Chapter 59 Wilderness-Acquired Zoonoses

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A zoonosis is an infectious disease that may be transmitted from animals to humans under natural conditions. There are more than 200 zoonotic pathogens, and potential infections vary by animal species (Table 59-1). The risk of acquiring zoonoses increases proportionately with the frequency and intensity of contact with animals. For example, hunters and trappers who handle and are exposed to the blood, viscera, secretions, and excretions of wild animals are at much greater risk than are recreational campers. Similarly, international travelers who frequent locations with a much higher density of infected animals are at greater risk for infection. The trekker in Nepal is more likely to confront rabies than is the hiker in California. With the current ease of international travel, travelers are increasingly exposed to a wider range of animals and potential zoonoses.

TABLE 59-1 Animals and Some Associated Zoonoses

Animals	Associated Zoonoses
Dogs	Rabies, echinococcal diseases, erlichiosis (via ticks), Pasteurella, Campylobacter, Toxocara, leptospirosis
Sheep	Anthrax, brucellosis, echinococcal disease, melioidosis
Cattle	Anthrax, brucellosis, Salmonella, Taenia tapeworms, variant Creutzfeldt–Jakob disease
Goats	Anthrax, brucellosis, melioidosis
Horses	Anthrax, glanders, Hendra virus, Coxiella (Q fever)
Cats	Bartonella infections (cat-scratch disease, bacillary angiomatosis), Pasteurella, Capnocytophaga, Toxoplasma, tularemia, cowpox
Swine	Brucellosis, influenza, melioidosis, Nipah virus, cysticercosis, trichinellosis
Rodents	Hantavirus, leptospirosis, rat-bite fever, plague, tularemia, monkeypox, cowpox, Salmonella typhimurium, rickettsial diseases
Wild mammals (raccoon, skunk, etc.)	Leptospirosis, rabies, Giardia
Rabbits	Tularemia, babesiosis
Birds	Avian influenza, psittacosis, Salmonella, West Nile virus
Monkeys	Rabies, herpes B, filoviruses, hepatitis, tuberculosis, parasitic infections, flaviviruses (yellow fever), chikungunya

This chapter emphasizes diseases in which wildlife plays a significant role in transmission to humans. Rabies is discussed in a separate chapter, as are the majority of arthropod and mosquito-borne diseases. Zoonoses acquired primarily from domestic animals that also have a minor reservoir in wildlife are mentioned briefly; standard texts of veterinary public health ^133,^241,²⁶¹ and infectious disease^118,¹⁷⁰ provide further discussion of zoonoses acquired from laboratory or exotic animals.

Anthrax

Anthrax is a traditionally zoonotic disease that has come to the forefront most recently as a result of bioterrorism. It still deserves attention as a disease acquired through exposure to animals. Anthrax has afflicted men and beasts for centuries.²⁶³ The word anthrax comes from the Greek word anthrakites for coal, referring to the black eschar seen in cutaneous anthrax. Anthrax is believed to have been one of the Egyptian plagues that affected cattle at the time of Moses.⁸⁴ Virgil described clinical anthrax as the murrain of Noricum in his works on agriculture, The Georgics: “The pelts of diseased animals were useless, and neither water or fire could cleanse the taint from their flesh. The sheepmen could not shear the fleece, which was riddled with disease and corruption, nor did they dare even to touch the rotting strands. If anyone wore garments made from tainted wool, his limbs were soon attacked by inflamed papules and a foul exudate.”²⁸⁶

The anthrax bacillus was the model first used by Robert Koch in the 1870s in the development of his postulates on the germ theory of disease. In the mid-19th century, anthrax was called woolsorters’ and ragpickers’ disease in England and Germany, because workers contracted the disease from working with hides and fibers contaminated with anthrax spores. In the United States in the early 1900s cutaneous anthrax cases were reported among textile and tannery workers. The decrease in the incidence of disease by the late 20th century is attributed to improved animal hygiene as well as the animal anthrax vaccine, developed by Louis Pasteur in 1881.

