupboards) and avoiding sleeping on the floor or on a bed that touches the wall.

* Checking external doors and windows to make sure they close with a tight seal.

* Keeping all food and garbage in tightly sealed containers and cleaning up any leftover or spilled food.

* Not feeding squirrels, chipmunks, and other rodents around dwellings.

* Eliminating woodpiles in or near the house. Store firewood outside, away from walls and stack wood on pallets, or raised a few inches off the ground.

* Eliminating existing rodents in your home via extermination, poison bait, or the use of spring-loaded mousetraps. Wear gloves and spray with bleach and water solution before and after handling dead mice.

Delousing and improved hygiene are needed for LBRF.

* Treating the person and other family members with head lice with a pediculicide to kill the lice.

* Machine wash using hot water (130[degrees]F) all clothing and bedding used by the infested person in the 2-day period prior to when treatment is started.

* Storing all clothing, stuffed animals, comforters, and other items that cannot be washed or dry cleaned into a sealed plastic bag for 2 weeks.

* Soaking combs and brushes for 1 hour in rubbing alcohol or wash with soap and hot (130[degrees]F) water.

* Vacuuming the floor and furniture, including the car interior.

* Avoiding head-to-head contact.

* Not sharing clothing (such as hats, scarves, coats, sports uniforms, or hair ribbons) or combs, brushes, or towels.

* Avoiding things that have recently been in contact with an infested person.

Summary

Relapsing fever is a disease characterized by relapsing or recurring episodes of fever, often accompanied by headache, muscle and joint aches, and nausea. There are two forms of relapsing fever: tick-borne relapsing fever (TBRF) and louse-borne relapsing fever (LBRF). TBRF is caused by several species of Borrelia spirochetes (mainly Bo. hermsii in the United States) and is transmitted to humans through the bite of infected soft ticks of the genus Ornithodoros. Most cases of TBRF occur in the summer months in mountainous areas of the western United States. LBRF is caused by Bo. recurrentis that is transmitted from human to human by the body louse (Pediculus humanus corporis). LBRF is rare in the United States. The relapsing nature of these diseases is associated with the development of antigenic variants. When the immune response develops to a predominant antigenic strain, variant strains multiply and cause a recurring infection.

Animals do not show clinical signs of disease. Clinical illness in people is marked by a febrile episode that lasts about 3 to 6 days, resolves, and then recurs 7 to 10 days later. Other signs include headache, muscle and joint pain, and lethargy. TBRF tends to have more relapses than LBRF. Borrelia organisms can be seen on microscopic examinations of thick and thin blood smears stained with Giemsa or Wright stain and darkfield or phase-contrast wet mounts. PCR, IFA, and ELISA tests are also available. Both tetracycline and erythromycin have been effective treatment in people; the disease is not treated in animals as a result of the lack of disease signs. Prevention of relapsing fever consists of avoiding likely tick and rodent habitats (TBRF) or eliminating lice infestations (LBRF). Cases of relapsing fever should be reported to local and/or state health departments.

TULAREMIA

Overview

Tularemia, also known as deerfly fever or rabbit fever in the United States, yato-byo in Japan, and lemming fever in Norway, is an infectious disease caused by the gram-positive bacterium Francisella tularensis. Tularemia was first described as a disease entity in Japan in 1837, but was not isolated until 1911 where it was cultivated by McCoy and Chapin from ground squirrels with plague-like illness in Tulare County, California. McCoy and Chapin named the organism Bacterium tularense. In 1914 the first link of this agent to human disease was documented when Wherry and Lamb isolated Bacterium tularense from an Ohio meat cutter. Several years later, Dr. Edward Francis, an epidemiologist of the U.S. Public Health Service, isolated the bacterium from the blood of patients with an ulcer-type illness following deerfly bites in Utah. In 1959 the organism was renamed Fr. tularensis because of the major contributions to the understanding of tularemia by Dr. Francis whose last name was designated for the genus name and the rural county in central California where it was first identified was designated for the species name. Fr. tularensis is found worldwide in more than 100 species of wild animals (mainly small mammals such as rabbits, rodents, squirrels, muskrats, beavers, and hares), birds, and insects and is found in nature from 20 degrees north of the equator to the Arctic Circle.

