Several zoonoses have been known and documented as animal-to-human diseases from much earlier times. Rabies was known and written of many centuries ago, as were ringworm, tetanus, and plague (Yersinia pestis). For example, the bite of a "mad dog" was known to transmit rabies in the 1300s, though obviously the knowledge of the virus came much more recently [1]. The invention of the light microscope by Leeuwenhoek in the late 1600s allowed visualization of the agents of zoonoses for the first time. Bacteria and parasites could be seen, and the connection between a disease and its causative agent could be confirmed.

In 1934, the electron microscope allowed viruses to be visualized for the first time [5]. Most were known to exist from cellular changes seen with the light microscope, but once the viruses could be visually identified, they were quickly classified. If a carrier state exists or if only a small number of the host's population carry the disease, discovery of the etiology is more difficult. There may be an intermediate host or vector yet to be identified that is involved in the transmission.

A host is an animal (including humans) that can support an infective agent of a zoonotic disease. Many agents require more than one host to complete their lifecycle. The definitive host is an animal that supports an organism in the final reproduction phase of its lifecycle. Without the definitive host, normal reproduction of the organism will not occur. The secondary or intermediate host is needed in multiple lifecycle agents for some phase of their development. For example, the dog flea (Ctenocephalides canis) and the cat flea (Ctenocephalides felis) are the intermediate hosts for the dog tapeworm Dipylidium caninum. Ingestion of the flea, which carries the infective agent, leads to infection with the tapeworm.

A dead-end or aberrant host is one in which the organism can survive, perhaps only briefly, but from which it cannot reproduce or transmit disease. Such is the case with eastern equine encephalomyelitis (EEE) and the horse. The virus cannot continue to spread from an infected horse because it will kill the animal before it has a chance to reproduce. The horse in this situation is a sentinel for EEE, because the incubation period is shorter in horses than in humans. Deaths in horses from the infection will be seen prior to documented human cases in the same area. Many horses are vaccinated against the disease in endemic areas, so the number of sentinels may be very small. Eastern encephalomyelitis (EE) in humans carries a high case fatality rate (33% to 70%), and the sentinel serves as an early warning that human cases may soon be presenting at emergency rooms in the same vicinity [6]. Transmission does not occur between horse and human, as both are aberrant hosts. Another animal must serve as the reservoir. In many cases, the zoonosis is seen only sporadically because the vector that transmits the disease is not present. In addition, the reservoir can vary in its carrier status from year to year.

An insect that allows multiplication or growth of an agent while it is in the host is a biologic vector, as with the earlier example of the flea. Ticks and mosquitoes are biologic vectors for many zoonoses. Some of the more serious zoonoses transmitted by arthropods are Lyme disease, RMSF, Q fever, malaria, plague, and West Nile encephalitis. Insects can also transmit less serious diseases, such as tapeworms and some species of trematodes (parasitic flatworms).

Transmission of zoonoses can be either direct or indirect. A disease that is directly transmitted from an animal to humans usually requires close or intimate contact. As examples, direct transmission occurs when the act of touching a ringworm lesion on a cat directly results in infection, or when rabies is transmitted from the bite of a rabid animal. Indirect transmission occurs with the presence of a vector between animal and human. Insects, inanimate objects, or animal food products can all be sources of indirect transmission of a zoonosis. Some insects can transmit an infectious agent in their bite, as in the case of ticks and mosquitoes. Flies, such as the housefly, can carry many pathogenic organisms in their mouth parts and on their feet. They can spread a zoonosis by contaminating open wounds or other breaks in the skin of the host. Many arthropods, such as the horse fly (Tabanus spp.), bite and spread disease in the same manner.

