Lesson 16, Volume 15—Zoonotic Pulmonary Disorders: Infection From Occupational and Environmental Exposures and the Potential for Bioterrorism

By Susanna Von Essen MD, MPH, FCCP; and Mark Rupp, MD

Objectives

1. To understand the occupational and environmental risk factors for contracting zoonoses that can cause pulmonary disease.
2. To recognize the signs and symptoms of zoonotic diseases with pulmonary manifestations that can be contracted through acts of bioterrorism.
3. To be able to prevent and treat zoonotic pulmonary disorders.

Key words

bioterrorism; zoonotic pulmonary disease

Abbreviations

PCR = polymerase chain reaction

A large number of infectious agents can be transmitted from animals to humans, at times causing significant pulmonary manifestations. These agents include bacteria, rickettsiae, viruses, and parasites. When these infections are transmitted from vertebrate animals to humans under natural conditions, they are called zoonoses. The resulting illnesses range from being mild and self-limiting to life-threatening. Many zoonotic pulmonary infections present as community-acquired pneumonias. Other pulmonary findings and symptoms that have been associated with zoonotic disease include pulmonary nodules, pleural effusions, cough, and wheezing. It is of note that some of the organisms that cause severe zoonotic pulmonary infections have potential for use as agents of bioterrorism. For example, anthrax, brucellosis, the plague, Q fever, and tularemia are diseases that could be spread through biological warfare or terroristic acts.¹

Taking a detailed occupational and environmental exposure history is essential for identifying zoonotic pulmonary disorders. Because these disorders are uncommon in most settings, it is important to have a high index of suspicion founded on relevant information from the exposure history. Physicians should obtain information regarding contact with domestic and wild animals and whether or not the animals appeared to be ill.² The nature of the illness in the animals can help establish the diagnosis in humans who are thought to suffer from a zoonotic disease. The history must also include information concerning recent travel and leisure time activities, such as camping, that may bring people in contact with animals. Occupations such as veterinary medicine that involve close contact with animals increase the risk of zoonotic infections.³ Working in a microbiology laboratory also causes increased risk for these infections. Whether or not the patient is immunocompetent should be considered. It must be remembered that while many patients with zoonotic lung infections have exposure histories that explain the presence of the infection, not all persons with such infections have well-defined risk factors. The organisms that are known to cause of zoonotic pneumonia, as well as the typical exposure histories, the clinical presentations, and medical management of these infections are discussed below. The causative organisms, the pulmonary disorders associated with the infection, the vertebrate animal exposure that leads to the infection, and any insect vectors are listed in Table 1.

Bacterial Infections

Anthrax

Anthrax is caused by the organism Bacillus anthracis, a spore-forming Gram-positive bacillus. In spore form, the organism can persist for decades in soil or elsewhere. It is mainly a disease of domestic and wild herbivores, including cattle and sheep. Animals become infected by coming in contact with spores in the soil and often die of the infection. Humans become ill when they have contact with infected animals or their products. Anthrax occurs in slaughterhouse workers, textile plant workers, farmers, veterinarians, wildlife biologists, and others who handle affected animals or products such as hair, wool, hides, and bone. Ingestion of infected meat can also cause infection. Anthrax is quite rare in industrialized countries but is still a public health problem in the developing world. Infection can occur secondary to exposure to materials such as wool that have been imported from developing countries. B anthracis has potential for use in biological warfare. An outbreak of anthrax in the former Soviet Union in 1979 is suspected to have been caused by an accidental release of anthrax spores at a secret germ warfare facility. In that incident, human cases of anthrax occurred up to 40 days after exposure and animal cases were documented at locations up to 30 miles downwind of the germ warfare plant. There have been several recent incidents in the United States in which anthrax infections occurred secondary to intentional release of B anthracis.^4,5 As this outbreak is evolving at the time of this writing, further discussion is beyond the scope of this lesson.

The most common form of anthrax is cutaneous anthrax, in which the characteristic finding is a painless ulcer with a black, necrotic eschar and a surrounding area of edema and erythema. The disease can also occur as a GI infection. Approximately 5% of cases occur as pulmonary infections. Respiratory anthrax shows a biphasic pattern. There is a mild initial phase consisting of nonspecific symptoms including low-grade fever, malaise, fatigue, myalgia, and a nonproductive cough. The patient may then show transient improvement. Two to 4 days after onset of the illness, patients with anthrax pneumonitis develop respiratory failure and high fever. Meningitis can complicate this phase of the illness. The patients may also develop septicemia. Death occurs in most persons within 24 h of the onset of this phase of the disease. The diagnosis of anthrax is supported by having the appropriate exposure history and clinical presentation. The organism can be cultured from nasal skin swabs, pleural fluid, and cerebrospinal fluid. Rarely, it grows in blood cultures. It may be difficult to distinguish the organism from other Bacillus spp. There is an enzyme-linked immunosorbent assay that measures antibodies to the lethal and edema toxins. A single titer > 1:32 in a patient with the appropriate clinical picture supports the diagnosis. Immunohistochemical staining of tissue biopsies can also help make the diagnosis. Chest radiographs may show a widened mediastinum, which is secondary to the hemorrhagic mediastinitis and lymphadenitis that is commonly found at autopsy.⁶

Naturally acquired anthrax can usually be treated with penicillin G. Ciprofloxacin, erythromycin and doxycycline are considered alternative therapies for the penicillin-allergic patient.^7,8 In contrast, anthrax infections that result from bioterrorism may involve bacteria resistant to penicillin and tetracyclines. If infections are contracted in that manner, ciprofloxacin or other fluoroquinolones are the drugs of choice.⁸ However, the pulmonary form of the disease is often fatal despite treatment, compared to 20% of cases with cutaneous anthrax.⁵ Of 6 recent cases of inhalational anthrax, 3 subjects survived.⁵ Tracheostomy may become necessary when cervical edema compromises the airway. Anthrax can be prevented using a killed vaccine derived from a component of the exotoxin produced by the bacterium. This vaccine is recommended for all workers at risk for exposure to infected animals, animal products, or environments. Control of the disease in humans depends on control in animals. Effective animal vaccines exist. The disease is reportable to state veterinary offices. If exposure is suspected secondary to biological warfare or an occupational exposure, chemoprophylaxis with ciprofloxacin or doxycycline should be given.⁴ In the United States, there is a human vaccine that is currently available only to the military.