There are four major strains of Francisella, which differ in both virulence and geographical range. Fr. tularensis, found primarily in North America, has two strains. The bacterium can survive for weeks at low temperatures in water, moist soil, hay, straw, or decaying animal carcasses. Its ability to infect whole populations was seen during outbreaks of waterborne disease in Europe and the Soviet Union in the 1930s and 1940s and in outbreaks associated with deerfly bites in the United States in 1919, 1936, 1937, and 1973.

Causative Agent

Fr. tularensis is a small, pleomorphic, nonspore-forming, faintly staining, gram-negative bacillus (some report it as a coccobacillus) that can be readily aerosolized in laboratory settings. Cultivation of Fr. tularensis is difficult because it requires strict aerobic conditions and enriched media containing cysteine and cystine for isolation. Media used to cultivate Fr. tularensis include glucose cystein agar, cystine-heart agar, Thayer-Martin agar, chocolate agar, and tryptic soy or Mueller-Hinton agar supplemented with IsoVitaleX. Fr. tularensis may require 2 to 4 days for maximal colony growth and are weakly catalase positive. Colony morphology is transparent and mucoid.
Fr. tularensis is one of the most infective
agents known with the infective dose
as low as ten bacteria. Typically, 90% to
100% of those exposed to the bacterium
develop disease. Even though tularemia
is highly infectious and has many routes
of transmission, it is not contagious
between people.


Fr. tularensis is an intracellular pathogen that has a capsule and is not known to produce toxins. Fr. tularensis produces ?-lactamase and can survive freezing, but is sensitive to water chlorination and heat and can be killed by cooking at 56[degrees]C for at least 10 minutes. Fr. tularensis is a Biosafety level 3 pathogen that requires laboratory workers to wear gloves/goggles and work under a biological safety cabinet when handling the bacterium.

There are four subspecies of Fr. tularensis:

* Fr. tularensis subspecies tularensis or type A, which is the most virulent form, is found in lagomorphs (rabbits and their relatives), and is common in North America.

* Fr. tularemia subspecies holoarctica or type B, is found in rodents (rats, mice, and their relatives) in Europe and Asia.

* Fr. tularemia subspecies mediasiatia is found in Central Asia and is not known to cause human disease.

* Fr. tularemia subspecies novicida is found in North America and is genetically similar to type A, but has lower virulence.

Epizootiology and Public Health Significance

Fr. tularensis is found throughout the United States, Europe, Russia, parts of the Middle East, central Asia, China, Japan, and the northern coast of Africa. Fr. tularensis is found in many different species of animals, but the most important animals in maintaining its cycle in nature and transmission to people are rodents such as voles, beavers, muskrats, and mice and lagomorphs such as hares and rabbits. Different rodents and lagomorphs vary in their resistance to tularemia; cottontail rabbits are highly susceptible to the disease and are usually killed by the infection. In North America, tularemia infections are most common in snowshoe hares, black-tailed jackrabbits, and eastern and desert cottontails. Carnivores are susceptible to the disease, but require high bacterial doses to become infected and rarely exhibit signs of disease. Infections in birds, fish, amphibians, and reptiles are relatively rare. Arthropods such as hard ticks, tabanid flies, mosquitoes, and fleas are important vectors of infection among vertebrates.

Approximately 200 cases of human tularemia are reported annually in the United States, mainly in rural areas of the southcentral and western states. The highest prevalence of cases is seen in Arkansas, Illinois, Missouri, Texas, Oklahoma, Utah, Virginia, and Tennessee. Most cases in the United States are associated with the bites of infected ticks, mosquitoes, and biting flies or with the handling of infected rodents, rabbits, or hares. Many cases are likely unreported or misdiagnosed. The frequency of tularemia in the United States has decreased markedly over the last 50 years, and has shifted from winter disease (usually from rabbits) to summer disease (more likely from ticks). Untreated cases of tularemia have a mortality rate of 5% to 15%; the use of appropriate antibiotics reduces this rate to about 1%.

