Current Diagnosis & Treatment in Infectious Diseases

Section VIII - Miscellaneous Infections

90. Zoonotic Infections

Scott D. Smith MD

David A. Relman MD

Essentials of Diagnosis

  • Occupations such as abattoir worker and hobbies such as hunting, outdoor activities, and fishing.
  • History of exposure to animals, birds, fish, and insect vectors such as mosquitoes, ticks, fleas, and lice; history of ingesting uncooked foods.
  • Clinical syndromes such as atypical pneumonia, encephalitis, and granulomatous lymphadenopathy.
  • Blood smear with visible microorganisms.
  • Radiographic evidence of calcified lesions in brain or muscle.

General Considerations

Zoonoses are infectious diseases of vertebrate animals that are capable of spreading to and affecting humans. This traditional definition is often broadened to include other nonhuman hosts as reservoirs or sources of the infectious agent. Many zoonoses have only historical significance in the developed world; however, they continue to exact a major toll on human health in less-well-developed regions. Of equal or greater concern is that zoonoses are over-represented among diseases that are currently defined as “emerging.” Emerging infectious diseases are those that are associated with newly recognized infectious agents or with agents that appear to be spreading and causing more cases of disease or more serious cases than they did previously. One survey has found that 114 of 156 emerging infectious diseases can be classified as zoonoses. The reasons for this important phenomenon are discussed later in this chapter.

  • Epidemiology.Zoonoses tend to occur under special circumstances of geography, climate, or human activity that create new opportunities for encounters between humans and zoonotic agents (see Pathogenesis below). As a result, zoonoses are often geographically focal, transient over months or years, and restricted to specific subpopulations. In the case of hantavirus pulmonary syndrome, the disease arises only when humans live or sleep near infected rodents, which in turn are found only in small geographic microenvironments. In general, humans at special risk for acquiring zoonoses are farmers, hunters, and those that handle and work with animals, birds, and fish. In addition, persons with unusual exposure to insect vectors and those that work in and near water are at increased risk for zoonoses. Most often, humans act as “dead-end” hosts for zoonotic disease agents; ie, they do not contribute to overall, long-term persistence or spread of the agent in nature.
  • Microbiology.There are numerous diverse pathogenic microorganisms associated with zoonotic disease including viruses, bacteria, fungi, and parasites (Box 90-1). A reservoir is a host in which a microorganism lives and multiplies. A primary reservoir is a host on which a zoonotic agent depends for its continued survival in nature. This host does not usually develop disease. As an example, the white-footed mouse is a primary reservoir for Borrelia burgdorferi, the agent of Lyme disease, in the northeastern United States. Although an infected mouse does not exhibit signs of disease, it permits prodigious replication of this spirochete and circulation of the organism in the murine bloodstream. As a result, ixodid ticks often acquire the spirochete during a blood meal. A secondary reservoir in contrast, is not necessary for the survival of the microbe in nature but may be important for the transmission of disease to humans. Plague and its causative agent, Yersinia pestis, illustrate this concept (Figure 90-1). Wild rodents serve as primary reservoirs; commensal rodents such as urban rats may serve as secondary reservoirs and as such may play disproportionately important roles in transmission of disease to humans in a peridomestic setting, via their fleas, as was so acutely illustrated during the Middle Ages. Many of the most common reservoirs for human zoonotic diseases are domestic animals or animals adapted to urban and suburban environments. As humans build their homes and move into the habitats of the primary reservoirs, their chances for contact with zoonotic pathogens increase (see below). Table 90-1 lists some of the more common associations of animals with zoonotic agents.

A vector is an organism, usually an arthropod, that carries a zoonotic agent from one host to another. Common vectors include mosquitoes, ticks, and fleas. Vectors can be categorized as mechanical or biological, depending on the degree of intimacy with the microorganism they transmit. A mechanical vector transmits disease agents by means of contamination of its legs, proboscis, or even its gastrointestinal tract. Mechanical transmission requires no multiplication or specific interaction between vector and pathogen to enable disease spread. The common housefly is an example.