Bordetella bronchiseptica Infection

Bordetella bronchiseptica is a Gram-negative coccobacillary organism that causes kennel cough in dogs, snuffles in rabbits, atrophic rhinitis in pigs, and pneumonia in koalas.^7,9 Rarely, it can cause a whooping cough—like illness in humans. It can also cause opportunistic infections in immunocompromised hosts, including pneumonia and peritonitis.¹⁰ Isolation of the organism in the laboratory can be difficult. There is now a polymerase chain reaction (PCR) assay that can identify the three Bordetella spp, Bordetella pertussis, Bordetella parapertussis, and B bronchiseptica.¹¹ Therapeutic agents effective against Bordetella infections include erythromycin, which is the drug of choice, as well as trimethoprim-sulfamethaoxazole.

Brucellosis

Brucellosis is caused by a small, Gram-negative coccobacillus of the genus Brucella. It is an infectious disease of a variety of animals, including cattle, sheep, goats, pigs, and dogs, that causes chronic infection and spontaneous abortions.^2,7,9 Persons at greatest risk for contracting brucellosis include slaughterhouse workers, veterinarians, farmers, and laboratory workers. Infection from a live attenuated strain of Brucella abortus used as a vaccine had been reported. Brucellosis is especially common in the Mediterranean basin, the Arabian peninsula, the Indian subcontinent, Mexico, and Central and South America. It is now uncommon in the United States. These bacteria are highly infectious through aerosolization and may survive for up to 6 weeks in dust or 10 weeks in soil or water. Thus, this organism could be used for biological warfare. The bacteria enter the body through abrasions in the skin, after inoculation on the conjunctiva, by inhalation, or by ingestion of unpasteurized dairy products. Brucella melitensis infection can be acquired via the ingestion of unpasteurized dairy products.

The bacteria enter the lymphatics and replicate in regional lymph nodes. Then, hematogenous dissemination occurs and the organism infects the reticuloendothelial system, causing lymphadenopathy, splenomegaly, and hepatomegaly. Nonspecific symptoms begin 2 to 4 weeks after inoculation and consist of fevers, sweats, malaise, anorexia, headaches, and back pain. If the patient is not treated appropriately at that point, an undulant fever pattern may develop. Patients may present with disease that appears to be localized to one of several organs, including a granulomatous hepatitis, bone and joint involvement, meningitis and encephalitis, and endocarditis. Signs and symptoms of pulmonary disease are reported in up to 25% of patients with brucellosis, including bronchitis, bronchopneumonia, solitary or multiple pulmonary nodules, lung abscesses, miliary lesions, hilar adenopathy, and pleural effusions. Thus, pulmonary symptoms are not a prominent aspect of the disease clinically. The organisms are rarely identified in sputum stains or cultures but may be identified more easily in blood or bone marrow. Rapid isolation techniques exist for recovering brucellae. When brucellosis is suspected, blood cultures should be maintained for 4 weeks. B melitensis can be misidentified as a Moraxella sp using automated systems.¹² Serologic tests can also be used to make a presumptive diagnosis.

Treatment serves the purpose of eliminating symptoms, shortening the illness, and preventing complications. A doxycycline (given for 6 weeks) plus gentamicin or streptomycin (given for 2 weeks) is thought to be the most effective therapy for uncomplicated brucellosis.¹³ Rifampin may be used in place of the aminoglycoside. Prevention of brucellosis centers on control of the disease in animals by eliminating infected animals and by routinely vaccinating herds of cattle and goats. There is no vaccine available for humans at risk for contracting this disease.

Psittacosis

Psittacosis, also known as ornithosis, is caused by Chlamydia psittaci, which is one of four Chlamydia spp.^2,7,9 Members of the genus Chlamydia are obligate, intracellular bacteria. This organism commonly causes illness is a variety of species of birds. Birds may also be asymptomatic carriers of C psittaci. The organism can cause spontaneous abortion in livestock. Persons at risk of acquiring the infection include those who keep birds as pets, those who raise or slaughter poultry, and veterinarians. The infection can also be acquired by handling tissues from parturient cows, goats, and sheep and from cats with pneumonitis secondary to C psittaci.¹⁴ Person-to-person transmission has been reported. The incidence of human infection with this organism is difficult to determine. Serologic surveys suggest that 40 to 80% of persons routinely exposed to poultry in their work have been infected with C psittaci.