The number of international cases of tularemia is unknown because it is not reportable.

Transmission

Fr. tularensis prefers cooler weather and in nature it is found north of the tropics. Natural sources of transmission include the bites of blood sucking ticks and insects or from water contaminated by infected animals (ticks are the most important vectors of Fr. tularensis, transferring the bacterium between rabbits, hares, and rodents). Ticks are biological vectors and maintenance hosts of Fr. tularensis and the bacterium can be introduced into mammals by both tick saliva and feces. Transmission in ticks is transstadially and transovarially. Deerflies also transmit Fr. tularensis and have been responsible for many outbreaks in the United States.
Fr. tularensis is classified as a category A
bioterrorism agent as a result of its high
infectivity, ease of dissemination, and
potential to cause disease. Anticipated
mechanisms for dissemination include
contamination of food or water and
aerosolization.


Another common source of human infection is contaminated wild meat (usually rabbit meat). Direct contact with excretions, blood, or organs of infected wild animals can be the source of Fr. tularensis infection in people. The bacterium enters the body through small skin lesions as well as through mucous membranes during contact with infected animals, especially during skinning or eviscerating of carcasses. Contact with contaminated environmental sources such as water, soil, or vegetation are also possible sources of infection. Inhaling airborne bacteria (which can be generated during transportation of infected bedding material or from handling contaminated animal skins) can also cause tularemia.
Wild rabbits should not be kept as pets,
since they may carry Fr. tularensis.
Domestically raised rabbits are typically
free of this bacterium.


Pathogenesis

The pathophysiology of tularemia depends on the route of infection, strain of bacteria, and host response. As few as 10 to 50 type A Fr. tularensis bacteria can cause disease if directly inoculated into the skin or inhaled (higher numbers are needed when the organism is ingested). After an incubation period usually between 2 to 10 days (varies from hours to weeks), acute disease develops. If the portal of entry is through skin a red papule appears, which enlarges, becomes purulent, and ulcerates. As bacteria spread through the blood and lymphatics, a primary complex arises in which regional lymph nodes enlarge, fill with pus, and ulcerate. Occasionally, there is lymph node enlargement without a primary lesion. Bacteria can spread to other organs of the body, particularly the lungs, pleura, spleen, liver, and kidneys where granulomas may develop. Widespread involvement of lymph nodes and viscera typically results in death. It is believed that Fr. tularensis is an obligate intracellular parasite that replicates within macrophages.
The dog tick, De. variabilis, is considered
the principle vector of Fr. tularensis
the United States.


In rabbits and ground squirrels, multiple chalky lesions of variable size scattered through the liver, spleen, and lymph nodes. Caseous necrosis is surrounded by a zone of lymphocytes, with a few neutrophils and macrophages. Early lesions may have a purulent center that becomes necrotic with time.

Clinical Signs in Animals

Clinical signs of tularemia in animals vary with the species infected. Species infected with Fr. tularensis include:

* Rabbits, hares, and rodents. Naturally-infected rabbits, hares, and rodents are most often found dead without any clinical signs. Experimentally infected rabbits, hares, and rodents show signs of weakness, fever, ulcers, regional lymphadenopathy, and abscesses. Death usually occurs in these animals in 8 to 14 days.

* Sheep. Clinical signs of tularemia in sheep include high fever, rigid gait, diarrhea, polyuria, weight loss, tachycardia, tachypnea, and dyspnea. Affected sheep may isolate themselves from the remainder of the flock. Death is most common in young animals within hours or days of developing clinical signs. Pregnant ewes may abort. Tularemia in sheep is typically a seasonal disease, coinciding with tick infestations.

