Continuing Education Activity

Zoonotic diseases are increasingly important due to the interaction between humans and animal habitats. To avoid the high morbidity and mortality associated with these diseases, they must be promptly diagnosed and treated. This activity reviews the evaluation and treatment of zoonotic diseases and highlights the role of the interprofessional team in evaluating and treating patients in a timely fashion.

Objectives:

• Review the risk factors for developing zoonotic diseases.
• Summarize the epidemiology of the most important zoonotic diseases.
• Outline the typical presentation of patients with zoonotic diseases.
• Describe how an interprofessional team can coordinate care to obtain the best outcomes in a patient with a zoonotic disease.

Introduction

Animals play a valuable role in our lives as food, livestock, hunting, travel, sports, zoo, fairs, research, pets, and guide-pets.[1][2] Zoonotic diseases encompass more than 200 diseases that are transmitted to humans from an animal origin, where humans are usually accidental hosts. They were first recognized by Rudolf Virchow and Osler in the 1800s. The word “zoonosis” consists of 2 parts; “Zoo” means an animal, and “nosis” means sickness.

Etiology

One important reason for the spread of zoonoses is anthropogenic changes in animal biodiversity, leading to the predominance of bats and rodents in the environment. Other important factors include the rapid increase in the human population, the intersection with animal habitats, deforestation practices, suburbs formation, bushmeat industry (worth $15 billion annually in the U.S.), effects of global warming, free travel and open trade, adoption of exotic pets, consumption of edible insects, genetic mutations, asymptomatic animal carriers especially poultry, and the spill-over effect, i.e., the transmission of a pathogen from one host species to another new one, crossing the biological barriers, due to the high infection prevalence in the former.[3][4][5][6][7][8][9][10][11]

Children below 5 years of age, the elderly above 65, immunocompromised persons, and pregnant women are all vulnerable populations at the highest risk for zoonotic diseases.[12][13] Those with specific occupations like veterinarians, butchers, hunters, etc., are by nature at a higher risk of acquiring zoonotic diseases. It is interesting to note that new and young pets carry a higher risk of transmitting zoonotic disease than old adult ones.[14]

More than 2200 species of rodents exist, making them the most abundant zoonotic hosts. Almost 1100 species of bats act as a reservoir for many serious zoonoses like Nipah, Hendra, Menangle, Corona, Ebola, and Marburg viruses.[15][16] Carnivores make up the greatest fraction of carrier zoonotic hosts, especially for bacteria and viruses.[17]

Classification of zoonotic diseases can be done according to pathogen type, transmission, animal source, affected human organ system, or ecosystem.

Table 1. List of the most common pathogens causing zoonoses[18][19][20][21][22][23][24][25][26]

(*: Avian: H5N1, H7N9, H9N2. Swine: H1N1, H1N2, H3N2, H7N2. Spanish Flu is H1N1 from bats)

(SARS: Severe Acute Respiratory Syndrome, MERS: Middle East respiratory syndrome, WNV: West Nile virus, EEE: Eastern Equine encephalitis, WEE: Western Equine encephalitis, VEE: Venezuela Equine encephalitis, LCMV: Lymphocytic Chorio-Meningitis virus, HIV: human immunodeficiency virus, vCJD: Variant Creutzfeldt-Jakob disease)

Epidemiology

In the U.S., 68% of households have pets. There are 45 million dog owners and 77 million cat owners.

Zoonoses constitute 61% of infectious diseases, 75% of emerging infectious diseases, and 80% potential bioterrorism pathogens.[27][28]

Per the last report by the Centers for Disease Control and Prevention (CDC), Department of the Interior, and U.S. Department of Agriculture, the eight most important zoonoses in the U.S., based on their pandemic potential, severity, economic impact, local potential, and bioterrorism risk, are influenza, salmonella, West Nile virus, plague, coronaviruses, rabies, brucella, and Lyme disease.