Because anthrax spores (Figure 59-1) are resistant to heat and drying and may remain dormant for decades, they have long been considered a potential biologic weapon. Germ warfare programs in the Soviet Union during the 1920s and 1930s included development and stockpiling of anthrax spores. The first report of anthrax spores used as a weapon of war was in the 1940s, when the Japanese army used them in Manchuria during the Chinese–Japanese war.¹²⁷ Japan killed thousands of Chinese in widespread attacks with anthrax, typhoid, and plague in its assault on Manchurian towns and cities. Bacillus anthracis spores were accidentally released at a military facility in Sverdlovsk in 1979, resulting in 66 deaths.¹⁸⁷ In 2001, the intentional contamination of U.S. mail with B. anthracis spores turned attention once again to anthrax as an agent of bioterrorism.

FIGURE 59-1 Anthrax spores.

(From http://bepast.org/docs/photos/Anthrax/anthrax%20spores.jpg.)

Bacteriology

Anthrax is caused by Bacillus anthracis bacteria (Figure 59-2), which are encapsulated nonhemolytic, nonmotile, spore-forming, gram-positive rods that grow well on blood agar. B. anthracis has a polysaccharide cell wall antigen and an anthrax toxin. Anthrax spores are resistant to heat, drying, ultraviolet light, and disinfectants, and they may survive up to decades in soil.²⁹² They are alleged to be destroyed by high heat (140° C [284° F] for 3 hours, or 10 minutes of boiling) but may survive for up to 70 hours in mercuric chloride.¹¹⁶ Infections are initiated by skin, pulmonary, or gastrointestinal (GI) contact with endospores, which are phagocytosed by macrophages and carried to regional lymph nodes.⁸⁶ Inside macrophages, the spores germinate into vegetative bacteria, which can then rapidly divide and initiate further spread of infection. B. anthracis produces a toxin that is a tripartite polypeptide consisting of a lethal factor, edema factor, and protective antigen. This tripartite toxin stimulates release of tumor necrosis factor alpha, interleukin-1β, and other factors that lead to disruption of water balance and neutrophil function in the body, inhibiting the innate and adaptive immune responses to bacteria. In essence, this allows the bacteria to proliferate in the body, potentially leading to sepsis and death.¹¹⁶

FIGURE 59-2 A photomicrograph of Bacillus anthracis bacteria using Gram stain technique. Anthrax is diagnosed by isolating B. anthracis from the blood, skin lesions, or respiratory secretions, or by measuring specific antibodies in the blood of persons with suspected cases.

(From Centers for Disease Control and Prevention Public Health Image Library. http://phil.cdc.gov/Phil/home.asp.)

Epidemiology

Most animals are susceptible to anthrax to some degree, but clinical anthrax is primarily a disease of herbivores, such as sheep, cattle, horses, and goats. Most birds are immune to anthrax, although they may carry it on their talons or beaks. The disease is rarely seen in countries where vaccination of herbivore stock is practiced. Outbreaks among herbivores are thought to occur under environmental conditions that are favorable for bacterial multiplication, such as where the pH is higher than 6.0 and the soil is rich in organic matter.²⁵¹ Such an outbreak occurred in North Dakota in 2005.⁸

Anthrax is rare in developed nations with aggressive vaccination of livestock, but it is still problematic in areas of Asia and Africa with sporadic vaccination and significant wildlife reservoirs. Most cases in industrialized nations are seen after exposure to contaminated animal products—for example, goat hair imported from Turkey and Pakistan.³¹⁹ Shepherds, farmers, and workers in industrial plants with potentially contaminated animal products are at highest risk. The most recent reported case was in 2006 from a person in New York who was exposed to contaminated dust while skinning a hide for a drum; 5 days later he developed inhalational anthrax.¹¹⁶

Even more concerning are anthrax-related bioterrorism events, such as the 2001 mail contamination outbreak in the United States. During this outbreak, 22 people were affected, of which there were 11 cases of inhalational and 11 of cutaneous anthrax. The majority of the people affected were mail workers. The survival rate for inhalational anthrax was 55%.

Transmission

Humans are infected by anthrax through contact with infected animals or animal products, or through a preparation of spores in the case of bioterrorism attacks. Notably, there has been no documented human-to-human transmission of anthrax.⁸⁶ Transmission occurs through direct contact with spores, ingestion of spores, or inhalation of spores.

Presentation and Symptoms

There are three forms of anthrax infection: cutaneous, inhalational, and gastrointestinal. The forms are defined by the route of entry of spores into the human body as well as by the constellation of manifesting symptoms.