Illness in humans begins after an incubation period of 5 to 15 days. Because this is a systemic illness, a variety of symptoms can be present, including photophobia, tinnitus, deafness, ataxia, nausea and vomiting, abdominal pain, diarrhea, sore throat, epistaxis, arthralgia, and rash. The physical examination can be remarkable for fever, pharyngeal erythema, and rales on chest auscultation, as well as hepatomegaly, splenomegaly, neurologic abnormalities, and dermatologic changes. The illness may present with fever and malaise, a mononucleosis-like syndrome, or a typhoidal form. Endocarditis can occur. An atypical pneumonia is the most common form of the disease, with nonproductive cough, fever, and headache. Cough may appear late in the illness. Chest radiograph findings can be more striking than expected given the clinical status of the patient. Radiographic findings are variable and include lobar consolidation, a homogenous ground-glass appearance, a patchy reticular pattern radiating from the hila, a miliary pattern, and unilateral or bilateral hilar enlargement.¹⁵ Small pleural effusions may be seen in up to 50% of cases. Chest radiograph abnormalities may take up to 20 weeks to resolve. Laboratory findings are notable for mild to no elevation in the WBC count. There may be a mild elevation in liver function tests. The diagnosis of psittacosis is made by demonstrating complement-fixing or microimmunofluorescent antibodies in serum.⁹ It is difficult to culture the organism from sputum and blood and doing so poses risk to laboratory workers because of the highly infectious nature of C psittaci. Serologic studies are very helpful. To make the diagnosis, there should be a fourfold or greater change in antibody titer to at least 1:32 or IgM of at least 1:16. PCR is now available as a tool to identify C psittaci.¹⁶

Treatment consists of tetracycline or doxycycline given for 10 to 21 days.⁷ Erythromycin is an alternative choice but may be less efficacious. Most patients respond quickly to antibiotic therapy. Without antibiotic therapy, the fatality rate in recognized cases is 20%. The best form of prevention of psittacosis is controlling the infection in birds, where it is known as Newcastle disease, and in livestock.

Leptospirosis

Leptospirosis is a generalized infectious disease caused by spirochetes of the genus Leptospira. It is a disease of wild and domestic mammals, including rats, dogs, livestock, wild mammals, and cats. The animals may appear to be ill or can be asymptomatic carriers of the infection. The disease is found throughout the world. Humans become infected from contact with the animals or their urine, often through contaminated soil or water. Persons at increased risk for this disorder include farmers, veterinarians, slaughterhouse workers, sewer workers, and campers. The infection can be contracted from direct contact with animals or from contact with fresh water (recent outbreaks have occurred in triathlon competitors), damp soil, or organic matter containing waste from infected animals.

Evidence of seroconversion is common in persons at risk of infection with leptospires who have no history of illness secondary to infection with this organism.¹⁷ The incubation period of infection is usually 5 to 14 days. Clinical manifestations of infection can include a mild, anicteric form or severe illness. The milder form of leptospirosis is characterized by the presence of fever, headache, myalgias, malaise, nausea, and vomiting in the first or septicemic stage. Approximately 20% of patients report cough and pharyngitis during this phase of the disease. The initial manifestations are followed by an immune phase with muscle tenderness, conjunctivitis, adenopathy, hepatosplenomegaly, and rash. Aseptic meningitis can occur during this phase as well. Pulmonary symptoms have been reported in 20 to 70% of patients in the second phase of the milder form of leptospirosis. Pulmonary involvement is characterized by infiltrates, cough, hemoptysis, and chest pain. Lung lesions consist of a hemorrhagic pneumonitis.¹⁸ A severe form of leptospirosis characterized by liver failure, renal failure, hemorrhage, myocarditis, and cardiovascular collapse may develop in the second phase of the illness. These patients require intensive supportive therapy. The diagnosis is made by isolation of leptospires during the acute phase from bodily fluids, including the urine. Serologic tests are helpful for diagnosis of the illness later in the disease.

The antibiotic of choice for leptospirosis is penicillin G.⁸ Doxycycline can be used to treat mild infections. Most patients with leptospirosis survive but death can occur from respiratory failure, cardiac involvement, or multiorgan failure. Mortality in those who go into respiratory failure has been reported to be 55%.¹⁹ Prevention consists of reducing direct contact with infected animals and with water and soil contaminated by animal urine. Vaccines against Leptospira are available for animals. Chemoprophylaxis with doxycycline may be indicated for persons at high risk of contracting this infection in certain outbreak situations.

Tuberculosis

Mycobacterium bovis is an organism that infects cattle. It formerly caused many infections in humans via ingestion of unpasteurized milk containing the organism. It is now uncommon in the United States. It continues to be a problem in regions where cattle are often infected, such as sub-Saharan Africa.²⁰ It has also been reported recently in France and Australia.^21,22 There has been a nosocomial outbreak in which M bovis was transmitted from one HIV-infected patient to others.²³ Mycobacterium tuberculosis can infect a variety of zoo animals, including nonhuman primates and elephants, but transmission of the infection to humans is uncommon.²⁴ Recent work has shown evidence for transmission of M tuberculosis between elephants and humans.²⁵ Persons at risk for zoonotic tuberculosis infections include zookeepers, veterinarians, and wildlife biologists. Persons who drink unpasteurized milk are also at risk of becoming infected and developing GI tuberculosis, from which spread to the lung can occur.

The majority of persons with tuberculosis have latent disease, which can be identified by use of the tuberculin skin test using purified protein derivative. Persons with active tuberculosis can experience a variety of symptoms. The symptoms of infection with M bovis resemble those of infection with M tuberculosis. Pulmonary disease is a common manifestation of tuberculosis. If symptomatic, patients typically complain of fevers, night sweats, weight loss, and cough with or without hemoptysis. Most persons infected with M bovis or M tuberculosis do not have radiologic abnormalities. When thoracic disease does occur, it may cause visible abnormalities of the pulmonary parenchyma, the mediastinal and hilar lymph nodes, the tracheobronchial tree, and the pleura. Chest radiograph findings may include airspace consolidation, cavitary upper lobe lesions, a miliary pattern, pulmonary nodules, hilar and mediastinal adenopathy, and pleural effusions.¹⁵ The parenchymal lesions and the lymph nodes may calcify.

Treatment of M bovis infections includes isoniazid, rifampin, and ethambutol given for 9 to 12 months.¹³ All isolates are resistant to pyrazinamide. Control of tuberculosis in livestock and zoo animals as well as routine pasteurization of milk are the best means of controlling the disease. The treatment of tuberculosis will not be discussed further here.