Important statistics about each zoonotic disease:

• Influenza has caused several outbreaks in different countries in the last few decades, especially H1N1 swine flu in 2009 & H5N1 avian flu since 2003.[29]

• Salmonella is the most common cause of zoonotic outbreaks in the USA in the last decade, per the CDC. 

• WNV is the most common mosquito-borne zoonosis in the USA. It is estimated that there are 70 unreported cases for each reported case of the disease.

• Plague is endemic in western states - California, Arizona, Colorado, and New Mexico. The incidence rate is 1-17 cases/year.

• Coronaviruses: SARS caused >8000 infections in 2003 in Southeast Asia. MERS has infected >2000 people since 2012.[30] SARS-CoV-2 has infected around 120 million people since 2019.

• Rabies: There are around 40,000 exposures reported per year in the U.S., which costs the health system $225 million to $500 million for post-exposure prophylaxis alone. There were only nine established rabies in humans from 2008 to 2019 due to stray animal control, rabies vaccine, and oral rabies vaccine baiting programs.[31]

• Brucella: Almost all cases in the U.S. are related to immigrants, imported animals, or unpasteurized milk. There are around 100 reported cases annually.

• Lyme disease is the most common vector-borne disease in the U.S., with 20,000 cases/year; 95% of the cases belong to 12 states in the Northeast & Mid-Atlantic U.S.

• Leptospira is the most common zoonotic disease worldwide. Most cases in the U.S. are seen in Hawaii in farmers, veterinarians, and surfers.

• RMSF is the most common rickettsial disease in the U.S., with 600 to 1200 cases/year, mainly in the Southeastern and South Central U.S., especially North Carolina and Arkansas.

• Hanta: The Sin Nombre & Seoul strains are found in the U.S., mainly Utah, Colorado, Arizona, and New Mexico.

• Babesiosis: B.microti is seen in the Northeastern states, and B.divergens is seen in Europe.

• Toxoplasma: 30% of the US population are asymptomatic carriers.[32]

• Giardia is one of the most common gastrointestinal parasites in the U.S.

Pathophysiology

Modes of Transmission:

• Direct Contact (touch, scratch, licking)
• Indirect Contact (fomites, soil, water)
• Animal Bites cause >4.7 million cases, 0.3 million ED visits, 10,000 hospitalizations, and 20 deaths in the U.S. per year, most commonly from dogs (80-90%) and cats (5% to 15%).[33][34]
• Vector-borne (ticks, mosquitoes, lice, fleas, mites)
• Inhalation (droplet, aerosols from products of animal conception and feces)
• Ingestion (vegetables, meats, eggs, milk, water)

According to ND Wolfe’s paper in Nature 2007, pathogens go through five stages to transmit infections from animals to man:[35]

• Stage 1: pathogens existing among animals only 
• Stage 2: limited infections from animals to some humans 
• Stage 3: limited outbreak level
• Stage 4: long outbreak level where human to human transmission can occur 
• Stage 5: the pathogen can become an exclusively human pathogen with free transmission potential

Table 2. Mode of transmission and animal source of important zoonotic diseases[36][37][38][39][40][41][42][43]

(*Deer only act as an alternative reservoir for the Ixodes scapularis itself; hence the name “deer tick.”)

History and Physical

A detailed history must be obtained from patients with special attention to travel history, location of residence, occupation, vaccination status, hobbies, pets, other animal exposure, and diet. Immunosuppressed patients have more aggressive diseases than the general population.

Table 3. The clinical picture of important zoonotic diseases classified by affected organ systems[44][45][13]

(WNV: West Nile Virus, vCJD: Variant Creutzfeldt-Jakob Disease, CLM: Cutaneous larva migrans, RMSF: Rocky Mountain spotted fever)

Evaluation

It is important to have public health data available at both national and local levels as a valuable reference while considering a possible zoonotic infection.