Cutaneous anthrax is the most common form, accounting for 90% to 95% of cases, and is most often acquired by close contact with infected animals or their products. The primary skin lesion typically begins 3 to 5 days after exposure as a nondescript, painless, and pruritic papule at an area of the skin with a previous abrasion or wound. This progresses within 1 to 2 days to a vesicle that undergoes necrosis and drying to leave the characteristic black eschar surrounded by edema (Figure 59-3).⁸⁶ Untreated, the disease can lead to tender regional lymph nodes with eventual spread to the bloodstream. Once in the bloodstream, anthrax can rapidly become systemic. Without treatment, anthrax has a mortality rate of up to 20%.²⁹² With treatment, death is rare (less than 1%).

FIGURE 59-3 Cutaneous anthrax lesion on the skin of the forearm caused by the bacterium Bacillus anthracis.

(From Centers for Disease Control and Prevention Public Health Image Library, http://phil.cdc.gov/Phil/home.asp.)

Gastrointestinal anthrax, which is more common outside of the United States, is caused by ingesting B. anthracis spores. These usually are found in putrid meat from infected animals.¹⁷ The two forms of gastrointestinal anthrax are oropharyngeal and intestinal, each with an incubation period of 1 to 6 days.

Symptoms of oropharyngeal anthrax include fever greater than 39° C (102.2° F), severe sore throat, dysphagia, posterior oropharyngeal ulcers, and regional lymphadenopathy. Oropharyngeal lesions begin as edematous ulcerations that variably progress to ulcerations with central necrosis and then a pseudomembranous covering. The oropharyngeal form of gastrointestinal anthrax is also associated with significant soft tissue neck swelling, which may progress to the point of upper airway obstruction.

The intestinal form of gastrointestinal anthrax is characterized by anthrax spore infection of the stomach or bowel wall. Initial symptoms include nausea, vomiting, anorexia, and fever greater than 39° C (102.2° F). Symptoms progress to include severe abdominal pain, hematemesis, and/or watery, melanotic, or bloody diarrhea. Patients can present with symptoms of an acute abdomen or new-onset ascites. Mortality can result from bowel perforation or B. anthracis septicemia.

Inhalational anthrax is rare worldwide and is associated most prominently with bioterrorism. Inhalational anthrax has an incubation period of 8 to 10 days after inhalation of spores into the airways.³¹ Symptoms include insidious flulike onset of malaise, fatigue, fever, nonproductive cough, and myalgia.²⁵¹ The rapid deterioration that follows includes dyspnea, cyanosis, respiratory failure, meningismus, mediastinal hemorrhage, hypotension secondary to septic shock, and possibly death.

Of the three forms of disease, inhalational anthrax has the highest mortality rate (45% with antibiotic treatment and 97% without), followed by gastrointestinal anthrax (40% with antibiotic treatment), and cutaneous anthrax (1% with antibiotic treatment and 10% to 20% without).^138,²⁵¹

Diagnosis

Cutaneous anthrax can be diagnosed by culture of cutaneous lesions. Gastrointestinal anthrax can be diagnosed by cultures from oropharyngeal lesions, blood, and ascites. Computed tomography (CT) of the abdomen is likely to show mesenteric adenopathy. Abdominal radiographs show nonspecific bowel gas patterns and do not aid in diagnosis of the disease. Stool culture has also not been shown to be useful in aiding the diagnosis of anthrax. Autopsies of patients dying of gastrointestinal anthrax show hemorrhagic inflammation of the small intestine with lymphadenopathy.²⁹² On entrance to the GI tract, anthrax is known to cause ulcerations that can be seen on autopsy to extend the length of the GI tract, but most commonly are found in the mouth, stomach, and duodenum.¹⁷

Patients with inhalational anthrax typically present with a normal to elevated white blood cell count. Chest radiographs typically demonstrate mediastinal widening secondary to hilar adenopathy, and they frequently demonstrate pleural effusions (Figure 59-4).¹³⁸ A CT scan of the chest, which can be the earliest diagnostic clue and is often pathognomonic for inhalational anthrax, is recommended in any suspected case.¹⁰⁵ The Centers for Disease Control and Prevention (CDC) recommends that cultures of blood, sputum, pleural and cerebrospinal fluid (CSF) be obtained for analysis in suspected cases of inhalational anthrax.

FIGURE 59-4 Anthrax-widened mediastinum.

(From Jernigan JA, Stephens DS, Ashford DA, et al: Bioterrorism-related inhalational anthrax: The first 10 cases reported in the United States, Emerg Infect Dis 7:933, 2001.)

