Public Health Interest Zoonosis

## **Chapter 3** Rabies: Incurable Biological Threat

*Jitendrakumar Bhogilal Nayak, Jeetendrakumar Harnathbhai Chaudhary, Prakrutik Prafulchandra Bhavsar, Pranav Ashok Anjaria, Manojbhai N. Brahmbhatt and Urvish Pravinbhai Mistry*

#### **Abstract**

Rabies is a lethal zoonotic disease that affects all the homeotherms, including humans, and is caused by the Rabies virus of *Rhabdoviridae* family. Every year, this disease kills about 55,000 individuals globally. The stray dog is a key player in the spread of rabies. The disease is usually transmitted through the bite of a rabid animal. After being exposed to the virus, the virus must travel to the brain before generating symptoms. Delirium, unusual behaviour, hallucinations, hydrophobia and insomnia may occur as the condition advances. Diagnostic tests such as direct fluorescent antibody test (dFAT), direct rapid immunohistochemical test (dRIT), lateral flow assay (LFA), reverse transcriptase polymerase chain reaction (RT-PCR), nuclear sequencing, etc. are used in diagnosis of this dreadful disease. The genotype and lineage of the rabies virus can be determined via N gene sequencing and phylogenetic analysis. There is no effective treatment for rabies. Even though a tiny number of people have survived rabies, the disease is usually fatal. Rabies can be completely avoided in people if they receive timely and adequate medical treatment. Vaccinating and sterilising the dogs in our neighbourhoods effectively and humanely limit their population and eliminate rabies in both dogs and humans.

**Keywords:** dFAT, N gene, rabies, street virus, vaccine

#### **1. Introduction**

Rabies is a highly fatal viral infection of the central nervous system caused by the Rabies virus, which belongs to the genus Lyssavirus of the *Rhabdoviridae* family that affects all warm-blooded animals and is a major occupational anthropozoonosis. It is one of the oldest recognised diseases. The word rabies comes from the Latin word *rabere*, which meant to be insane, enraged or ravenous. It is one of numerous zoonotic diseases that go unnoticed, resulting in more than 55,000 deaths per year. According to the Association for Prevention and Control of Rabies in India (APCRI) in 2003, a person dies of rabies every 9 minutes. It is one of the most important zoonotic diseases in history, with a fatality rate of around 100% and a global distribution [1, 2]. While rabies is thought to affect all mammalian species, including nonhuman primates and humans, it is not predominantly a human disease. Human infection is

an unintended consequence of the disease's reservoir in wild and domestic animals. In the natural world, rabies is a disease that affects wild carnivores, with reservoirs and vectors including dogs, cats, wolves, foxes, coyotes, jackals, raccoons, skunks and bats. Bats are the main tanks for 10 known lyssavirus serotypes [3]. In 400 BC, Aristotle stated that 'dogs suffer from the madness. This causes them to become very irritable and all animals they bite become diseased'.

Rabies is sustained in two epidemiological cycles, one urban and the other sylvatic. Dogs are the principal reservoir host in the urban rabies cycle. This cycle is most prevalent in areas of Africa, Asia, Central and South America where there are a large number of unvaccinated, semi-owned or stray dogs. In Europe and North America, the sylvatic (or wildlife) cycle is the most common. In animals, disease patterns might be relatively stable or evolve into a slow-moving epidemic.

The skin or mucous membrane is the most common site of rabies virus entrance in humans and animals, where the virus enters the muscle and subcutaneous tissue through biting, licking or scratching by a rabies-virus-infected animal. Acute encephalomyelitis is the pathogenic manifestation in the CNS. In animals, disease can manifest itself in two ways. The classical or encephalitic (furious) form of rabies accounts for 80–85% of rabies cases. Hydrophobia, pharyngeal spasms and hyperactivity are all symptoms of the furious type of rabies, which can lead to paralysis, coma and death. The dumb type, also known as the paralytic form, is characterised by the development of pronounced and flaccid muscular weakness and is less prevalent. In humans, symptoms of cerebral dysfunction, agitation, anxiety and confusion develop. Later the person experiences abnormal behaviour, delirium, hallucinations, insomnia and respiratory failure. Once the symptoms develop, the disease is often fatal.

Even though Louis Pasteur achieved his first breakthrough against rabies with post-exposure vaccination in 1885, the disease continues to haunt the mankind, particularly in impoverished countries, more than 125 years later [4]. Despite recent advances in diagnosis, post-exposure treatment, the production of human and veterinary vaccines and the control of rabies in dogs and wild animals, rabies remains a major health hazard in many countries in Africa, South America and Asia and an economic burden for both developed and developing countries. Rabies is currently found on all continents except Antarctica, although Asia and Africa account for more than 95% of human mortality. Domestic/wild animals, as well as humans, are the primary transmitters. Many countries, including Japan, the United Kingdom, Denmark, Sweden, Greece, Scandinavia, Iceland, Portugal, New Zealand and Australia, are rabies-free, according to the World Health Organisation (WHO). Vaccination, public awareness, responsible participation, continued cooperation among stakeholders and the removal of the stray dog population are some of the measures to avoid rabies [5].