* Domestic cats. Cats infected with Fr. tularensis may show signs that include fever, lymphadenopathy, abscesses, oral or lingual ulceration, gastroenteritis, hepatomegaly, splenomegaly, icterus, anorexia, weight loss, pneumonia, and sepsis.

* Dogs. Clinical signs of tularemia in dogs may be inapparent or mild and are related to the route of transmission. Clinical signs include fever, mucopurulent oculonasal discharge, pustules at inoculation sites, lymphadenopathy, and anorexia.

* Cattle. Natural infection in cattle occurs, but clinical disease is not observed.

* Horses. Reports of tularemia in horses are limited; however, fever, dyspnea, incoordination, and depression have been described following extensive tick infestation.

Clinical Signs in Humans

The incubation period for tularemia in people is typically 3 to 5 days, but may range from 1 to 14 days. Fever, chills, lethargy, myalgia (muscle pain), and vomiting are followed by more specific signs of disease that depend on route of entry. All forms of tularemia can progress to pleuropneumonia, meningitis, sepsis, shock, and death.

Occasionally tularemia in humans is divided into 2 categories: the external form which includes the ulceroglandular form (in which local or regional signs predominate) and the internal form which includes the more lethal typhoidal form (in which systemic signs dominate the clinical picture). More commonly tularemia is divided into six forms that reflect the mode of transmission and include:

* Ulceroglandular. Ulceroglandular tularemia is the most common form (75% to 85% of reported cases) with the bacterium entering the body through a scratch, abrasion, or tick or insect bite. After introduction of as few as 10 organisms into the body bacteria spread via the lymphatic system. At the site of entry, usually the fingers or hands in cases associated with exposure to rabbits, hares, or rodents, an ulcer develops that progresses to necrosis and lymphadenopathy (Figure 4-17). Lymph nodes may suppurate and ulcerate.

* Glandular. The glandular form of tularemia is rare. There is no development of an ulcer and the organism is believed to have entered the lymphatic system and/or bloodstream through clinically undetectable abrasions. Signs of glandular tularemia are similar to ulceroglandular tularemia with the exception of a skin ulcer.

* Oculoglandular. The oculoglandular form of tularemia is rare (approximately 1% of cases) and results from contamination of the conjunctiva from either a splash of infected blood into the mucous membrane or rubbing the eyes after contact with infectious materials such as blood from an infected rabbit carcass. Ulcerated papules, which are usually located on the lower eyelid, are seen as well as lymphadenopathy.

* Oropharyngeal. Oropharyngeal tularemia is rare and is contracted through ingestion of Fr. tularensis (usually undercooked rabbit meat containing the bacterium) and results in acute pharyngeotonsillitis, which may be exudative or membranous, with cervical lymphadenopathy.

* Pulmonary. Pulmonary tularemia represents about 30% of tularemia cases and develops after inhalation of aerosolized bacteria. Pneumonia in one or both lungs is the typical clinical sign. Pulmonary tularemia is most frequently observed in laboratory workers. Pneumonia also occurs in 10% to 15% of patients with ulceroglandular tularemia and in one-half of those patients with typhoidal tularemia.

* Typhoidal. Typhoidal tularemia, also known as septicemic tularemia, occurs in about 10% to 15% of cases and results from ingestion of contaminated food or water. Clinical signs include fever, weight loss, gastroenteritis, and sepsis. Mortality rates in untreated cases can range from 40% to 60%. This form is more severe than the others and often includes pneumonia. Ingestion may be the mode of transmission; however, in most cases, the portal of entry may be unknown.

[FIGURE 4-17 OMITTED]

Diagnosis in Animals

Definitive diagnosis of Fr. tularensis is through bacterial culture from clinical specimens such as blood, exudates, or biopsy. Cultivation of this bacterium is difficult as a result of its fastidious nature and the fact that is grows very slowly in culture. Cultures should be considered dangerous and many laboratories may not attempt to isolate this bacterium because of the potential to infect laboratory personnel.