Pasteurellosis

Species of the genus Pasteurella are facultatively anaerobic, Gram-negative coccobacilli that inhabit the oral cavity and GI tract of many animals, in which they can cause septicemia and pneumonia.⁷ Human infection is usually caused by the bite of an infected animal, most commonly a cat or dog. The infection can also occur after a cat scratch. Infection in humans can result in cellulitis, abscesses, and several other syndromes including bone and joint infections, CNS infections, sepsis, intra-abdominal infections, and endocarditis. The organism is isolated most commonly from skin, but the respiratory tract is next in terms of frequency of recognized infections with Pasteurella multocida. Respiratory manifestations include pneumonia, empyema, sinusitis, and bronchitis. Pneumonia usually occurs as a lobar process in persons with underlying COPD or bronchiectasis. The clinical presentation includes malaise and respiratory symptoms but the patients often are afebrile. The organism can be isolated from sputum.²⁶

Penicillin G is the drug of choice for respiratory infections as well as for other manifestations. Penicillin VK, ampicillin, and amoxicillin are alse effective. Cefuroxime, cefixime, ceftriaxone, and cefoperazone can also be used to treat pasteurellosis. Mortality from pneumonia secondary to Pasteurella infection is high, likely in part because of the underlying pulmonary process present in most cases. Because as many as 50% of cat bites and 20% of dog bites become infected, it has been suggested that persons with such bite wounds should be given prophylactic therapy with an oral antibiotic known to be effective against P multocida, such as amoxicillin with clavulanic acid.

Glanders

Glanders is a serious infection of equine animals caused by the organism Pseudomonas mallei, a Gram-negative bacillus. Rarely, it infects goats, cats, and dogs. Glanders has not been reported in the United States for 60 years, but sporadic cases still occur in Asia, Africa, and South America. Human disease mainly occurs in persons who have contact with horses, mules, or donkeys, but can also occur in laboratory workers. Human-to-human transmission has been reported.

Clinical manifestations are determined by the route of infection. Glanders can present as an acute localized suppurative infection, acute pulmonary infection, acute septicemic infection, or chronic suppurative infection. Infection by inhalation causes fever, pleuritic chest pain, fatigue, myalgias, and headache after an incubation period of 10 to 14 days. Chest radiograph findings in the acute pulmonary form of the disease may include multiple pulmonary densities or infiltrates. Visceral involvement, including pulmonary and pleural disease, is seen in < 25% of cases of glanders. Sulfadiazine is considered to the treatment of choice. The prognosis is good for localized disease, but the acute septicemic form of glanders is usually fatal. The best form of prevention is control of the disease in animals.

Rhodococcus equi Pneumonia

Rhodococcus equi pneumonia is well known as an agent of pneumonia in horses.⁷ Rarely, it infects cattle, sheep, and pigs. The organism lives in the soil. It is transmitted to humans by inhalation, with or without prior known contact with animals. Almost all infections in humans occur in persons with defects in cell-mediated immunity, including patients with AIDS. Patients receiving chronic corticosteroid therapy are also at increased risk for this infection.

R equi is a facultative intracellular organism that lives inside macrophages and causes granulomatous inflammation. Pneumonia is the most common manifestation of this infection. Extrapulmonary infections, including brain abscesses and osteomyelitis, can occur. The clinical presentation consists of an insidious illness with fatigue, fever, and a nonproductive cough. Chest radiograph findings include cavitary lesions with air-fluid levels, which are more likely to occur in the upper lobes of the lung. The organism can be cultured from pulmonary or other lesions to establish the diagnosis. Treatment consists of several weeks of antibiotics that concentrate inside the cell. Surgical treatment of the pulmonary lesions may also be helpful. There is evidence that erythromycin or imipenem and rifampin act synergistically in treating this infection.¹³ Resistance to b-lactam agents occurs readily. Although the organism is susceptible to vancomycin, it is not the best choice because the intracellular location of the organism impairs efficacy of this antibiotic.

Plague

Plague is caused by the organism Yersinia pestis, a bipolar staining bacillus.⁷ A variety of rodents serve as the primary host for this organism, but rats are the most important urban reservoir. The domestic cat can also be infected. Plague is transmitted by the bite of an infected flea, penetration of infected flea feces into abraded skin, or by ingestion of contaminated animal tissues. The greatest risk to humans occurs when rodents die in large numbers and their fleas seek out humans as an alternate host. Plague has caused three pandemics, including one that began in the late 19th century and continues to this day. In the United States, the occurrence of plague is sporadic and uncommon, with most cases seen in spring and summer months because of increased contact with the vector. Approximately 90% of reported cases occur in New Mexico, Arizona, Colorado, and California. Y pestis is considered a possible bioweapon. A biological attack would presumably involve aerosolization of the microbe, resulting in a primary pneumonia.

There are several plague syndromes, including the bubonic, septicemic, pneumonic, and cutaneous forms, as well as meningitis. Symptoms begin 2 to 8 days after exposure, during which time bacteria proliferate in regional lymph nodes. The patient then develops abrupt onset of fevers, rigors, malaise, and headache with or without GI symptoms. Within 24 hours, a bubo develops, which is a mass of tender lymph nodes occurring most commonly in the groin. Pneumonic plague, in which the lungs become involved by hematogenous dissemination, can occur as a complication of the bubonic form of the infection. Primary pneumonic plague is acquired by via inhalation directly from an infected patient or domestic cat. This means of transmission is relatively rare. The presentation of pneumonic plague includes fever, cough, chest pain, and often hemoptysis. Disseminated intravascular coagulation is common in plague. The chest radiograph is remarkable for the presence of patchy bronchopneumonia, cavities, or confluent consolidation. Patients produce purulent sputum containing plague bacilli. Blood cultures also may be positive, as may be aspirates of buboes. A fluorescent antibody test can be applied to bubo aspirates and sputum for rapid diagnosis.