Treatment

Effective treatment of all forms of anthrax requires a high index of suspicion and prompt antibiotic therapy. In the 2001 outbreak of bioterrorism-related anthrax, all isolates were susceptible to ciprofloxacin and doxycycline, as well as to other agents.⁵⁰ Because B. anthracis has the potential for penicillinase and cephalosporinase activity, ciprofloxacin and doxycycline, rather than penicillin-based antibiotics, are the first line of therapy.

For active disease, treatment for cutaneous anthrax is oral ciprofloxacin or doxycycline twice daily for 60 days. In children, the dose is ciprofloxacin 10 to 15 mg/kg/day divided every 12 hours (not to exceed the adult dose of 500 mg every 12 hours), or doxycycline 4.4 mg/kg/day divided every 12 hours (not to exceed the adult dose of 100 mg every 12 hours). If systemic symptoms are present, intravenous treatment should be initiated. If patients are clinically improved, therapy may be changed to amoxicillin 500 mg three times daily for adults or 80 mg/kg/day divided three times daily for children.

For inhalational and gastrointestinal anthrax, treatment begins with intravenous therapy of ciprofloxacin or doxycycline as well as one or two additional agents (options include rifampin, chloramphenicol, vancomycin, penicillin, ampicillin, imipenem, clindamycin, and clarithromycin). If symptoms improve, treatment switches to an oral regimen of ciprofloxacin or doxycycline for a total course of 60 days. Treatment is the same during pregnancy; the risk of doxycycline or ciprofloxacin during pregnancy is outweighed by the potential mortality resulting from undertreated anthrax infection.

In the event of potential exposure to inhaled anthrax spores, the CDC recommends 60 days of ciprofloxacin or doxycycline in combination with a three-dose regimen (0, 2, 4 weeks) of anthrax vaccine (BioThrax, formerly known as AVA) as an emergency public health intervention. There is no recommended postexposure prophylaxis for exposure to cutaneous anthrax alone.

Prevention

The first vaccine was created in 1881 by Louis Pasteur in an effort to prove the germ theory of disease.²⁶³ In the 1950s, a human anthrax vaccine was created by the Army Chemical Corps. This was replaced by a vaccine licensed in 1970. At first, this vaccination was mandatory for all U.S. military personal, but after concerns for vaccine safety arose, refusal followed. Safety was proved, so mandatory vaccination was reinstituted for the military. Vaccinations for the public are still debated. Opponents of routine vaccination argue that most anthrax in the United States is cutaneous and easily treatable with oral antibiotics. The vaccine is given in five injections and immunity is thought to last 2 years; therefore, the vaccine has been judged not suitable for public dispersal.²⁹⁵ According to a study done by Fowler and colleagues, given a 1% risk of anthrax attack each year, it would be more cost effective and safer to give postexposure antibiotics and vaccines than to prevaccinate the entire population.⁸ People who are at risk for acquiring the disease, including wool handlers, mail officers, and the military, can be inoculated. Prevention of zoonotic anthrax infection largely relies on vaccination of animals and people at risk. Travelers should avoid contact with infected animals and undercooked meat.

Bacillary Angiomatosis

Bacillary angiomatosis, first described in 1983 during the early years of the acquired immunodeficiency syndrome (AIDS) epidemic, forced reconsideration of cat-scratch disease (CSD), bartonellosis, and trench fever.²⁶⁵ In the early 1990s, it was determined that organisms of the genus Rochalimaea caused a diverse array of clinical syndromes, including cutaneous bacillary angiomatosis, bacillary peliosis hepatitis, fever with bacteremia (formerly known as Rochalimaea bacteremic syndrome), and CSD. Whether the different clinical syndromes result from subtle differences in the infecting organisms or in the response of the immune system remains unclear. Each of these conditions can be caused by the bacteria now known to be Bartonella (formerly Rochalimaea) henselae and Bartonella quintana, also the agent of trench fever.