Nematodes are commonly referred to as roundworms, with hookworm being a common example. There are many zoonotic forms of nematode infections. One example is trichinosis, which will be discussed in detail later in this course. In general, most nematode zoonoses are transmitted through ingestion of the egg stage of the organism [10]. When in the feces, the eggs will hatch into the infective larval stage after 24 hours in most species. Occasionally, the larval phase of the parasite will penetrate the skin, usually through the sole of the foot because an individual has walked barefoot where larval forms of the nematode are present. This form of infection is referred to as cutaneous larval migrans. It is one of the better reasons not to walk barefoot in a city park, an unfamiliar backyard, or a veterinarian's office.

The first signs of Lyme disease are usually flu-like symptoms and joint pain. In an elderly person, pre-existing arthritis may complicate early diagnosis. Three distinct stages have been described in patients with untreated infections [27]. Stage 1 (early localized stage) occurs 3 to 30 days after the tick bite and is associated with the appearance of the characteristic "bull's-eye" skin lesion of erythema migrans. Various sources estimate that approximately 70% to 80% of the documented infections will have the characteristic expanding rash [18]. This initial stage may show the nonspecific clinical signs of malaise, headache, arthralgia, fever, myalgia, and regional lymphadenopathy. If they never see a rash, many patients will not consider Lyme disease as the source of their symptoms.

Stage 3 (late disseminated stage) is the chronic phase, which may appear months to years after the initial infection [18]. Various names for this stage have been proposed and are currently used, including post-Lyme syndrome, post-Lyme disease syndrome, post-treatment chronic Lyme disease, or chronic Lyme disease [29]. One of the most common findings in this stage is oligoarthritis, with the knee being the most frequently affected joint, although other joints can become inflamed [18,28]. Pain is usually out of proportion to the swelling [18]. Musculoskeletal pain, spinal radiculopathy with paresthesias, encephalopathy, and the symptom complex of fibromyalgia or chronic fatigue syndrome may be present. This stage is associated with chronic borreliosis; consequently, cardiac arrhythmias, respiratory compromise, and spread to the entire nervous system are liable to occur. It is suspected that fibromyalgia may be a long-term sequela to chronic Lyme disease. If untreated, chronic expression results in potentially crippling arthritic changes as well as organ system involvement. The organism can establish itself in the bladder wall and reoccur with another exposure or stress from another illness [25].

The CDC recommends using diagnostic tests for Lyme disease that have been cleared or approved by the U.S. Food and Drug Administration (FDA) [34]. The CDC recommends sampling blood with a two-step process. Both steps are required and can be done using the same blood sample [35]. The first test should include either an enzyme-linked immunosorbent assay (ELISA) or, rarely, an indirect immunofluorescence assay (IFA); however, false positives occur with cross reactions to other spirochetes, such as syphilis, mononucleosis, some autoimmune diseases, and oral cavity flora. If the first step is positive or indeterminate (sometimes called "equivocal"), the second step should be performed. The overall result is considered positive only when the first test is positive (or equivocal) and the second test is positive (or, for some tests, equivocal) [35]. The second step, the Western blot test, identifies antibodies for the different spirochetes [18]. Western blot serology is both more sensitive and more specific than ELISA. Serologic assays for immunoglobulin G (IgG) and M (IgM) are frequently used blot tests but are not recommended without a previous ELISA [34]. In any serologic testing, a comparison test repeated after an interval of a few weeks should be performed. Antibody levels should be monitored over this period of time to determine if the disease is worsening or improving as determined by the immune system's reaction. The CDC recommends that ELISA or IFA should always be performed before immunoblot testing in order to decrease the likelihood of false positive results [18]. In 2019, the FDA cleared several Lyme disease serologic assays with new indications for use, allowing for an ELISA, rather than Western immunoblot assay, as the second test in the testing algorithm [36,37]. With this new paradigm, two ELISAs can be run either concurrently or sequentially, rather than the traditional two-step process [36,37]. According to the FDA, this new option is easier to interpret in a clinical laboratory due to the streamlined method of conducting the tests [37]. It is prudent to check the laboratory standards for what is deemed positive, as there is variability between individual testing laboratories. It is highly recommended that the laboratory report and specify the bands; many will just list the test as positive, equivocal, or negative. The CDC has published a list of laboratory tests and practices that are not recommended [34].

