In lymph node biopsies, the typical histopathologic pattern is characterized by geographic areas of necrosis with neutrophils and necrotizing granulomas. The pattern is non specific and similar to other infectious lymphadenopathies.

The laboratorial isolation of "F. tularensis" requires special media such as buffered charcoal yeast extract agar. It cannot be isolated in the routine culture media because of the need for sulfhydryl group donors (such as cysteine). The microbiologist must be informed when tularemia is suspected not only to include the special media for appropriate isolation, but also to ensure that safety precautions are taken to avoid contamination of laboratory personnel.

Serological tests (detection of antibodies in the serum of the patients) are available and widely used. Cross reactivity with "Brucella" can confuse interpretation of the results, so diagnosis should not rely only on serology. Molecular methods such as PCR are available in reference laboratories.

A doctor or veterinarian will perform a physical exam which includes asking about the medical history and possible sources of exposure.

The following possible test could include:

- Blood samples (detect antibodies)

- Culture samples of body fluids(check for the bacteria "Yersinia pestis")

- Kidney and liver testing

- Check lymphomic system for signs of infection

- Examine body fluids for abnormal signs

- Check for swelling

- Check for signs of dehydration

- Check for fever

- Check for lung infection

There are no safe, available, approved vaccines against tularemia. However, vaccination research and development continues, with live attenuated vaccines being the most thoroughly researched and most likely candidate for approval. Sub-unit vaccine candidates, such as killed-whole cell vaccines, are also under investigation, however research has not reached a state of public use.

Optimal preventative practices include limiting direct exposure when handling potentially infected animals, such as wearing gloves and face masks while handling potentially infected animals (importantly when skinning deceased animals).

Laboratory testing is required in order to diagnose and confirm plague. Ideally, confirmation is through the identification of "Y. pestis" culture from a patient sample. Confirmation of infection can be done by examining serum taken during the early and late stages of infection. To quickly screen for the "Y. pestis" antigen in patients, rapid dipstick tests have been developed for field use.

Samples taken for testing include:

- Buboes: Swollen lymph nodes (buboes) characteristic of bubonic plague, a fluid sample can be taken from them with a needle.

- Blood

- Lungs

The following steps and precautions should be used to avoid infection of the septicemic plague:

- Caregivers of infected patients should wear masks, gloves, goggles and gowns

- Take antibiotics if close contact with infected patient has occurred

- Use insecticides throughout house

- Avoid contact with dead rodents or sick cats

- Set traps if mice or rats are present around the house

- Do not allow family pets to roam in areas where plague is common

- Flea control and treatment for animals (especially rodents)

Since human plague is rare in most parts of the world, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas with enzootic plague, meaning it occurs at regular, predictable rates in populations and specific areas, such as the western United States. It is not even indicated for most travellers to countries with known recent reported cases, particularly if their travel is limited to urban areas with modern hotels. The CDC thus only recommends vaccination for: (1) all laboratory and field personnel who are working with "Y. pestis" organisms resistant to antimicrobials; (2) people engaged in aerosol experiments with "Y. pestis"; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas).

A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine.

Sylvatic plague is most commonly found in prairie dog colonies; the flea that feeds on prairie dogs (and other mammals) serves as the vector for transmission to the new host.

If diagnosed in time, the various forms of plague are usually highly responsive to antibiotic therapy. The antibiotics often used are streptomycin, chloramphenicol and tetracycline. Amongst the newer generation of antibiotics, gentamicin and doxycycline have proven effective in monotherapeutic treatment of plague.

The plague bacterium could develop drug-resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found in Madagascar in 1995. Further outbreaks in Madagascar were reported in November 2014 and October 2017.

On infection the microorganism can be found in blood and cerebrospinal fluid (CSF) for the first 7 to 10 days (invoking serologically identifiable reactions) and then moving to the kidneys. After 7 to 10 days the microorganism can be found in fresh urine. Hence, early diagnostic efforts include testing a serum or blood sample serologically with a panel of different strains.

Kidney function tests (blood urea nitrogen and creatinine) as well as blood tests for liver functions are performed. The latter reveal a moderate elevation of transaminases. Brief elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) levels are relatively mild. These levels may be normal, even in children with jaundice.

Diagnosis of leptospirosis is confirmed with tests such as enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). The MAT (microscopic agglutination test), a serological test, is considered the gold standard in diagnosing leptospirosis. As a large panel of different leptospira must be subcultured frequently, which is both laborious and expensive, it is underused, especially in developing countries.

Differential diagnosis list for leptospirosis is very large due to diverse symptoms. For forms with middle to high severity, the list includes dengue fever and other hemorrhagic fevers, hepatitis of various causes, viral meningitis, malaria, and typhoid fever. Light forms should be distinguished from influenza and other related viral diseases. Specific tests are a must for proper diagnosis of leptospirosis.