• CBC: lymphocytosis is seen in influenza and brucellosis, lymphopenia is seen with COVID-19, thrombocytopenia in babesiosis, Coxiella, RMSF and leptospirosis, eosinophilia in trichinellosis.
• Peripheral blood smear: maltese cross appearance is seen in babesiosis
• Kidney function tests, liver function tests
• Imaging as a chest x-ray
• CSF testing: to look for WNV, vCJD, rabies
• EEG: to look for waveform abnormalities as seen with WNV and vCJD
• Cultures (blood, sputum, tissue): to detect plague, anthrax, salmonella, and Capnocytophaga
• Serology: to detect Lyme disease, WNV, psittacosis, Bartonella.
• PCR / RT-PCR: to detect influenza, COVID-19, WNV, psittacosis
• Matrix-assisted laser desorption/ionization (MALDI-TOF): as in anthrax
• Animal autopsy: for rabies

Treatment / Management

Treatment varies with the pathogen.

• Influenza is usually self-limited. Otherwise, treatment regimens include Oseltamivir or Baloxavir.

• Salmonella is usually managed supportively. Quinolones, azithromycin, trimethoprim-sulfamethoxazole, and ceftriaxone are all available options.

• Plague is classically managed with aminoglycosides, tetracyclines, and quinolones as a last resort.

• A combination treats brucella of doxycycline and an aminoglycoside or rifampicin in non-pregnant adults.

• COVID-19  is currently managed per the latest guidelines on remdesivir, dexamethasone, and supportive measures.

• Lyme disease is treated by doxycycline or a beta-lactam depending on the stage and presentation.

• RMSF is managed by doxycycline as the drug of choice.

• Psittacosis is recommended to be treated by tetracyclines, with azithromycin as an alternative.

• Coxiella is managed with doxycycline, with the addition of hydroxychloroquine in vascular complications.

• A combination lately treats anthrax of quinolones, carbapenems, linezolid, and immunoglobulin for systemic infections. Quinolones or doxycycline are utilized for limited cutaneous infections.

• Dermatophytes: Topical or systemic antifungals in addition to animal treatment as well.

• WNV, Rabies, and Rift Valley Fever are managed through supportive treatment only.

• Ebola is suggested to be managed with the new agents atoltivimab, maftivimab, odesivimab (REGN-EB3), and ansuvimab.

Government strategies to decrease zoonoses include ensuring safe food products of animal origin, scaling back economic development in the wild, the shift from reactionary to pre-emptive approach on zoonoses, and availability of travel medicine guidelines.[46]

The ‘One Health 2006 Initiative’ focuses on the collaboration between human (physicians, nurses, and public health practitioners), animal (veterinarians), plants (agricultural workers), and environmental (ecologists, and wildlife experts) sectors to achieve optimal health since they are all interconnected.[47] This was started after the 1999 WNV outbreak in New York City, where one-sided prevention was shown to be inefficient. One Health Zoonotic Diseases Prioritization (OHZDP) workshops aim to prioritize zoonoses, develop action plans, maintain equative collaborative sectors’ input, and appropriately focus resources.[48]

Differential Diagnosis

Zoonotic diseases must not be confused with other groups of diseases, including:[49]

• Zooanthroponosis (reverse-zoonosis), which are infections transmitted from humans to animals, such as tuberculosis

• Amphixenosis, which are infections transmitted in both directions from animals to humans and vice versa, such as staphylococcal infections

• Euzoonosis, where humans act as an obligatory host in the pathogen’s life cycle, such as Taenia solium and Taenia saginata

• Zoonoses also have to be differentiated from other common infections of similar presentations, and one should not be completely misled by a certain animal exposure in the context. Similarly, contact with animals, insects, and the wilderness, can cause other non-infectious pathologies like allergic reactions, which have to be considered in the differential diagnosis.

Prognosis

Prognosis varies with the pathogen:

• Influenza: Case fatality is up to 60% in Avian flu and less than 1% in Swine flu.

• WNV: Case fatality is 6%.