Prompt and complete treatment of early Lyme disease with antibiotics is important to prevent the development of chronic Lyme disease and/or chronic neuroborreliosis and their troublesome sequelae. The International Lyme and Associated Diseases Society (ILADS) suggests that Lyme disease should be treated with doxycycline as the antibiotic of choice for prophylaxis following an Ixodes tick bite with known feeding, irrespective of the amount of tick engorgement or the local tick population infection rate [41,42]. Where doxycycline is contraindicated, antibiotics known to be effective for treating Lyme disease, such as amoxicillin, azithromycin, or cefuroxime, may be substituted. The recommended adult dose and prophylactic regimen is 100–200 mg doxycycline twice daily for 20 days [42].

There are several classification systems for clinical tularemia. One such system categorizes tularemia as either ulceroglandular (occurring in the majority of patients) or typhoidal [49]. Ulceroglandular disease is characterized by lesions on the skin or mucous membranes (including conjunctiva), lymph nodes larger than 1 centimeter, or both. Typhoidal tularemia describes systemic manifestation of the disease without skin or mucous membrane lesions [46,49]. In addition to these two types, pneumonic tularemia, caused by inhalation and primarily manifesting as pleuropneumonic disease, also occurs [46,49]. Pneumonic tularemia is often considered a type of typhoidal tularemia.

As noted, typhoidal tularemia is an acute, nonspecific febrile illness and is not associated with prominent lymphadenopathy or skin lesions [46]. This type of tularemia is caused by inhalation or ingestion of bacilli and may involve significant gastrointestinal symptoms. It is believed that this type would be most prevalent during an act of bioterrorism [47,50].

RMSF is the most common rickettsial disease in the United States. The incidence of RMSF and other rickettsial infections has increased over the past two decades, from 495 reported cases of spotted fever rickettsiosis in 2000, to more than 6,000 cases in 2017. Cases reported in 2018 and 2019 were slightly lower [58]. The case fatality rate for rickettsial infection has declined since the 1940s, when tetracycline antibiotics cane into use. Using surveillance data, the CDC estimates that the current case fatality rate for all spotted fever rickettsioses is roughly 0.5%, somewhat higher for RMSF [58].

Symptoms usually appear within 2 to 14 days after the tick bite and can also include malaise, myalgia, nausea, and vomiting [58]. In rare cases, severe respiratory distress, circulatory failure, and neurologic complications may occur; this is especially true for patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

West Nile virus is transmitted from the primary reservoir, birds, to a vertebrate host after being maintained in a bird-mosquito-bird cycle. More than 160 species of birds have been documented to harbor the virus. Passerine birds have been noted to be the most commonly affected type of birds [69]. This group includes perching species such as songbirds and sparrows. The passerine group, crows, and many other common birds in the United States and around the world are evidently capable of being the amplifying host, in which the West Nile virus can replicate and markedly increase in number. It is also possible that other animals can harbor and amplify the organism. In a somewhat alarming finding, investigators confirmed that farmed alligators in Florida were capable of serving as an amplifying reservoir for West Nile virus. Humans and domestic animals that become infected with the organism are aberrant hosts, and the viremia is usually brief and low-grade [69,74,75,76].

Most (70% to 80%) human West Nile virus infections are subclinical and unapparent. Approximately 20% of those who contract the virus experience a mild febrile illness called West Nile fever [44,77]. Only about 1 out of 150, or less than 1%, of those infected will develop severe neurologic effects [44]. Among patients with neuroinvasive disease, the case fatality rate is approximately 11% [70]. Although the full spectrum of West Nile fever cases in the United States has not been determined, there are degrees of clinical involvement that can be noted [77,78].