#### **2. History**

The deity of death was accompanied by a dog as the ambassador of death in India about 3000 BC. Rabid canines continue to kill 20,000 people each year in modernday India. The Mosaic Esmuna Code of Babylon, written around 2300 BC, is the first documented record of rabies causing death in dogs and humans. Babylonians had to pay a fine if their dog communicated rabies to another person. Democritus, in the fifth century BC, accurately described the disease in dogs, as did Aristotle in the third century BC [6].

#### *Rabies: Incurable Biological Threat DOI: http://dx.doi.org/10.5772/intechopen.105079*

The medical literature of the ancient world was littered with ineffective folk cures. Scribonius Largus, a physician, proposed a poultice of cloth and hyena skin, while Antaeus suggested a concoction prepared from a hung man's skull. The Roman scholar Celsus correctly predicted that rabies was transmitted through the saliva of the bitten animal in the first century A.D. He wrongly suggested that placing the victim under water would cure rabies. Those who did not drown succumbed to rabies. In eighteenth-century America, the most intriguing rabies therapy was the usage of madstones. Madstones are calcified hairballs found in ruminant stomachs including cows, goats and deer. They were supposed to have healing properties since they drew the craziness from the bite wound.

In the 1880s, the first effective rabies treatment was developed. When Louis Pasteur, a French chemistry instructor, was experimenting with chicken cholera, he discovered that virulent cultures exposed to the elements no longer caused sickness. He also discovered that chickens inoculated with this weaker or 'attenuated strain' were immune to fresh, virulent cultures. Pasteur then attempted an attenuated anthrax vaccination in cattle. It was successful! He next turned his attention to the world's scourge, rabies. Pasteur wanted more time to purify his attenuated vaccine before trying it on himself, despite the positive results of his initial animal experiments. In the year 1885, a rabid dog mauled a 9-year-old kid named Joseph Meister. The wounds were treated by a local doctor, who informed Joseph's family that Louis Pasteur was the only person who could rescue him. Pasteur consented only after speaking with a few of genuine doctors, who stated Joseph was a 'dead lad walking'. Joseph recovered completely after receiving 13 inoculations in just 11 days. The nerve tissue vaccine developed by Louis Pasteur in 1885 was a success, and it was modified over time to decrease the typical severe side effects [7].

#### **3. Mode of transmission**

Although dogs are the predominant reservoirs, other domesticated animals and wildlife also play a role in rabies transmission [8]. The virus can easily be passed from one mammal to another, whether they are of the same species or not. Humans are most infected with rabies after being bitten or scratched by an infected dog or cat. Bats, foxes, coyotes, skunks, raccoons, wolves, opossums and other animals are among the commonly infected wild or feral animals. Rabid dogs infect most people in poor countries. These dogs are frequently aggressive and drool frequently, although they act very withdrawn. Humans and domestic animals contract the disease after coming into contact with infected saliva.

Bites, non-bite exposure and human-to-human transmission are all possible routes for rabies transmission. The most common way to contract rabies is through a bite from a rabid animal, although infection can also be spread through skin wounds contaminated by infected saliva. The incubation period is the time between the bite and the onset of symptoms, and it can span anywhere from weeks to months. Because the virus has not yet made it to the saliva, a bite by the animal during the incubation stage carries no danger of rabies. Other inoculation routes are uncommon. The rabies virus can enter the body through wounds or direct contact with mucous membranes. The virus cannot pass through intact skin. The chance of contracting rabies from a bite (5–80%) is at least 50 times higher than the risk of contracting it from a scratch (0.1–1%). Virus particles are present in all the body secretions 2 days after it first enters the CNS, and the victim is fully contagious. At or shortly after this point, clinical symptoms develop.

Non-bite exposures are uncommon sources of transmission. Non-bite exposure includes scratches, abrasions, open wounds or mucous membranes infected with saliva or materials such as rabid animal brain tissue. Inhalation of aerosolised rabies virus is another non-bite route of infection, although most people, except for laboratory personnel, are unlikely to encounter an aerosolised rabies virus. Rare cases of rabies in humans have been reported because of breathing air in a cave home to thousands of bats. As rabies virus can be found in the milk of infected animals, milk can be a vehicle for virus transmission. During the consumption of infected milk, an ulcer, abscess or other lesion in the mouth may trigger rabies. Transmission between humans is extremely rare, although it can happen through transplant surgery or even more rarely through bites, kisses or sexual relations. There were outlined a number of cases of rabies transmission from human to human through cornea transplant. Some dogs slaughtered for human consumption may be infected with the rabies virus, exposing handlers of dog meat to the disease because the virus may be present in the meat's nerves. Rabies transmission to butchers is increased during handling, catching, loading, transportation and holding prior to slaughter.