Epidemiology

Although clinically different from CSD, bacillary angiomatosis is also closely associated with a recent cat scratch or bite. A recent study showed that two-thirds of patients suffering from bacillary angiomatosis had cats with the same genotype of B. henselae.⁵⁷ The vast majority of victims are human immunodeficiency virus (HIV) positive, usually with CD4 count less than 200 cells/mm³.^188,²⁷³ In 34% of cases, this infection was the first one to establish the diagnosis of AIDS in a given patient. AIDS patients with bacillary angiomatosis can die if untreated, but erythromycin is usually effective.²¹

Symptoms

Most cases of bacillary angiomatosis involve cutaneous or subcutaneous lesions. The lesions typically consist of elevated, friable, red granulation tissue that is papular, verrucous, or pedunculated and resembles pyogenic granulomas, numbering a few to thousands (Figure 59-5). They tend to enlarge if left untreated. Deeper subcutaneous nodules with or without overlying tenderness and erythema are seen in about one-half of the victims. These lesions can be nearly indistinguishable from those of Kaposi’s sarcoma and can also coexist in the same patient.²¹ Similar lesions can occur in other body tissues, with nearly all visceral organs, including the brain, heart, larynx, cervix, and vulva, being vulnerable.²¹ Visceral lesions may be the first sign of infection; patients often have fever, weight loss, and malaise.⁷⁶ Hepatic involvement (bacillary peliosis hepatitis) can lead to hepatic failure or even rupture. This usually manifests with GI symptoms (nausea, vomiting, diarrhea, or abdominal distention), fever, chills, and hepatosplenomegaly. Histopathologic examination of liver biopsy specimens reveals dilated capillaries or multiple blood-filled cavernous spaces, some of which can be seen on endoscopy or bronchoscopy.¹⁸⁸ Bacillary angiomatosis may cause osteomyelitis, manifesting as an extremely painful focal area of a bone that appears as a lytic lesion on radiographic analysis. This usually occurs on the tibia, radius, or fibula and occasionally has a cellulitic tender erythematous plaque overlying the area of concern.¹² The organism can also cause bacteremia, even in immunocompetent patients. Bartonella bacteremia is characterized by a prolonged symptom complex of malaise, fatigue, anorexia, weight loss, and fevers that are recurring, with ever-increasing temperatures.^19,²⁰ Often no site of focal infection is apparent. The symptoms are usually present for weeks to months before the diagnosis is finally made by isolation of the organism in blood cultures.²⁵⁵

FIGURE 59-5 Bacillary angiomatosis.

(From http://prn.org/index.php/complications/article/common_skin_problems_of_HIV_disease.)

Diagnosis

B. henselae and B. quintana can be isolated from blood using lysis-centrifugation blood cultures,¹³ but both species have also been isolated with traditional blood culture systems.

Serologic diagnosis can also be made using techniques of indirect fluorescent antibody (FA) testing. Serum samples can be sent (for both B. henselae and B. quintana) to the CDC. A commercially available enzyme immunoassay for detection of IgG antibodies to B. henselae is reportedly 5 to 10 times more sensitive than is the indirect FA test.⁷⁷ Positive results should be interpreted cautiously, taking into account the clinical context, because the meaning of positive serologic results awaits further evaluation with stricter epidemiologic methods.

Diagnosis of bacillary angiomatosis is usually made from clinical features and biopsies of lesions, with characteristic histopathologic findings in tissue sections. Blood cultures should be obtained and incubated for a prolonged period. As more is learned about the growth requirements of the causative organisms, they may become easier to culture directly from skin lesions and lymph nodes. Serologic analysis will become an important means of diagnosis.¹

Treatment

Treatment is with erythromycin. If patients cannot tolerate this therapy, rifampin and doxycycline or trimethoprim-sulfamethoxazole (TMP-SMX) should be given. Norfloxacin, gentamicin, and ciprofloxacin are also clinically effective.²⁴² Penicillin and first-generation cephalosporins are not beneficial. Therapy is for a minimum of 6 weeks and may have to continue indefinitely in an immunosuppressed patient. Immunocompromised patients may develop a Jarisch-Herxheimer reaction after the first several doses of antibiotics.²⁷³

Prevention

There is ongoing discussion regarding prevention of bacillary angiomatosis in HIV/AIDS patients. Many HIV/AIDS patients possess cats for companions and in doing so, risk contracting B. henselae. The current recommendation is for these patients to decrease rough play with the animals and make medical caregivers aware that they own a cat.²⁷³ There is no vaccine for animals or patients at risk.