Imaging studies may be helpful after the development of meningoencephalitis to exclude other etiologies [81]. Computed tomography (CT) scans usually do not show evidence of acute disease, but about one-third of the magnetic resonance imaging (MRI) studies revealed changes in the leptomeninges or periventricular areas. MRI studies have also shown lesions in the basal ganglia and thalamus [69].

The incubation period is usually about two weeks but can be as long as several months [112]. Shorter incubation periods appear to be associated with inoculations closer to the head [119]. If untreated, rabies is almost 100% fatal [8,112]. The only existing treatment for non-vaccinated humans is injection with rabies immune globulin and rabies vaccine within days after exposure; therefore, timely diagnosis of the disease is extremely important.

Several tests are necessary to diagnose rabies in humans; no single test is sufficient [122]. Fortunately, there are several very good diagnostic procedures that can be performed fairly quickly on serum, saliva, CSF, or skin biopsies taken from the nuchal region of the neck. Antibody analysis can be performed on serum or CSF, and skin biopsy samples can be examined for rabies antigen in the cutaneous nerves at the base of the hair follicles [122]. Other laboratory tests include electron microscopy, virus culture, and immunohistochemistry. Laboratory analysis also allows for the determination of the type of animal involved and, in many cases, the locality from which the infection originated. There are many public health and other designated facilities available to perform these procedures. Neuroimaging procedures, including CT scans and MRIs, are usually normal initially but show signs of cerebral edema and other features of encephalitis as the disease progresses.

If possible, the suspected animal should be tested for rabies antigen. Tests on animals may require samples of their brain tissue from at least two locations in the brain, preferably the brain stem and cerebellum [122]. Because of its high sensitivity and specificity, the direct fluorescent antibody (DFA) test is considered the gold-standard diagnostic method for rabies determination in animals in the United States [122]. The presence of Negri bodies, characteristic intracytoplasmic inclusion nodules within neurons, is confirmatory evidence of the disease. The rapid determination of whether an animal is rabid can save a potential victim from psychologic trauma and an expensive treatment regimen [122].

The WHO suggests that an intradermal administration of CCV 0.1 mL be used in three doses at day 0, 7, and then between 21 and 28 days or, alternately, intramuscular administration of 0.5 to 1 mL, depending on the type of vaccine, on the same three-day schedule[130]. However, rabies vaccine adsorbed is no longer available in the United States and therefore intradermal administration is no longer recommended[120]. Intramuscular vaccinations should be administered in the deltoid area of the arm for adults and the anterolateral area of the thigh for children younger than 2 years of age; the vaccine should not be administered in the gluteal area. Serologic analyses should be performed every six months for those at high risk and every two years for those at lower risk; a booster injection is not recommended unless rabies-virus neutralizing antibody titers fall below 0.5 IU/mL[130]. Booster injections are not recommended for individuals travelling to high-risk areas if they have previously completed pre-exposure or post-exposure prophylaxis.

The hemagglutinin antigens that historically have caused human influenza are H1, H2, and H3. Although all known hemagglutinin subtypes occur in birds, H5, H7, and H9 have been implicated more in recent outbreaks. Various combinations with the neuraminidase antigens occur. All of these AI viruses are type A, as B and C do not infect birds. Some of the cases focused on in the past two decades have included the following [143,144]:

Most cases of AI in humans have resulted from contact with infected poultry or contaminated surfaces. It is also possible for the virus to become aerosolized and then land on exposed surfaces of the mouth, nose, or eyes. Aerosolized virus could also be inhaled directly into the lungs. Eating poultry products has not been associated with the development of AI. Influenza viruses are destroyed by adequate heat.

As noted, humans have no immunity to avian influenza A viruses, so illness tends to be severe and the fatality rate is high. The symptom complex can range from the typical influenza findings of fever, headache, myalgia, sore throat, and cough to severe respiratory distress. Many humans develop conjunctivitis, which can be the initial complaint. This usually includes red, itching, and tearing eyes with associated photophobia and purulent discharge. The severe form progresses to pneumonia, which can be fulminant and followed by multiorgan failure and death. Although the very young and very old are most at risk for the viral pneumonia, fatalities have occurred among previously healthy adults [151].