• Plague: Case fatality is 13% with treatment and more than 80% without treatment.

• The fatality of SARS is 9.6%, MERS is 35%, and SARS-CoV-2 is 3% to 6%, resulting in more than 2.5 million deaths.[50]

• Rabies: Globally causes more deaths than any other zoonosis at 30,000 to 70,000 annually.[51][52]

• Brucella: Case fatality is 2% to 5% if untreated.

• Anthrax: Case fatality is more than 80% from inhalation anthrax.

• Coxiella: Case fatality is 2% in acute and 20% in chronic disease.

• Ebola: Case fatality is around 50%.

• RMSF: Case fatality is 22% without treatment and 6% with treatment.[53]

Low mortality zoonoses (less than 1%) include salmonellosis, Lyme disease, rift valley fever, and psittacosis.

Complications

Known complications of the important zoonotic diseases are as follows:[54]

• Influenza: Secondary pneumonia, myositis, myocarditis, encephalitis, and Guillain-Barre syndrome

• Salmonella: Bacteremia, osteomyelitis, endocarditis, and mycotic aneurysms

• WNV: Meningitis, encephalitis, chorioretinitis, fatal hemorrhagic fever, hepatitis, and myocarditis

• Plague: Meningitis, shock, DIC, and multiorgan failure

• COVID-19: Respiratory failure, arrhythmias, acute coronary syndrome, shock, thromboembolic manifestations, acute kidney injury, and systemic inflammation

• Rabies: Seizures, coma, respiratory failure, arrhythmias, and myocarditis

• Brucella: Arthritis, meningitis, pneumonia, orchitis, abortion, uveitis, and endocarditis

• Lyme: Bannwarth syndrome, facial palsy, meningitis, atrioventricular blocks, acrodermatitis chronica atrophica, and post-Lyme syndrome

The economic impact of zoonotic diseases is a major concern, mostly due to its notorious effect on international travel, tourism, and trade, especially about animals and animal products. For example, the avian flu 2015 outbreak has caused a $3.3 billion loss to the U.S. economy.

Many zoonotic diseases also have the potential for causing severe complex diseases in transplant patients and other immunocompromised individuals. Also, many of them can be utilized as bioterrorism weapons.

Deterrence and Patient Education

Veterinarian visits should be scheduled regularly and for any pet illness. Catclaw clipping is recommended to avoid scratches. Owners should avoid feeding their pets any raw meat or eggs.[12] Reptile pets are strongly recommended to be kept away from children less than 5 years old and away from kitchens.

Proper tetanus immunization with or without immunoglobulins for bites is to be followed per guidelines. Animal vaccination for rabies, leptospira, and brucella, is also an essential practice. WNV vaccination is essential for horses. New vaccines are in process for several zoonoses, such as the new influenza A strains and plague.

Tick and flea control can be done by advising the public to wear light-colored clothes, long sleeves, tucking-in pants, using DEET spray, conducting body checks for early removal of ticks, and inspecting pets for ticks after going into wooded areas. Leaf debris removal and importation of fire ants to eat tick eggs can be done by environmental authorities to control the breeding of ticks and fleas.[55] Measures should be taken to avoid mosquito bites.

Public awareness programs to encourage handwashing is important. Awareness should be raised among healthcare workers about emerging infectious diseases and the available resources for the same. Continuous surveillance, disease reporting, and mapping programs for zoonotic diseases are ongoing in humans and animals.

Enhancing Healthcare Team Outcomes

Medical providers, including physicians, nurse practitioners, and physician assistants, must keep in mind the possibility of certain zoonotic diseases, depending on the geographical location, travel history, and exposure to certain animals.[56] The COVID-19 pandemic typifies the importance of the human-animal interface and the One World One Health paradigm.  Appreciation of the effect of human behavior as a coordinated interprofessional team, and the potential disruption of natural barriers to species jumping infections can help prevent a pathogenic emergency, which may lead to epidemics or pandemics.