Brucellosis

Brucellosis is an anthropozoonotic disease with a broad clinical spectrum caused by a number of species of Brucella, a small, gram-negative bacterium (Figure 59-6). Brucellosis fits into the differential diagnosis of fever of unknown origin. Brucellosis usually results from ingestion of contaminated milk or milk products or by direct skin contact. Brucella organisms are carried chiefly by swine, cattle, goats, and sheep and may be recovered from almost all tissues in a sick patient. Most animals used as livestock are susceptible to brucellosis, whereas the occurrence in wild animals is rather small.¹⁷⁹

FIGURE 59-6 Electron micrograph of Brucella abortus.

(Courtesy Dennis Kunkel Microscopy, Inc.)

Bacteriology

Brucellae organisms are small, gram-negative, unencapsulated, aerobic, intracellular coccobacilli. The species causing disease in humans include B. abortus, suis, melitensis, and less commonly, B. canis. The bacterium can survive in soil for up to 10 weeks, in goat cheese for up to 180 days (at 4° to 8° C [39.2° to 46.4° F]), and in tap water for up to 60 days. It is, however, very sensitive to heat and most disinfectants, and is entirely killed by pasteurization.

Epidemiology

Brucella in domesticated animals tends to be species specific, with Brucella abortus infecting cattle, Brucella melitensis goats, Brucella suis swine, Brucella canis dogs, and Brucella ovis sheep. The disease is found worldwide and has an annual attack rate of approximately 500,000; U.S. cases number less than 200. Significant endemic areas include Mexico, Central and South America, Mediterranean countries, the Arabian Gulf, and India. Most cases of brucellosis in the United States are found in Texas and California, and risk factors for the disease include Hispanic ethnicity, travel to Mexico, and ingestion of unpasteurized dairy products.²⁷⁶

Humans can be infected with Brucellae by ingestion of contaminated food, direct inoculation through cuts and skin abrasions, transplacental transmission, and inhalation of infected aerosols.³¹⁵ Internationally, most cases are transmitted by ingestion of fresh, nonpasteurized goat cheese and raw goat’s milk. Most human cases are caused by infection with B. melitensis. The disease caused by B. melitensis has a higher attack rate and is more severe, whereas brucellosis caused by B. abortus from cattle produces mild clinical disease and is usually occupationally acquired. A proved case of transmission by dog bite has been reported, and dogs carry their own pathogenic species.²¹⁵

Symptoms

Brucellosis may affect many organ systems, with a wide range of disease severity and acuity.⁶⁸ Because of this, it can cause fever with vague and varied symptoms, and should be considered as a cause of chronic unexplained fever. The disease can be classified into three forms: acute, subacute, and chronic. In acute brucellosis, the victims complain of headache, weakness, diaphoresis, myalgias, and arthralgias. This is the most common presentation. Anorexia, constipation, and weight loss are often seen in the first 3 to 4 weeks. Physical examination may reveal lymphadenopathy, hepatomegaly, or splenomegaly. Bacteremia in the early stages typically induces lesions of the viscera, bones, and joints; osteomyelitis, particularly spondylitis, is a common complication. Rare but serious complications include endocarditis, neurobrucellosis with meningitis, and hepatic abscess.

In subacute, or undulant, brucellosis, symptoms are milder but with more frequent arthritis and orchitis. The clinical picture is more varied, and the diagnosis is considered in any fever of undetermined origin. In the pre-antibiotic era, most patients spontaneously cleared their disease in 6 to 12 months.

In chronic brucellosis, symptoms have persisted for more than 1 year. It is rare in children but increasingly common as patients age. Many describe chronic arthralgias and extra-articular rheumatism. Chronic brucellosis can mimic chronic fatigue syndrome.

Diagnosis

Brucellosis is most often diagnosed by serologic testing, including serum agglutination, rose bengal, complement fixation, and enzyme-linked immunosorbent assay (ELISA).¹⁶⁴ A polymerase chain reaction (PCR) test is an effective method for detecting brucellosis.¹⁷⁸ After acute infection, high titers may persist for 18 months. False-positive results may be caused by Francisella tularensis or Yersinia enterocolitica infection. Isolation of Brucella organisms by blood culture may be used for definitive diagnosis, although the cultures are not always positive. Blood cultures have sensitivities of 50% to 80%. Bone marrow biopsy and culture can be used in patients with clinically suspected brucellosis but negative serologic tests and blood cultures.