Biological vectors on the other hand may have a sophisticated and accommodating relationship with the infectious organism, enabling multiplication and cyclic development within vector gut or salivary glands. It is common for pathogens to recognize the distinct environments of a vector and to respond to the relevant cues by expressing a unique set of genes and gene products accordingly. These products facilitate adaptations to the vector. For example, B burgdorferi preferentially expresses the surface protein OspA in the tick gut. OspA may play a role in colonization of B burgdorferi and its translocation through the tick gut wall. Nocturnal biting patterns of the mosquito vectors that transmit Wucheria bancrofti, one of the agents of human filariasis, match the nocturnal periodicity of parasitemia of the microfilariae. Other features of the feeding pattern of the vector may also enhance transmission efficiency or competence; for example, the Simulium black fly feeds on subcutaneous pools of blood, enabling it to ingest skin-dwelling microfilaria of Onchocerca volvulus.

 

Figure 90-1. Transmission and maintenance of Yersinia pestis, the agent of plague, in nature. (Reprinted, with permission, from Plague. In Hoeprich PD et al: Infectious Diseases, 5th ed. Lippincott, 1994.)

  • Pathogenesis.There are three primary routes of transmission of zoonoses to humans: (1) through the skin, by the bite of a vector or animal (eg, Pasteurella multocida from animal bites) or by direct inoculation (eg, cutaneous anthrax from animal skin handling), (2) through inhalation (eg, Coxiella burnetii or Chlamydia psittaci), and (3) by ingestion (eg, Giardia lamblia or Brucella or Salmonella species). The route of transmission usually determines the nature of the ensuing clinical syndrome in the human host, especially with regard to the sites of disease involvement. Some zoonotic agents are transmitted to humans by more than one route; for example, C burnetii is occasionally tickborne, and Francisella tularensis, the agent of tularemia, can be acquired from a tick as well as through direct inoculation of the skin from an abrasion while handling an infected animal. Furthermore, the route of disease transmission to humans may differ from the route between reservoir hosts.

Table 90-1. Animals, birds, and fish and associated zoonotic disease agents.1

Animal

Dog

Cat

Ferret

Rabbit

Rats and Mice

Hamster and Guinea Pig

Turtle

Fish

Avian Species

Lizard/Snake

Cattle

Sheep/Goat

Horse

Pig

Fox, skunk bat, raccoon

Virus

Rabies

Rabies

Rabies

 

Hanta virus

 

 

Rabies virus

 

Influenza

Lymphocytic choriomeningitis virus

 

Viral encephalitis

Viral encephalitis

 

Bacterium

Pasteurella multocida

Pasteurella multocida

Campylobacter jejuni

Pasteurella multocida

Pasteurella multocida

Salmonella spp.

Salmonella spp.

Salmonella spp.

Salmonella spp.

Salmonella spp.

Bacillus anthracis

Bacillus anthracis

Bacillus anthracis

Bacillus anthracis

 

Brucella canis

Campylobacter jejuni

Salmonella spp.

Francisella tularensis

Salmonella spp.

Yersinia enterocolitica

Yersinia enterocolitica

Streptococcus iniae

Campylobacter jejuni

Yersinia enterocolitica

Brucella spp.

Brucella spp.

Brucella spp.

Brucella spp.

Campylobacter jejuni

Capnocytophaga canimorsus

Listeria monocytogenes

Yersinia pestis and Y enterocolitica

Yersinia pestis and Y enterocolitica

Campylobacter jejuni

Campylobacter jejuni

Mycobacterium marinum

Listeria monocytogenes

Edwardsiella tarda

Babesia spp.

 

Leptospira spp.

Leptospira spp.

Borrelia burgdorferi

Yersinia pestis

Leptospira spp.

 

Streptobacillus moniliformis or Spirillium minus

Pasteurella spp.

Aeromonas spp.

Erysepelotrix rhusiopathiae

Pasteurella spp.

Plesiomonas spp.

Campylobacter spp.

Campylobacter spp.

Borrelia spp.

 

Leptospira interrogans

Coxiella burnetti

Leptospira spp.

Leptospira spp.

Vibrio cholerae

Chlamydia psittaci

Leptospira spp.

Erysipelothrix rhusiopathiae

Francisella tularensis

Francisella tularensis

Salmonella spp.

Salmonella spp.

Yersinia enterocolitica

Listeria monocytogenes

Listeria monocytogenes

Salmonella spp.

Listeria monocytogenes

Francisella tularensis

Francisella tularensis

Borrelia spp.

Leptospira spp.

Campylobacter jejuni

Yersinia enterocolitica

Coxiella burnettii

Coxiella burnettii

Rickettsia rickettsiae

Francisella tularensis

Francisella tularensis

Salmonella spp.

Salmonella spp.