Under circumstances of limited access (e.g., developing countries) to specific diagnostic means, close attention must be paid to the medical history of the patient. Factors such as certain dwelling areas, seasonality, contact with stagnant contaminated water (bathing, swimming, working on flooded meadows, etc.) or rodents in the medical history support the leptospirosis hypothesis and serve as indications for specific tests (if available).

"Leptospira" can be cultured in Ellinghausen-McCullough-Johnson-Harris medium (EMJH), which is incubated at 28 to 30 °C. The median time to positivity is three weeks with a maximum of three months. This makes culture techniques useless for diagnostic purposes but is commonly used in research.

Sylvatic plague is primarily transmitted among wildlife through flea bites and contact with contaminated fluids or tissue, through predation or scavenging. Humans can contract plague from wildlife through flea bites and handling animal carcasses.

Common vectors for urban plague are house mice, black rats, and Norway rats.

Several classes of antibiotics are effective in treating bubonic plague. These include aminoglycosides such as streptomycin and gentamicin, tetracyclines (especially doxycycline), and the fluoroquinolone ciprofloxacin. Mortality associated with treated cases of bubonic plague is about 1–15%, compared to a mortality of 40–60% in untreated cases.

People potentially infected with the plague need immediate treatment and should be given antibiotics within 24 hours of the first symptoms to prevent death. Other treatments include oxygen, intravenous fluids, and respiratory support. People who have had contact with anyone infected by pneumonic plague are given prophylactic antibiotics. Using the broad-based antibiotic streptomycin has proven to be dramatically successful against the bubonic plague within 12 hours of infection.

Urban plague is an infectious disease among rodent species that live in close association with humans in urban areas. It is caused by the bacterium Yersinia pestis which is the same bacterium that causes bubonic and pneumonic plague in humans. Plague was first introduced into the United States in 1900 by rat–infested steamships that had sailed from affected areas, mostly from Asia. Urban plague spread from urban rats to rural rodent species, especially among prairie dogs in the western United States.

The diagnosis is aided by obtaining a history of the circumstances surrounding the bite. The time the bite was experienced, the location of the bite, and examination of the bite is noted. The person may have drainage from the site of the bite. They may also be febrile. Swelling may also occur. Because the wound from the bite may have healed over the punctures, the wound it may be opened and explored. The site is anesthetized prior to exploration of the wound for is examined for damage. Neurovascular status is assessed. Immune status may determine treatment as does

the presence of transplanted tissue or organs, rheumatic disease, diabetes, HIV/AIDS and sickle cell disease.

Swollen glands (lymph nodes) and red streaks radiating upward may be evident.

The diagnosis of a cat with rabies is evident by observing the cat. Cats with rabies may also appear restless, pant, and attack other animals, people, or objects. Animals with rabies typically die within a few days of appearing sick. Vaccination of the cat can prevent rabies being transmitted by the cat through a bite. If the cat is suspected of being infected with rabies, the person begins treatment with rabies vaccine.

Pneumonic plague is a very aggressive infection requiring early treatment. Antibiotics must be given within 24 hours of first symptoms to reduce the risk of death. Streptomycin, gentamicin, tetracyclines and chloramphenicol are all effective against pneumonic plague.

Antibiotic treatment for seven days will protect people who have had direct, close contact with infected patients. Wearing a close-fitting surgical mask also protects against infection.

The mortality rate from untreated pneumonic plague approaches 100%.

Doxycycline has been provided once a week as a prophylaxis to minimize infections during outbreaks in endemic regions. However, there is no evidence that chemoprophylaxis is effective in containing outbreaks of leptospirosis, and use of antibiotics increases antibiotics resistance. Pre-exposure prophylaxis may be beneficial for individuals traveling to high-risk areas for a short stay.

Effective rat control and avoidance of urine contaminated water sources are essential preventive measures. Human vaccines are available only in a few countries, such as Cuba and China. Animal vaccines only cover a few strains of the bacteria. Dog vaccines are effective for at least one year.

Outbreaks of zoonoses have been traced to human interaction with and exposure to animals at fairs, petting zoos, and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings. The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians, include educational responsibilities of venue operators, limiting public and animal contact, and animal care and management.

Cat bites can often be prevented by:

- instructing children not to tease cats or other pets.

- being cautious with unfamiliar cats.

- approaching cats with care, even if they appear to be friendly.

- avoiding rough play with cats and kittens.

Rough play causes is perceived as aggressive. This will lead to the cat being defensive when approached by people. Preventing cat bites includes not provoking the cat.