Early treatment is essential to reduce mortality. If treatment is delayed by more than 1 day after onset of the illness, pneumonic plague is usually fatal. Streptomycin or gentamicin is the drug of choice. Doxycycline and chloramphenicol are suitable alternatives. Preventive measures include eliminating sources of food and shelter for rodents near homes. Plague vaccine is recommended for persons at high risk for plague exposure, including laboratory workers who handle Y pestis organisms.

Tularemia

This disorder is caused by the organism Francisella tularensis, a Gram-negative coccobacillus that primarily infects a variety of animals. It is one of several organisms that has potential for use in biological warfare. Used in this way, it is anticipated that it would have an approximately 80% attack rate and 6% death rate. Tularemia is found in North America, Asia, and Europe. In the United States, most cases are reported from the following states: Arkansas, Missouri, Oklahoma, South Dakota, Montana, Tennessee, Kansas, Colorado, and Illinois. The incidence has been declining in the United States. Most cases occur in persons who are at risk because they have been bitten by ticks or bloodfeeding flies or have contact with infected animals. It can be acquired through consumption of infected water. Rodents and lagomorphs most often transmit the infection. Skinning, dressing, eating, or being bitten by infected animals can lead to tularemia. Hunters, trappers, cooks, farmers, and veterinarians are at increased risk of contracting the disease. Laboratory workers who culture F tularensis may also become infected.

The clinical presentation of tularemia varies, depending on the virulence of the organism causing the infection, the portal of entry into the body, the extent of systemic involvement, and the immune status of the individual.²⁷ The incubation period averages 3 to 5 days but can be as long as 21 days. Symptoms begin abruptly and can consist of fever, chills, headache, malaise, anorexia, and fatigue. Respiratory symptoms may also consist of cough that usually nonproductive, substernal chest tightness, and pleuritic chest pain. Other common symptoms of the disease include myalgias, vomiting, sore throat, abdominal pain, and diarrhea. The six classic forms of tularemia are as follows: ulceroglandular, glandular, oculoglandular, typhoidal, pharyngeal, and pneumonic. The pneumonic form may occur after inhalation of the organisms or from hematogenous spread to the lung. Pneumonic tularemia is found in 7 to 20% of all tularemia cases. Radiographic findings are variable and nonspecific.¹⁵ The most common findings are airspace consolidation, hilar lymph node enlargement, and pleural effusions.

The drug of choice is streptomycin.⁸ Alternative drugs include gentamicin, a tetracycline, chloramphenicol, and ciprofloxacin. Without treatment, the fever lasts for several weeks, and chronic fatigue, weight loss, and adenopathy can last for a number of months. The disease can lead to multiorgan failure and death. Prevention consists of avoiding bites from the insect vectors known to transmit the disease and use of personal protective equipment when handling animals that could be infected.

Rickettsial Infections

Rickettsiae are coccobacillary obligate intracellular parasites that are transmitted to humans by a variety of arthropods. These arthropods include ticks, mites, fleas, and lice, which transmit the diseases from dogs, rodents, and other small mammals to people. Workers at high risk for disease caused by rickettsiae include farmers, foresters, rangers, trappers, hunters, construction workers, and surveyors. Persons engaged in recreational activities outdoors in endemic areas are also at risk.

Rocky Mountain Spotted Fever

Rocky Mountain spotted fever is caused by Rickettsia rickettsii.⁷ The tick is the vector and main reservoir of this infection. This infection is found in the southeastern and south-central United States and in the Rocky Mountain region, as well as in Canada and Central and South America. Dermacentor variabilis, the American dog tick, is the main vector in the southeastern United States, while Dermacentor andersoni, the Rocky Mountain wood tick, carries the infection in western states. Persons who are at greatest risk include those who spend a great deal of time outdoors from late spring to early fall in areas with heavy exposure to ticks.

Rickettsiae introduced into the skin spread via lymphatics and small blood vessels to the systemic and pulmonary circulation and then to their target cells in the vascular endothelium. This process results in increased vascular permeability, which in turn results in noncardiogenic pulmonary edema, hypovolemia, and hypotension. Between 12 and 17% of patients have been reported to have evidence of pneumonitis.⁷ Platelets are consumed locally in foci of infection, leading to thrombocytopenia. The cardinal manifestations of Rocky Mountain spotted fever are headache and fever. Other associated symptoms and signs include rash, conjunctivitis, splenomegaly, hepatomegaly and jaundice, meningismus and seizures, and nausea, vomiting, diarrhea, and abdominal pain. The laboratory diagnosis can be made by isolation of the organism from the blood, but this is undertaken in few hospital laboratories because of the risk of transmission of the infection to laboratory workers. The diagnosis can also be confirmed by demonstration of rickettsiae in a skin biopsy specimen by immunofluorescence. Serology is used to make the diagnosis retrospectively.

Doxycycline is considered the drug of first choice, with chloramphenicol, a fluoroquinolone, and rifampin being alternative drugs.⁸ Severely ill patients require intensive supportive care to facilitate recovery. With appropriate treatment, the mortality rate is 3 to 5%.

Q Fever

Q fever is caused by Coxiella burnetii, a pleomorphic coccobacillus with a Gram-negative cell wall that lives within the phagolysosome of host cells. It has a spore variant that allows it to survive harsh conditions, which could make it suitable for use in bioterrorism. The organisms can be highly infective, having caused illness in persons living near roads over which infected animals were transported. The most common animal reservoirs are cattle, sheep, and goats, but C burnetii has been shown to infect horses, deer, dogs, cats, pigs, camels, squirrels, several species of mice, rabbits, domestic fowl, and wild birds. The disease can be contracted by cleaning up the products of conception (particularly from cats), by ingestion (including drinking raw milk), via skin contact, and possibly from ticks. Persons who are immunocompromised are at risk for developing a chronic form of the disease that may include endocarditis. Workers at risk for contracting Q fever include farmers and ranchers, slaughterhouse workers, wool processors, and any other persons who have direct contact with animals in their work. Pet ownership does not appear to be a risk factor.