Salmonella spp.

Pasteurella multocida

Yersinia enterocolitica

Yersinia enterocolitica

Yersinia enterocolitica

 

Rickettsia rickettsiae

Parasite

Giardia lamblia

Giardia lamblia

Giardia lamblia

Cheyletiella parasitovorax (rabbit fur mite)

Babesia microti

Hymenolepis nana

Diphyllobothrium latum

Cryptosporidium spp.

Cryptosporidium spp.

Cryptosporidium spp.

Cryptosporidium spp.

Cryptosporidium spp.

Toxocara canis

Toxocara cati

Toxocara spp.

 

 

 

Toxoplasma gondii

Toxoplasma gondii

Cryptosporidium parvum

Cryptosporidium parvum

Taenia saginata

Giardia lamblia

Ancylostoma spp.

Toxoplasma gondii

Fungus

 

 

Dermatophytes

Dermatophytosis (Trycophyton mentagrophytes)

Dermatophytosis (T. mentagrophytes)

Cryptococcus neoformans

Taenia solium

Taenia solium

Histoplasma capsulatum

 

1These lists are not all-inclusive, but rather are meant to highlight diseases that are life-threatening or most comonly encountered.

The expression of zoonotic disease reflects an intimate interplay between nonhuman reservoirs, vectors, a human host, and a pathogen. This complex ecosystem is easily disrupted, and when disease emerges in one sector, it often spills over into or has consequences for another sector (Figure 90-2). A classification of factors responsible for the emergence of zoonotic disease can be organized according to host, vector, and pathogen. Host and vector factors include physical translocation and encroachment by one host into the territory of another, travel, crowding, human conflict, globalization of food supply, and environmental changes such as deforestation, global warming, and El Nino Southern Oscillation events. Pathogen factors include acquisition or expression of genes encoding toxins, adherence factors, or outer surface antigenic structures (antigenic variation) and other genetic events that confer upon the microorganism an improved growth rate or transmissibility, broadened host range, and drug resistance. The spread of Lyme disease in the northeastern United States over the past two decades is attributed to the reforestation of New England, human encroachment on deer and mouse habitats, uncontrolled deer population growth, and climate effects on tick population size.

BOX 90-1 Microbiology of Zoonoses

 

Central Nervous System

Pulmonary

Abdominal Pain ± Diarrhea

Rash

Cutaneous Lesion

Lymphadenopathy

More Frequent 1

·  Listeria monocytogenes

·  Toxoplasma gondii (in immunocompromised hosts)

·  Coxiella burnetii

·  Histoplasma capsulatum

·  Giardia lamblia

·  Cryptosporidium parvum

·  Salmonella spp.

·  Campylobacter jejuni

·  Rickettsia rickettsii, R. typhi, R. conorii

·  Dengue fever virus

·  Salmonella typhi

·  Borrelia burgdorferi

·  Pasteurella multocida

·  Trypanosoma cruzi

·  Toxoplasma gondii

·  Bartonella henselae

Less Frequent 1

·  Leptospira spp. (interrogans)

·  Arboviruses: Japanese B encephalitis, Yellow fever, Dengue fever

·  Borrelia spp.

·  Rickettsia spp.

·  Trypanosoma gambiense or rhodiense

·  Bacillus anthracis

·  Chlamydia psittaci

·  Francisella tularensis

·  Toxocara canis

·  Yersinia pestis

·  Sin Nombre hantavirus

·  Echinococcus granulosus

·  Brucella spp.

·  Trichinella spiralis

·  Anisakis spp.

·  Echinococcus granulosus

·  Taenia solium (pig) or saginata (cow)

·  Listeria monocytogenes

·  Yersinia enterocoliticaand Y. pseudotuberculosis

·  Campylobacter jejuni

·  Isospora belli

·  Babesia microti andrelated spp.

·  Ehrlichia spp.

·  Brucella abortus

·  Pseudomonas mallei

·  Spirillum minor

·  Borrelia recurrentis

·  Trichinella spiralis

·  Histoplasma capsulatum

·  Acute infection:
African Trypanosoma

·  Francisella tularensis

·  Bacillus anthracis

·  Cowpox virus

·  Orf virus

·  Erysipelothrix rhusiopathiae

·  Rickettsia conorii

·  Orientia tsutsugamushi

·  Mycobacterium marinum

·  Spirillum minor

·  Streptobacillus moniliformis

·  Seal finger agent

·  Yersinia pestis

·  Francisella tularensis

·  Dengue virus

·  Brucella spp.