Contact with farm animals can lead to disease in farmers or others that come into contact with infected animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses, tanneries and wool mills. Close contact with sheep who have recently given birth can lead to clamydiosis, or enzootic abortion, in pregnant women, as well as an increased risk of Q fever, toxoplasmosis, and listeriosis in pregnant or the otherwise immunocompromised. Echinococcosis is caused by a tapeworm which can be spread from infected sheep by food or water contaminated with feces or wool. Bird flu is common in chickens. While rare in humans, the main public health worry is that a strain of bird flu will recombine with a human flu virus and cause a pandemic like the 1918 Spanish flu. In 2017, free range chickens in the UK were temporarily ordered to remain inside due to the threat of bird flu. Cattle are an important reservoir of cryptosporidiosis and mainly affects the immunocompromised.

The clinical definition of smallpox is an illness with acute onset of fever equal to or greater than followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development without other apparent cause. If a clinical case is observed, smallpox is confirmed using laboratory tests.

Microscopically, poxviruses produce characteristic cytoplasmic inclusions, the most important of which are known as Guarnieri bodies, and are the sites of viral replication. Guarnieri bodies are readily identified in skin biopsies stained with hematoxylin and eosin, and appear as pink blobs. They are found in virtually all poxvirus infections but the absence of Guarnieri bodies cannot be used to rule out smallpox. The diagnosis of an orthopoxvirus infection can also be made rapidly by electron microscopic examination of pustular fluid or scabs. All orthopoxviruses exhibit identical brick-shaped virions by electron microscopy. If particles with the characteristic morphology of herpesviruses are seen this will eliminate smallpox and other orthopoxvirus infections.

Definitive laboratory identification of variola virus involves growing the virus on chorioallantoic membrane (part of a chicken embryo) and examining the resulting pock lesions under defined temperature conditions. Strains may be characterized by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Serologic tests and enzyme linked immunosorbent assays (ELISA), which measure variola virus-specific immunoglobulin and antigen have also been developed to assist in the diagnosis of infection.

Chickenpox was commonly confused with smallpox in the immediate post-eradication era. Chickenpox and smallpox can be distinguished by several methods. Unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly. A variety of laboratory methods are available for detecting chickenpox in evaluation of suspected smallpox cases.

The infection is treated with antibiotics. Intravenous fluids and oxygen may be needed to stabilize the patient. There is a significant disparity between the untreated mortality and treated mortality rates: 10-60% untreated versus close to 0% treated with antibiotics within 8 days of initial infection. Tetracycline, Chloramphenicol, and doxycycline are commonly used. Infection can also be prevented by vaccination.

Some of the simplest methods of prevention and treatment focus on preventing infestation of body lice. Complete change of clothing, washing the infested clothing in hot water, and in some cases also treating recently used bedsheets all help to prevent typhus by removing potentially infected lice. Clothes also left unworn and unwashed for 7 days also cause both lice and their eggs to die, as they have no access to their human host. Another form of lice prevention requires dusting infested clothing with a powder consisting of 10% DDT, 1% malathion, or 1% permethrin, which kill lice and their eggs.

The American Public Health Association recommends treatment based upon clinical findings and before culturing confirms the diagnosis. Without treatment, death may occur in 10 to 60 percent of patients with epidemic typhus, with patients over age 60 having the highest risk of death. In the antibiotic era, death is uncommon if doxycycline is given. In one study of 60 hospitalized patients with epidemic typhus, no patient died when given doxycycline or chloramphenicol. Some patients also may need oxygen and intravenous (IV) fluids.

The diagnosis of relapsing fever can be made on blood smear as evidenced by the presence of spirochetes. Other spirochete illnesses (Lyme disease, syphilis, leptospirosis) do not show spirochetes on blood smear. Although considered the gold standard, this method lacks sensitivity and has been replaced by PCR in many settings.

An epidemiological investigation can be done to determine a patient's exposure to raw infected meat. Often, an infection arises from home-preparation of contaminated meat, in which case microscopy of the meat may be used to determine the infection. Exposure determination does not have to be directly from a laboratory-confirmed infected animal. Indirect exposure criteria include the consumption of products from a laboratory-confirmed infected animal, or sharing of a common exposure with a laboratory-confirmed infected human.

Pneumonic plague can be caused in two ways: primary, which results from the inhalation of aerosolised plague bacteria, or secondary, when septicaemic plague spreads into lung tissue from the bloodstream. Pneumonic plague is "not" exclusively vector-borne like bubonic plague; instead it can be spread from person to person. There have been cases of pneumonic plague resulting from the dissection or handling of contaminated animal tissue. This is one type of the plague formerly known as the Black Death.