The incubation time from contact with the virus until the onset of symptoms is thought to be about one to eight weeks. Almost everyone who develops the disease will have fatigue, fever greater than 38.3 degrees C, and myalgia, usually in the large muscles of the back, thighs, and shoulders. There is usually hypotension, tachypnea, and tachycardia. About one-half of patients experience nausea and vomiting, headache, dizziness, and abdominal pain [184,187]. After 4 to 10 days, the late symptoms of HPS appear with the onset of coughing, shortness of breath, increasing pulmonary distress, and pulmonary edema [184]. HPS appears to resemble acute respiratory distress syndrome in patients with advanced disease. In some patients, renal impairment may also develop, but this is more common in illness caused by hantaviruses other than the Sin Nombre virus.

Rodents infected with LCM virus show little sign of illness. Serologic testing of the rodents has not been very reliable, and the animals can shed virus for the duration of their lives without appearing to be ill [190]. In humans, LCM is characterized by a flu-like illness lasting only a few days. A few cases will relapse afterward, and these rare cases may develop meningeal inflammation signs, beginning with nuchal rigidity, headache, fever, malaise, and muscular pain. A limited number of cases progress to meningoencephalitis with paralysis and coma. Most will recover, although severe cases may have a protracted recovery time [190,191]. If a pregnant woman contracts the disease in the first or second trimester, there can be serious consequences for the fetus. Case fatalities are rare, except in immunocompromised patients. LCM can be isolated from the blood of febrile patients or from CSF in patients with meningitis; however, laboratory diagnosis in a patient suspected of having LCM is usually made by CSF PCR or by serologic studies (IgM and IgG antibody titers) on acute and convalescent serum.

As noted, the firm diagnosis of vCJD is made with either a brain biopsy during life or examining pathology material at autopsy; however, Western blot analysis of lymph node specimens has shown the presence of prion material in patients with the disease. Florid plaques have been described in brain sections of patients with vCJD but not in those with classic CJD. The vacuolation (spongiform change) has been seen in many portions of examined brains, with most disease found in the occipital cortex and cerebellum [194,205].

The agent of toxoplasmosis is Toxoplasma gondii (phylum Apicomplexa). T. gondii is one of the most widely disseminated parasites known in the world [208]. It has a two-host lifecycle, present in both predator and prey. The intermediate hosts are humans, swine, goats, sheep, dogs, rodents, cattle, and cats. Cats are the definitive host but can be intermediate hosts as well. All members of the cat family can carry the organism, but domestic cats are clearly the source of zoonosis in most people, resulting from fecal-oral transmission [14,208,209]. Studies of cat populations show 16% to 80% of cats in the United States have been infected; the estimated worldwide prevalence in domestic cats is 30% to 40% [210].

Diagnosis of toxoplasmosis is usually made with serologic testing. Indirect IFAs of IgG and IgM are positive within a few days after infection [208]. Imaging studies and PCR analysis of CSF are useful in immunocompromised patients with signs of encephalitis or focal mass lesions within the brain. In such patients, a brain biopsy may be considered for definitive diagnosis and to exclude other diagnostic possibilities (e.g., brain abscess, lymphoma, metastatic carcinoma). In many cases, the history of the consumption of undercooked or raw meat aids in making the diagnosis [211].

Treatment is rarely necessary in people with normal immune systems as most recover without treatment. Suspected cases in persons who are ill may be treated with the combination of pyrimethamine and sulfadiazine, plus folinic acid (leucovorin) for a period of three to four weeks. Clindamycin may be substituted for sulfadiazine in patients sensitive to sulfa drugs [208]. For encephalitis, the treatment is continued for four to six weeks. Patients with HIV/AIDS who are toxoplasma-seropositive and who have CD4 counts <100 cells/mcL should receive prophylaxis against toxoplasmosis. This can be accomplished with trimethoprim/sulfamethoxazole (TMP-SMX) double-strength daily dose or alternately, TMP-SMX double-strength three times weekly [213]. The recommended therapy for acquired toxoplasmosis in HIV-infected children is sulfadiazine plus pyrimethamine and leucovorin [214].