Q fever is most often a self-limited febrile illness. It is likely that the infection can be asymptomatic. Serologic surveys of farm populations have revealed that farmers commonly have antibodies to C burnetii.²⁸ It may also present as endocarditis, hepatitis, and osteomyelitis. Patients with Q fever may present with atypical pneumonia or rapidly progressive pneumonia. All of these patients are febrile, and most complain of fatigue, chills, and headache. Myalgias, nausea, vomiting, and diarrhea are other common symptoms. A nonproductive cough is present in a minority of patients with radiographic evidence of pneumonia. The classic presentation of Q fever pneumonitis is pneumonia demonstrated radiographically in a febrile person without pulmonary symptoms. Some patients complain of pleuritic chest pain. Pleural effusion is found in up to 35% of cases. Radiographic findings can include multiple rounded opacities. There has been a case report of a patient presenting with severe and ultimately fatal alveolar hemorrhage. The WBC count is usually normal. A slight elevation of hepatic transaminase levels commonly occurs. The diagnosis can now be made by means of amplification of C burnetii DNA using PCR. The diagnosis of Q fever is made serologically, usually by complement fixation, in most laboratories because they lack the facilities required to isolate the organism.

Recovery from the symptoms of acute Q fever, including the form with pneumonitis, does not require antibiotic therapy. However, antibiotics are recommended to reduce the risk of chronic Q fever infection.¹³ The antibiotic of first choice is doxycycline. Erythromycin and a fluoroquinolone are alternative antibiotics suitable for treatment of this infection. Most patients recover from Q fever without complications. However, there is a chronic form of the disease that can include interstitial pulmonary fibrosis as well as prolonged fever, a purpuric rash, endocarditis, infection of vascular prostheses and aneurysms, osteomyelitis, and hepatitis. The chronic form of the disease may require up to 3 years of therapy with doxycycline plus other antibiotics.⁹

Viral Infections

Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome was described in 1993 after an outbreak of fatal respiratory illness in the Four Corners area of the southwestern United States was found to be secondary to what was named the Sin Nombre virus.²⁹ The Sin Nombre virus is a member of the hantavirus genus of the Bunyaviridae family. The virus is carried by Peromyscus maniculatus, the deer mouse, and is shed in saliva, urine, and feces. Human infection occurs through aerosolized virus inhaled from rodent excreta, through contamination of broken skin or the conjunctiva, or through ingestion of contaminated water or food. Persons at risk include individuals who live in dwellings infested with deer mice, particularly during seasons when the mice are abundant. Occupations found to be at risk include farmers and ranchers, repairmen and maintenance workers, construction workers, animal pest control workers, field biologists, and utility employees. Cases have been reported from the majority of the states in the United States and correspond to the distribution of P maniculatus. A few cases have been described outside the range of P maniculatus and appear to be caused by other rodents serving as a reservoir for the Sin Nombre virus, such as the cotton rat (Sigmodon hispidus) in the southeastern US.

Hantavirus causes a severe illness associated with respiratory failure. The case-fatality rate is approximately 50%. However, as additional cases are described due to increased awareness and more widespread serologic testing, it is anticipated that the mortality rate will decline as less severe cases are diagnosed. Hantavirus pulmonary syndrome patients commonly present with a prodromal illness consisting of myalgia, fever, cough, headache, and GI symptoms that may persist for up to 5 days before onset of respiratory failure.³⁰ Respiratory distress can develop abruptly. Chest radiographs typically show signs of increased permeability, pulmonary edema, and pleural effusions. Laboratory findings include leukocytosis, thrombocytopenia, prolonged prothrombin and partial thromboplastin times, and an increased hematocrit (reflecting hemoconcentration). These patients can develop an atypical form of septic shock caused by myocardial depression and hypovolemia. The diagnosis is made using serology. The detection of hantavirus IgM antibodies in serum or a fourfold or greater rise in serum IgG antibodies to hantavirus confirms the diagnosis. To confirm the clinical diagnosis of acute infection, use of the reverse transcriptase PCR, used to identify the virus in peripheral blood mononuclear cells, and detection of hantavirus antigen by immunohistochemistry are recommended.

Treatment consists of supportive care. Survivors typically recover completely. It is essential that steps be taken to reduce exposure to the hantavirus for workers at greatest risk. Centers for Disease Control and Prevention recommendations for prevention and control of hantavirus pulmonary syndrome center on reducing rodent populations in areas where people may be at risk, securing food in rodent-proof containers, use of high-efficiency particulate air-filter respirators when cleaning rodent-infested structures, and prompt medical treatment for workers who develop a respiratory illness within 45 days of the last possible exposure.³¹

Hendra Virus

Hendra virus, formerly called equine morbillivirus, was recently described as causing outbreaks of respiratory illness in the communities of Hendra and Mackay, Queensland, Australia. Hendra virus is a member of the family Paramyxoviridae. Human infection occurred through contact with blood, bodily fluids, or excretions of infected horses.