ELISA, hemagglutination, microagglutination, and tube agglutination are all serologic methods used to identify agglutinating antibodies to Fr. tularensis. Tularemia is generally a postmortem diagnosis in wild animals.

Diagnosis in Humans

For humans, a presumptive diagnosis is based on a patient's history, clinical signs, and a history of exposure. Definitive diagnosis is through bacterial culture of lesions, pus, biopsy, sputum, or blood. In routine laboratories, serology is the preferred method of identification because of the risk of infection to personnel. Agglutinating antibodies can be expected in the second week of the disease with titers of _1:40 being suspicious. In nonendemic areas, a single convalescent titer of 1:160 or greater is considered diagnostic. In endemic areas, acute and convalescent titers are required and a fourfold change of titer between samples obtained 2 to 4 weeks apart is considered to be diagnostic. ELISA tests for detection of IgM, IgA, and IgG antibodies are also available as well as lymphocyte stimulation tests. PCR tests are being evaluated for the diagnosis of tularemia that directly measure DNA from the organisms.

Treatment in Animals

Streptomycin and tetracycline are the antibiotics of choice for treating wild and domestic animals. Early treatment should prevent death.

Treatment in Humans

The treatment of tularemia in humans consists of antibiotics such as streptomycin, tetracyclines (especially doxycycline), gentamicin, fluoroquinolones, and chloramphenicol. Tularemia typically responds well to antibiotics. Fluid therapy and antipyretics may be helpful in treating clinical signs.

Management and Control in Animals

Control of tularemia between animals is difficult. Tick control is an important part of tularemia prevention as are rapid diagnosis and treatment of the disease.

Management and Control in Humans

Preventing tularemia in people involves avoiding the various routes of exposure. People who hunt, trap, butcher, skin, or handle wild animals are most at risk and should thoroughly cook wild game before consumption; wear gloves when handling wild game, their skins, and carcasses; and properly dispose of or disinfect equipment used in the diagnosis, care, or collection of animals suspected or known to be infected with Fr. tularensis. In endemic areas, handling of dead and diseased animals should be avoided. Washing of hands after handling any wild animal is recommended. Tick and insect bites should be controlled by the use of insect repellent containing DEET for skin application and insect repellant containing permethrin for clothing.

Contact with untreated water should be avoided when contamination with Fr. tularensis is suspected. Healthcare professionals working with animal and human tularemia patients should wear personal protective clothing including gowns, gloves, and face masks. Diagnostic laboratories should be notified if tularemia is suspected when specimens are submitted. Biosafety level 2 precautions are recommended for diagnostic work on suspect material and biosafety level 3 precautions are required for culture. Tularemia is a reportable disease in the United States, but not internationally.

A live attenuated vaccine to protect against typhoidal tularemia administered by scarification (the method used for smallpox vaccines) is no longer available under its Investigational New Drug protocol.

Summary

Tularemia is a disease caused by Fr. tularensis, a small, pleomorphic, nonsporeforming, faintly staining, gram-negative bacillus. This bacterium is transmitted by tick and insect bites and by contact with infected animals. There are four subspecies of Fr. tularensis: Fr. tularensis subspecies tularensis or type A, which is the most virulent form, is found in lagomorphs (rabbits and their relatives), and is common in North America; Fr. tularemia subspecies holoarctica or type B, is found in rodents (rats, mice, and their relatives) in Europe and Asia; Fr. tularemia subspecies mediasiatia is found in Central Asia and is not known to cause human disease; and Fr. tularemia subspecies novicida is found in North America and is genetically similar to type A, but has lower virulence. Clinical signs of tularemia in animals vary with the species infected and include rabbits, hares, and rodents, sheep, domestic cats, and dogs (rarely cattle and horses). Most animals exhibit signs of high fever, lethargy, anorexia, gait abnormalities, and altered respiratory rates. In humans the incubation period is typically 3 to 5 days and clinical signs include fever, chills, lethargy, myalgia (muscle pain), and vomiting. In humans, tularemia is divided into six forms that reflects the mode of transmission and include ulceroglandular, glandular, oculoglandular, oropharyngeal, pulmonary, and typhoidal. Fr. tularensis is diagnosed via bacterial culture (it is difficult to culture requiring strict aerobic conditions and enriched media) and serology. Treatment of tularemia involves the early use of antibiotics in both humans and animals. Prevention of tularemia involves tick control, rapid diagnosis and treatment of the disease, using proper hygiene procedures, and using personal protection when handling suspect tissues. Tularemia is a reportable disease in the United States.
Table 4-1 Features of Hard and Soft Ticks