Prevention includes the avoidance of potentially contaminated water and foodstuffs. Drinking water from a stream, shallow well, or other unfiltered source can lead to ingestion of the cysts. The cysts can live for extended periods of time in an outdoor environment. However, they are inactivated by chlorine and can be eliminated from a water source by filters of less than 1 micron (e.g., National Safety Foundation [NSF] Standard 53 or NSF Standard 58 for cyst and oocyst reduction) [215].

Most cases of anthrax are cutaneous in humans. The pulmonary and gastrointestinal forms are less common. If untreated, the pulmonary (inhalation) form has a 45% case fatality rate, intestinal 40%, and the cutaneous form less than 1% to 2% [230].

Cholera is rarely spread from person to person without the contamination of food or water by animals or people. The organism can live in or on foodstuffs for up to five days at ambient temperatures and for 10 days at 5 to 10 degrees C. Most cases in endemic areas are in young children [243].

There are good antitoxins available; however, they only halt the progression of future symptoms and do not reverse the existing clinical presentation. A licensed heptavalent antitoxin for all known types of botulinum (A, B, C, D, E, F, and G) has been approved by the FDA and is recommended for all cases of botulism in patients other than infants [180,246]. The antitoxin is of equine origin, which means that skin testing must be performed to help prevent serum sickness or anaphylaxis in susceptible individuals [251]. Intravenous human botulism immune globulin (BIG-IV, BabyBIG) is available for the treatment of patients younger than 1 year of age with infant botulism caused by toxin type A or B. In cases of suspected infant botulism, for consultation, and to obtain BabyBIG, physicians should call (510) 231-7600 [252]. Antibiotics (i.e., penicillin G, chloramphenicol, clindamycin) are useful in wound botulism, but not in foodborne botulism [246].

The common presentation of salmonellosis is gastroenteritis with fever, abdominal cramping, vomiting, diarrhea that is often bloody, chills, and weight loss [254,255]. There is often a history of ingesting a possibly contaminated food product within the past few days, but in many cases a full epidemiologic investigation is necessary to find the source of infection. The symptoms usually appear within 12 to 72 hours after ingestion of the infective organism.

Trichinosis, also known as trichinellosis, is caused by the nematode Trichinella spiralis. It is common in Europe and the United States and is a reportable disease [267]. Several other Trichinella spp. are found around the world in carnivorous mammals and birds. The typical hosts of the worm in North America are pigs, rats, and bears. Less commonly, humans, dogs, cats, wolves, and horses can also be hosts. In the host, the adult organism typically lives in the intestine. There, it produces larvae, which penetrate the intestinal wall and migrate into skeletal muscle, where they encyst.

The treatment of choice is removal of the organisms during fiberoptic endoscopy or surgery [272,273]. Successful treatment of anisakiasis with albendazole 400 mg orally twice daily for 6 to 21 days has been reported in cases with a strong presumptive diagnosis based on history and/or serology [272]. Prevention is almost absolute if raw or uncooked fish is avoided. However, this is not practical in many parts of the world, including the United States. Fortunately, most chefs trained in handling and preparing raw fish can spot tainted fish. Freezing at negative 4 degrees F for at least seven days will kill the larvae, as will "blast-freezing" at negative 31 degrees F for 15 hours [272]. Irradiation of fish can also kill the organisms as will the cooking of thawed or fresh fish. Salting, in high concentration, and smoking may provide some prevention but not enough to assure a safe product [275]. When smoking, the flesh must reach 65 degrees C to kill the parasites.