·  Histoplasma capsulatum

·  Leishmania spp.

·  Acute Trypanosoma infection: African and American

·  Francisella tularensis

·  Trichinella spiralis

1In the United States

Clinical Findings

Zoonotic disease should be suspected in the setting of fever and either an unusual history of exposure to a potential reservoir or vector or a more specific clinical syndrome suggestive of zoonotic disease. “Unusual” exposure histories include frequent, prolonged, or intimate contacts with animals, birds, fish, or disease vectors, especially those contacts that involve bites or scratches, or to sick nonhuman hosts. In general, clinical syndromes associated with zoonotic disease reflect the route of transmission. For example, agents that are transmitted by percutaneous inoculation tend to cause local cutaneous disease such as ulcers, cellulitis, or regional lymphadenopathy; airborne agents tend to cause pneumonia or other lower respiratory tract syndromes; and agents that are transmitted by ingestion usually lead to abdominal or intestinal syndromes. Therefore, the differential diagnosis can be limited to the subset of zoonotic agents that use that route of transmission. More specific syndromes that suggest zoonotic disease are fever and cutaneous eschar (eg, Mediterranean and other spotted fevers and scrub typhus); cough, respiratory distress, and widened mediastinum (inhalational anthrax); and fever, preauricular lymphadenopathy, and conjunctivitis or Parinaud's syndrome (tularemia, cat scratch disease, and others).

 

Figure 90-2. The overlap and interplay between emerging infectious diseases (EID) in wildlife, domestic animals, and humans. (Reprinted, with permission, from Daszak P et al: Emerging infectious diseases of wildlife. Science 2000;287:443.)

Diagnosis

The diagnosis of zoonotic diseases depends heavily on a high index of suspicion and a thorough clinical history. A careful series of questions often reveals travel, contacts, or activities that raise the probabilities of zoonosis substantially. Any potential clue should be pursued by acquiring further information about the intensity of the exposure and duration of stay in a particular location and background data on the prevalence of various zoonotic agents in relevant circumstances. In contrast, there are few clues from physical examination that are likely to be helpful. Bite wounds and lesions are certainly important findings. Cutaneous eschars or certain syndromes such as Parinaud's syndrome (conjunctivitis, preauricular lymphadenopathy, and fever) should suggest zoonoses as part of the differential diagnosis. The laboratory diagnosis of zoonoses relies on serologic testing and thus clinical suspicion of specific disease agents. The finding of microorganisms or poorly explained intracellular inclusions and structures on microscopic examination of a blood smear is a common initial indication of a zoonosis such as malaria, babesiosis, ehrlichiosis, or relapsing fever. Some zoonotic agents require special stains to be visualized under the microscope; for example, Bartonella species can be seen reliably only by using the Warthin-Starry silver stain. Agents that enter the body via an oral route may require stool examination and culture for a diagnosis.

Treatment

The diversity of zoonotic agents precludes any simple protocol for empiric therapy. However, certain clinical syndromes and exposures may be amenable to empiric therapy because of a restricted list of possible zoonotic pathogens that share susceptibility to a few common antimicrobial agents (Box 90-2). For example, febrile illness in the United States in a person with a recent tick bite can be treated empirically with doxycycline until a specific diagnosis is achieved. Doxycycline provides reasonably good treatment for the following tick-borne diseases: Lyme disease, ehrlichiosis, Rocky Mountain spotted fever, tularemia, and relapsing fever. Some zoonoses such as Rocky Mountain spotted fever and anthrax are medical emergencies and, when suspected, require immediate empiric therapy.

BOX 90-2 Empiric Therapy of Zoonoses1, 2

 

Children

Adults

Fever ± Rash and Animal/Vector Exposure3

   First Choice

·  Chloramphenicol, 50–100 mg/kg/d

·  Doxycycline, 100 mg twice daily

   Second Choice

·  Doxycycline, 2.2 mg/kg every 12–24 h4

·  Ciprofloxacin, 500 mg twice daily

Fever, Lymphadenopathy, and Animal/Vector Exposure5

   First Choice

·  Trimethoprim-sulfamethoxazole, 6–12 mg/kg daily

·  Streptomycin, 20–40 mg/kg daily (if plague is suspected)