Common Name   Family Name   Unique Features       Examples

Hard tick     Ixodidae      * Have a hard plate   There are seven
                              called a scutum     genera that transmit
                              covering the        disease:
                              dorsal body
                              surface.            * Ixodes
                            * Mouthparts          * Dermacentor
                              protrude and are    * Amblyomma
                              visible from        * Haemaphysalis
                              above.              * Hyalomma
                                                  * Rhipicephalus
                                                  * Boophilus *

Soft tick     Argasidae     * Lack a scutum.      There is only one
                            * Have a cuticle      genus that transmits
                              that is soft        disease to humans:
                              and leathery.
                                                  * Ornithodoros
                                                  * Otobius *
                                                  * Argas *
* do not transmit disease to humans

Table 4-2 Different Types of Diseases Transmitted From Ticks

Tick               Diseases             Region Found      Hosts
                                        (U.S.)

Dermacentor        Rocky Mountain       Western states    Dogs
andersoni          spotted fever        south to          Horses
(Wood tick) *      Tularemia            Arizona and       Livestock
                   Q fever              New Mexico        Mammals
                   Tick paralysis                         Humans
                   Cytauxzoonosis
                   Colorado tick
                   fever virus
                   Powassan
                   encephalitis
                   virus

Dermacentor        Rocky Mountain       Eastern           Dogs
variablilis        spotted fever        two-thirds        Cats
(Dog tick) *       Tularemia            of the            Mammals
                   Q fever              United States     Humans
                   Tick paralysis
                   Ehrlichiosis
                   Cytauxzoonosis

Ixodes             Lyme disease         Most of the       Mammals
scapularis         Ehrlichiosis         United States,    Birds
(Blacklegged       Babesiosis           especially the
tick) *            Tick-borne           Northeast,        Humans
(sometimes         encephalitis         and upper
called the         Tick paralysis       midwest,
deer tick)                              Northern
                                        California

Amblyomma          Rocky Mountain       East of central   Livestock
americanum         spotted fever        Texas to the      Dogs
(Lone star         Tularemia            Atlantic coast,   Deer
tick) *            Q fever              north to Iowa     Birds
                   Ehrlichiosis                           Humans
                   Tick paralysis

Rhipicephalus      Tick paralysis       Most of the       Dogs
sanguineus         Babesiosis           United States
(Brown dog         Ehrlichiosis
tick) *            Rocky Mountain
                   spotted fever
                   Hepatozoonosis
                   Haemobartonellosis

Ornithodoros       Relapsing fever      Idaho, Oregon,    Chipmunks
hermsii                                 Washington,       Squirrels
(Relapsing                              California,       Humans
fever                                   Nevada, and
tick) ([dagger])                        Colorado

Ornithodoros       Relapsing fever      Southwest         Chipmunks
tunicatae                               United States     Squirrels
(Relapsing fever                                          Humans
tick) ([dagger])

Ornithodoros       Painful tick         California        Mammals
cariaceus          bite reaction                          Humans
(Pajaroello
tick)([dagger])

* Diseases transmitted by hard ticks.

([dagger]) Diseases by soft ticks.
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Title Annotation:Part 1: OVERVIEW-TULAREMIA
Author:Romich, Janet Amundson
Publication:Understanding Zoonotic Diseases
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Jan 1, 2008
Words:14993
Previous Article:Chapter 3 Bacterial zoonoses.
Next Article:Chapter 4 Tick-borne bacterial zoonoses.
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