Influenza

Influenza viruses are single-stranded RNA myxoviruses that are classified as types A, B, or C. Only influenza A can be contracted from animals. Influenza A virus commonly occurs in pigs in the United States and elsewhere, causing a respiratory illness in the animals. Influenza A causes a respiratory illness in chickens. Persons who live and work on farms, veterinarians, and those who slaughter pigs and chickens are at some risk of contracting the virus directly from animals infected with influenza A. Human-to-human spread of the strain of influenza virus originally contracted from the animals also can occur. Influenza A virus undergoes genetic recombinations. Animal viruses can be a source of antigenic variations in the subtypes. Influenza A virus undergoes genetic recombinations, with pigs serving as the mixing vessel for reassortment between influenza viruses.³² Avian strains of influenza can also directly infect humans.³³

The symptoms of influenza are well known to most clinicians. Briefly, the illness usually begins with fever, chills, headache, malaise, myalgias, and anorexia. Respiratory symptoms, including a dry cough and pharyngitis, are usually present at the onset of illness and become more prominent as the illness progresses. Influenza infection can be complicated by primary viral pneumonia or secondary bacterial infection, most often with Staphylococcus aureus or Haemophilus influenza. Influenza infection can lead to death, often in patients who have suffered these complications. Treatment of illness secondary to influenza A infection includes the antiviral drugs amantadine, rimantadine, zanamivir, and oseltamivir, as well as antibiotics suitable for treatment of bacterial suprainfections.^7,13

Influenza A infections in humans can be prevented by use of vaccines. Control of the disease in animals can be best accomplished by elimination of the infected animals when feasible, as was done in the avian influenza outbreak in Hong Kong in 1997–1998. Influenza vaccines are not available for nonhuman species.

Nipah Virus

Nipah virus belongs to the family Paramyxoviridae and was recently identified as a zoonotic disease after outbreaks in Malaysia and Singapore in people exposed to infected pigs.³⁴ This family of virues possesses a single-stranded RNA genome that is fully encapsulated by protein. It is closely related to Hendra virus, which is described above. Nipah virus is carried by pigs, in whom it causes a respiratory illness that is usually not fatal. There is evidence that cats, dogs, guinea pigs, horses, and bats can also be infected with this virus. The primary pathology is a multiorgan vasculitis with infection of endothelial cells. Patients present with symptoms of encephalitis or, less commonly, pneumonitis. Diagnosis of infection can be made by detection of IgM antibodies in blood and cerebrospinal fluid.

Parasitic Infections

Anisakiasis

This term is given to human infection with marine nematodes of the genera Anisakis or Pseudoterranova, which commonly parasitize marine mammals. Fish serve as intermediate hosts. The flesh of a variety of fishes may contain the larval stage of the nematodes. Ingestion of raw or undercooked fish can cause human infection. Usual symptoms include severe abdominal pain, nausea, vomiting, and diarrhea within hours of eating the infected fish, secondary to attachment of the larval worm to the gastric mucosa. The worm may invade the gastric or intestinal mucosa, then migrate to the lung, omentum, pancreas, or liver.³⁵ The presence of leukocytosis and eosinophilia in a person with characteristic complaints and a history of eating raw fish helps support a diagnosis of anisakiasis. The patient with pulmonary infection may cough up the characteristic worm.

Dirofilariasis

Dirofilaria spp are nematodes that parasitize many mammals, including dogs and raccoons. Dirofilaria immitis is mosquito-borne and the adult form of the worm ordinarily inhabits the right ventricle and pulmonary arteries of dogs, where mating occurs, and females produce circulating microfilaria that are picked up when a mosquito bites an infected dog. It is commonly known as the dog heartworm. D immitis can be transmitted to humans by the bite of infected mosquitoes. This occurs most often in the southwestern United States, where dog heartworm is most common. On rare occasions, human infection with D immitis can cause a pulmonary nodule.³⁶ This nodule may be an incidental finding or can present with such symptoms as fever, cough, and pleuritic chest pain. Peripheral blood eosinophil counts are usually normal. The diagnosis can be made by resecting the nodule. Serologic testing can be helpful diagnostically. No treatment is required. However, antihelminthic drugs such as ivermectin may be given for conservative therapy of pulmonary nodules suspected to be caused by D immitis.

Echinococcosis (Hydatid and Alveolar Cyst Disease)

Adult tapeworms of the genus Echinococcus occur in members of the families Canidae and Felidae.⁷ They are causative agents of echinococcus and each species has unique pathologic characteristics. The four recognized species and diseases they cause include Echinococcus multilocularis (alveolar cyst disease), Echinococcus granulosis (hydatid or unilocular disease), Echinococcus vogeli, and Echinococcus oligarthrus (polycystic hydatid disease). E granulosis, the most commonly reported species in human cases worldwide, normally has a life cycle in which the adult cestodes occur in dogs, and sheep, camels, goats, llamas, and horses serve as intermediate hosts. Humans become infected by ingesting eggs from the feces of infected dogs. Infection in humans usually occurs in livestock-raising areas.³⁷ E multilocularis occurs in the more northern regions of the earth, with the adult parasite occurring in wolves, foxes, or dogs. Voles and field mice serve as the intermediate host. Humans become infected by ingesting eggs from the feces of infected dogs that have eaten wild rodents. This disease is different from cystic hydatid disease in that the cyst proliferates and can spread from the liver to the lungs and brain. At one time, the primary cause of death in Eskimos on St. Lawrence Island was hydatidosis. E vogeli and E oligarthrus are South American species in wild canids and felids, respectively, that cause polycystic hydatid disease in humans. Rodents serve as their intermediate hosts and humans become infected by association with domestic dogs and cats. E oligarthrus (specific to cats) has recently been reported from a bobcat just south of Brownsville, Texas. This observation indicates that cats may soon be important in domestic life cycles of this species in the United States.