Treatment

Treatment for brucellosis is with doxycycline 100 mg PO twice daily for 6 weeks plus either streptomycin 1 g intramuscularly (IM) daily for the first 14 to 21 days, gentamicin 5 mg/kg/day IM for 7 days, or rifampin 600 to 900 mg PO once daily for 6 weeks.^67,¹²⁸ The role of quinolones has been investigated, particularly in combination with rifampin.³ In pregnancy, treat with rifampin 900 mg daily for 6 weeks, with the addition of TMP-SMX during the second trimester.²⁵⁶ The American Academy of Pediatrics recommends children younger than age 8 years take oral TMP-SMX plus rifampin for 4 to 6 weeks, with gentamicin added for the first 14 days if osteoarticular, neural, or endocarditis manifestations are present. For children aged 8 years and older, antibiotic choices are the same as for adults. Focal disease is generally more difficult to eradicate than is mild diffuse disease. Mortality is low, with only two deaths reported in several thousand cases.¹⁰³

Cat-Scratch Disease

Cat-scratch disease is a disease typically transmitted from a cat through a break in the skin (bite, scratch, lick, or other injury). It is usually self-limited and lasts 6 to 12 weeks. The first reference to the disease was in 1889 in the French literature by Henri Parinaud. The first to recognize the cat as the vector for the disease was Robert Debré at the University of Paris in 1931; however, the disease was not officially reported until 1951. CSD is probably the most common cause of unilateral lymphadenopathy in children.²⁵⁹ The current cause of CSD is thought to be the gram-negative bacteria, Bartonella henselae, previously known as Rochalimaea henselae.²⁸

Epidemiology

CSD has been reported from all countries and in all races. An estimated 24,000 cases are recognized each year in the United States.¹⁷⁴ Most cases are found in the fall and winter months, a seasonality thought to be due to the increase in kitten births in the summer and a subsequent rise in flea infestation.²¹⁴ Compared with healthy cat-owning control subjects, patients with CSD are more likely to have at least one kitten aged 12 months or younger, to have been scratched or bitten by a kitten, and to have at least one kitten with fleas.³¹⁸ It has been postulated that the domesticated cat Felis domesticus is the reservoir for the disease and that, as with other Bartonella species, the organisms may be transmitted by fleas and ticks between cats.²¹⁴

Transmission

About 90% of cases are caused by scratches from cats, but dog and monkey bites, as well as thorns and splinters, have also been implicated in transmission.⁶⁹ The organism may be on the claws or in the oral cavity of the offending cat. Most cases occur in children, particularly boys, who tend to play more aggressively with domestic animals.

Symptoms

The average incubation period is 3 to 10 days. The characteristic feature of CSD is regional lymphadenitis, usually involving lymph nodes of the arm or leg. In one series, 54% of lymphadenopathy occurred in the axilla, with the remainder in the neck.²⁵⁹ Often, only one node is involved. The nodes are often painful and tender, and about 25% suppurate.²⁹¹ Adenopathy may spread proximally; occasionally, cervical adenopathy is mistaken for Hodgkin’s disease. Inguinal lymphadenopathy misdiagnosed as lymphogranuloma venereum has later found to be due to B. henselae from CSD.²⁴⁴ In most cases, a characteristic raised, erythematous, slightly tender, and nonpruritic papule with a small central vesicle or eschar that resembles an insect bite is seen at the site of primary inoculation. Constitutional symptoms are mild, with approximately two-thirds of patients presenting with fever, which is rarely greater than 38.8° C (102° F). Chills, malaise, anorexia, and nausea are common. Infrequent evanescent morbilliform and pleomorphic skin rashes lasting for 48 hours or less have been reported in less than 5% of patients.²⁴⁴ This typical clinical course occurs in 88% of victims; the remainder seek medical treatment for complications such as encephalopathy, atypical pneumonia, and severe systemic disease. The most common of the atypical forms of presentation is Parinaud’s oculoglandular syndrome, which occurs in about 6% of cases and consists of granulomatous conjunctivitis and an ipsilateral, enlarged, tender preauricular lymph node.¹⁷⁵

Serious complications are rare and include encephalitis, seizures, transverse myelitis, osteolytic bone lesions, arthritis, splenic and hepatic abscesses, mediastinal adenopathy, optic neuritis, and thrombocytopenic purpura.^27,^175,^194,²⁰⁸ Although encephalopathy is rare, CSD is becoming a more common cause of encephalopathy as other viral infectious diseases disappear; the incidence of CSD-associated neurologic complications now ranks with those of varicella and herpes simplex infections, Lyme disease, Rocky Mountain spotted fever, and Kawasaki disease.³⁴ CSD encephalopathy should enter the differential diagnosis of patients (especially young ones) with unexplained coma, seizures (one-half of whom may be afebrile) or those with fevers of unknown origin. The prognosis for encephalopathy generally is good and to date there have been rare documented neurologic sequelae in immunocompetent patients.