·  Ciprofloxacin, 500 mg twice daily PO or IV

·  Streptomycin, 1 g IM or IV every 12 h if plague is suspected

   Second Choice

·  Doxycycline, 2.2 mg/kg every 12–24 h4

·  Doxycycline, 100 mg twice daily

Fever, Local Cutaneous Lesion, and Animal/Vector Exposure6

   First Choice

·  Amoxicillin, 6.7–13.3 mg/kg every 8 h

·  Doxycycline, 100 mg twice daily

·  Penicillin G, 6–12 mU daily if anthrax or pasteurellosis is suspected

   Second Choice

·  Erythromycin, 30–50 mg/kg daily, or other macrolide

·  Ciprofloxacin, 500 mg twice daily

   Penicillin Allergic

·  Erythromycin, 30–50 mg/kg daily, or other macrolide

·  Ciprofloxacin, 500 mg twice daily, OR

·  Erythromycin, 500 mg four times daily, or other macrolide, especially if anthrax or pasteurellosis is suspected, respectively.

Respiratory Disease and Animal/Vector Exposure7

   First Choice

·  Erythromycin, 30–50 mg/kg daily, or other macrolide

·  Doxycycline, 100 mg twice daily

   Second Choice

·  Doxycycline, 2.2 mg/kg every 12–24 h4

·  Erythromycin, 500 mg four times daily, or other macrolide

Diarrhea, Fever, and Animal/Vector Exposure8

   First Choice

·  Ceftriaxone, 50–100 mg/kg every 12–24 h

·  Ciprofloxacin, 500 mg twice daily

   Second Choice

·  Trimethoprim-sulfamethoxazole, 6–12 mg/kg/d

·  Trimethoprim-sulfamethoxazole, 160 mg/800 mg twice daily

1Begin empiric therapy immediately for potentially life-threatening diseases, eg, Rocky Mountain spotted fever and malaria. Pursue diagnosis vigorously in potentially life-threatening cases.

2The route of administration for any of these antibiotics depends on the severity of the clinical illness, as well as, in some cases, the formulation of the specific drug (eg, streptomycin, intramuscularly).

3Must make diagnosis immediately if malaria is suspected.
4Tetracyclines may cause teeth discoloration in children younger than 9 years.
5Must make diagnosis immediately if plague is suspected; otherwise, most patients do not require empiric antimicrobial therapy.
6Must make diagnosis immediately if anthrax is suspected.
7Must make diagnosis immediately if pneumonic plague, tularemia, or anthrax is suspected.
8Most patients do not require empiric antimicrobial therapy.

BOX 90-3 Control of Zoonoses

 

Fever ± Rash, and Animal/ Vector Exposure

Fever, Lymphadenopathy, and Animal/Vector Exposure

Fever, Local Cutaneous Lesion, and Animal/Vector Exposure

Respiratory Disease, and Animal/Vector Exposure

Diarrhea, Fever, and Animal/Vector/Exposure

Prophylactic Measures

·  Avoid tick, mosquito bites

·  Avoid cat bites or changing cat litter box

·  Avoid tick, animal bites

·  Avoid parturient animals

·  Avoid ingestion of suspect food and water

Isolation Precautions

·  Blood/universal if hemorrhagic fever is suspected

·  None

·  Contact (??) for cutaneous anthrax

·  Respiratory if pneumonic plague, or tularemia are suspected

·  Enteric

Control

The complexity that governs the origin and spread of zoonoses also provides an equally diverse and interwoven set of opportunities for disease intervention and interruption (Box 90-3). Lyme disease is a useful example, in which strategies for disease reduction include tick avoidance, early detection and removal of attached ticks, tick reduction, by making acaricide-impregnated cotton balls available to white-footed mice in their burrows, and vaccination of humans. OspA is a potent immunogen and is the basis of the current Lyme disease vaccine (see Microbiology above). Vaccine programs can be expanded in some cases to other hosts: the spread of rabies in the eastern United States has been limited through vaccination of wild animals (oral vaccine-laden bait) and peridomestic animals that have close contact with potentially infected wild animals.

REFERENCES

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Daszak P, Cunningham AA, Hyatt AD: Emerging infectious diseases of wildlife-threats to biodiversity and human health. Science 2000;287:443.

Hart CA, Trees AJ, Duerden BI: Zoonoses. J Med Microbiol 1997;46:4.

Talan DA et al: Bacteriologic analysis of infected dog and cat bites. N Engl J Med 1999;340:85.

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