Echinococcus eggs hatch in the gut to form oncospheres that penetrate the mucosa and enter the circulation. Several years usually elapse between infection and onset of disease. During this time, cysts form in the liver (50 to 70%), the lung (20 to 30%), or other organs including the brain, heart, and bones. These grow slowly over years and become filled with daughter cysts. These cysts often fail to cause symptoms. If the patient does become symptomatic, it is often because of the mass effect of the cyst. The cysts also may cause postobstructive infection in a bronchus. Bacteria can enter a cyst, resulting in abscess formation within the cyst. Cyst leakage or rupture may be associated with severe allergic reactions to parasite antigens. Anaphylactoid reactions may occur, with hypotension, syncope, and fever. Cyst rupture can be associated with secondary seeding of daughter cysts throughout the body, with subsequent failure of other organs. The presence of hydatid cysts is often detected through radiographic imaging studies that reveal structures with well-demarcated walls and internal septae. This may be an incidental finding. The diagnosis can be confirmed by specific enzyme-linked immunosorbent assay/Western blot serology confirming exposure to the parasite, which is available through the Centers for Disease Control and Prevention. Serology is quite sensitive and specific for liver infections but less sensitive for lung infections.

The infection is ordinarily self-limited, such that < 10% of patients develop serious complications. Known cysts should be followed carefully. Cysts that cause symptoms should be removed in toto with great care to avoid rupture and spillage. Inoperable cysts may respond to albendazole or mebendazole.⁷ Prevention of this infection centers on interruption of the life cycle and good hygiene.

Toxoplasmosis

Toxoplasma gondii is a coccidian parasite of cats and other felids that is found throughout the world.⁷ Humans as well as a variety of animals can serve as intermediate hosts. Infection of humans usually occurs through ingestion of raw or undercooked meat containing the cysts but can also occur via blood transfusion and by exposing mucosal surfaces to the parasite. Coprophagous invertebrates can also function as transport hosts to reach the GI tracts of humans.

T gondii multiplies intracellularly in the GI tract of humans. The organisms spread to regional lymph nodes and then to other organs via the lymphatics and the blood. The infection is without symptoms in most immunocompetent hosts but may cause a mononucleosis-like illness. Cyst formation takes place within the first week of infection and is responsible for latent infection. Organs where cyst formation occurs include the brain, skeletal muscle, the heart, and the eye. This chronic infection is of no clinical significance in immunocompetent individuals. However, in immunodeficient individuals, the cysts can be disrupted and result in proliferation of organisms in a variety of organs, including the lung, brain, eye, skeletal muscle, and GI tract. In the lung, it causes a pneumonitis. The lung can also be involved in the congenital form of the disease. The diagnosis of toxoplasmosis is supported by a history of exposure to cats. Use of serologic tests for the demonstration of antibodies to T gondii is the primary means of diagnosis. The acute infection can be diagnosed by isolation of the organism or PCR amplification of its DNA in blood or body fluids.

The treatment of toxoplasmosis consists of pyrimethamine plus sulfadiazine with folinic acid, given to avoid bone marrow suppression. Immunodeficient patients should be treated for 4 to 6 weeks after signs and symptoms of disease have resolved, which may require 6 months or more of therapy. Prevention of toxoplasmosis is very important for seronegative pregnant women and immunodeficient patients. This can be accomplished by cooking meat thoroughly, controlling vectors such as flies and cockroaches, wearing gloves while cleaning cat litter boxes, and cleaning the litter boxes every day.

Trichinosis

Trichinosis is caused by the roundworm Trichinella spp.⁷ There are five species of this parasite, which infects a variety of animals including pigs, rats, horses, bears, foxes, hyenas, lions, and panthers. The disorder develops when humans become an incidental host by ingesting undercooked meat contaminated with the larvae of Trichinella spp The disorder has become rare in the United States because the practice of feeding meat to pigs has been discontinued.

Most infections with Trininella spp are subclinical. Persons who ingest a large number of larvae are most likely to become symptomatic. The symptoms are varied and nonspecific. Symptoms may include fever, myalgia, weakness, periorbital edema, headache, rash, diarrhea, nausea, vomiting, and cough. Approximately 6% of patients report cough. The diagnosis is supported by taking a history of ingestion of undercooked pork or other meat. Eosinophilia is common. Serum creatine phosphokinase and lactate dehydrogenase may be elevated when there is considerable muscle involvement. Serologic studies may be helpful in establishing the diagnosis.

There is no good treatment available for trichinosis. Early in the infection, thiabendazole may be effective because it is active against the intestinal worms. There is no consensus on treatment of the infection when it has begun to involve muscle. Albendazole has been recommended for this phase of the infection.¹³ The best measure of prevention is proper cooking of meat. Smoking, salting, and drying meat are not adequate for the prevention of trichinosis.

Visceral Larval Migrans

Visceral larval migrans is the clinical syndrome usually caused by infection with the nematode Toxocara canis or Toxocara cati.⁷ Rarely, other helminths can cause a similar syndrome. The worms infect dogs and cats through ingestion of eggs, which results in larvae migrating to the liver, lungs, and trachea. The larvae are then swallowed and they mature in the small intestine, and eggs are shed via the feces. Eggs contaminate the environment and may then be ingested by humans. Persons at risk include those who live in areas where the eggs survive in the soil and those who have contact with dogs or cats. Visceral larval migrans is most common in children < 6 years of age.

Serologic studies suggest that many persons are seropositive without having symptoms. Symptoms of visceral larval migrans most commonly consist of cough, fever, and wheezing. Lung involvement with radiographic changes is common but rarely results in severe disease. Hepatomegaly is also common. The diagnosis is suggested by eosinophilia and leukocytosis. Serologic tests are also helpful in establishing the diagnosis.

Treatment often is not necessary. When there are complications secondary to involvement of the brain, lungs or heart, the drug of choice is albendazole.¹³ Prevention includes testing and treating dogs and cats for T canis and T cati, keeping animal feces from contaminating the environment, and keeping children from ingesting the eggs.

Selected References

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