Diagnosis

Results of routine laboratory studies, including urinalysis and complete blood cell count, are usually normal, although mild leukocytosis and/or elevation of ESR may be seen as well. An indirect FA test for B. henselae is commercially available.

Immunity is thought to be largely cell mediated.¹¹³ An intradermal skin test of 0.1 mL of CSD antigen is positive in approximately 95% of victims, although 10% of the population has a false-positive reaction. In confusing cases, biopsy of lymph nodes can yield characteristic findings of areas of granulomatous change and necrosis with central neutrophilic infiltration, a peripheral zone of histiocytic cells, and an outermost zone infiltrated by small lymphocytes and plasma cells.¹⁷² This picture is not diagnostic, however, and is also seen in lymphogranuloma venereum (LGV), histoplasmosis, tularemia, brucellosis, sarcoidosis, and tuberculosis. Thus, lymph node biopsy is most useful to rule out malignancy. Warthin-Starry or Brown-Hopps staining of the nodes or the primary skin lesion usually demonstrates small, pleomorphic bacilli.¹⁷⁵

In most cases, clinical diagnosis is based on finding three of four criteria: (1) single or regional lymphadenopathy without obvious signs of cutaneous or throat infection, (2) contact with a cat (usually an immature one), (3) detection of an inoculation site, and (4) a positive skin test.³⁷ The skin test has largely replaced serologic testing for confirmation of the disease.¹⁷³

The workup should exclude other causes of regional lymphadenopathy, such as tuberculosis, tularemia, LGV, lymphoma, brucellosis, and sporotrichosis.²³⁷ In general, only sporotrichosis and LGV demonstrate localized unilateral lymphadenopathy; LGV usually occurs in the groin. Cat scratches are normally found on the upper extremities. Skin tests, cultures, serologic tests, and biopsies are available for differentiation of these other diseases.

The tendency for dissemination is greater in immunocompromised patients, who may develop bacillary angiomatosis, which is discussed in the section on this topic.

Treatment

CSD usually resolves spontaneously in weeks to months, although in 2% to 14% of persons (usually adults) the course is prolonged and involves systemic complications.^173,¹⁷⁵ Systemic CSD in an adult has been successfully treated with gentamicin,¹⁶¹ and in a child, with cefuroxime.¹¹⁴

Clear guidelines for the treatment of CSD do not exist mainly because few randomized controlled trials have been done. A randomized controlled trial with azithromycin for CSD showed significant decrease in volume of lymphadenopathy with treatment.¹⁴ In a retrospective series of 71 patients, TMP-SMX was seen to have had good results; this was not the case with other antibiotics.⁶⁶ The largest study, of 268 patients, was also retrospective and found a response rate of 87% with rifampin, 84% with ciprofloxacin, 73% with intramuscular gentamicin, and 58% with TMP-SMX.¹⁷³ Antibiotics that were of no benefit included amoxicillin-clavulanate, erythromycin, dicloxacillin, cephalexin, tetracycline, cefaclor, ceftriaxone, and cefotaxime. No sequelae of CSD other than the rare complications mentioned above are known. One recent article showed that one bout of CSD seems to offer lifelong immunity, with recurrences of lymphadenopathy shown only rarely.²⁵⁸

For the majority of immunocompetent patients, many experts recommend withholding antibiotic therapy and reassuring patients that the prognosis is excellent. Other experts recommend antibiotic treatment for all patients with CSD. For isolated lymph node involvement, a 5-day course of azithromycin (10 mg/kg on day 1 [500 mg max], followed by 5 mg/kg/day for 4 days [up to 250 mg/day]) may shorten the duration of disease and possibly prevent complications. For patients intolerant to azithromycin, treat with clarithromycin, rifampin, TMP-SMX, or ciprofloxacin. For patients with severe or prolonged disease, or for immunocompromised patients, antibiotic treatment is definitely indicated.