#### **4. Pathogenesis**

The virus enters the body via transdermal inoculation (wounds) or direct contact with infectious materials (saliva, cerebrospinal fluid, nerve tissue) on mucous membranes or skin lesions. The virus is incapable of penetrating intact skin. After its entry in the skin, it can undergo eclipse phase, which is not easily detected. Virus replication begins in non-nervous tissue such as striated muscle cells at the site during this phase [9]. The virus can survive for a long time here, influencing the incubation period (the time between exposure and the development of sickness) in different individuals. The virus uses nicotinic acetylcholine receptors to connect to the cells at the inoculation site. The amount of virus acquired through the bite, the amount of tissue innervated and the tissue's proximity to the brain all influence how long it takes for clinical indications to appear. The faster the signals appear, the higher the dose and the closer it is to the central nervous system. It can last anywhere from 4 days to several years, but it usually lasts between 20 and 90 days. Muscle cell replication occurs without causing any noticeable signs. It normally does not elicit an immunological response at this time, but if antibodies are present, it can be neutralised. Because the virus is neurotropic, its absorption into peripheral neurons is critical for infection progression. The neuromuscular spindles are a critical entrance point for viruses into the neurological system. Motor end plates can also be used to gain access to the nervous system by the virus [9].

The rabies virus can infect a variety of cell types, although it is most seen in neurons. Virus infection and replication include several processes, including:


After replication in the originating neuron's cell body, infection spreads through multiple neurons by retrograde axonal transport and transsynaptic dissemination. The ability of a virus to proliferate within the CNS via synaptic connections is known as transsynaptic spread. The rabies virus infects neurons, causing changes in neurotransmitter function that impact serotonin, GABA and muscarinic acetylcholine transmission. After that, acinar cells are infected, and the virus is discharged into the oral cavity. This explains why the virus can be found in saliva.

#### **5. Pathology**

In rabies, there are no visible lesions. Rabies lesions are microscopic, restricted to the CNS and have a wide range of severity. Except for early necrosis of neurons with cytoplasmic inclusion bodies in the afflicted nerve cells, they may be difficult to detect. Pathologic evidence of rabies encephalomyelitis (inflammation) in brain tissue and meninges includes the following:


There are diffuse perivascular cuffing, neuronophagic nodules and other alterations for neuron destruction throughout the brain in some cases. The hippocampus in the brain stem and the gasserian ganglia are notably affected. Lesions in the gasserian ganglia are more particular, occur earlier and are more consistent than lesions in other parts of the body. Babes nodules, which are clumps of growing glial cells, are

the major lesion. Most of the histopathologic markers of rabies were identified by 1903, but rabies inclusions had yet to be discovered. Dr. Adelchi Negri reported the discovery of the Negri body, which he believed to be the etiologic agent of rabies. Negri bodies are round or oval inclusions within the cytoplasm of nerve cells of rabies-infected animals. The size of Negri bodies can range from 0.25 to 0.27 metres. The pyramidal cells of Ammon's horn and the Purkinje cells of the cerebellum are the most potential sites for them. They're also found in medulla cells and a variety of other ganglia. Negri bodies can be detected in the salivary glands, tongue and other organs' neurons. They're generally found in the hippocampus in dogs, but they are more common in the Purkinje cell of the cerebellum in cattle. In preparations stained with Mann's or Seller's stain, a granular, somewhat basophilic interior structure can be detected. When the virus infects the salivary glands centrifugally, the acinar epithelium undergoes degenerative alterations that lead to necrosis, primarily affecting the mucogenic cells of the mandibular salivary glands. Fluorescent antibody methods and electron microscopy can easily show virus within these cells. The degenerative alterations are accompanied by a moderate infiltration of lymphocytes and plasma cells.

#### **6. Clinical signs**

Rabies clinical indications are rarely conclusive. Rabid animals of all species show similar symptoms of CNS abnormalities, with slight differences across species. It's likely that the animal is seeking solitude. Rabid wild animals may lose their fear of humans, and traditionally nocturnal species may be found walking around during the day. The clinical course can be split into three stages: prodromal, furious and dumb.

Prodromal form—The term prodromal is initial period of rabies with non-specific period.

Furious form—It refers to animals in which the aggression is pronounced.

Dumb form—It refers to animals in which the behavioural changes are minimal, and the disease is manifest principally by paralysis.

#### **6.1 Prodromal form**

It is initiated when rabies virus travels up the peripheral nerve axons to the spinal ganglia which form the junction between the peripheral and central nervous systems.

#### **6.2 Furious form**

During this stage, there is very little evidence of paralysis. The animal becomes restless and may lash out with its fangs, claws, horns or hooves at the slightest provocation. These animals lose their fear of other animals and lose their caution. Carnivores infected with this strain of rabies are known to roam freely, attacking other animals, including humans and moving objects. Rabid dogs may shatter their teeth by chewing the wire and frame of their cages. Saliva either flows out of the mouth or is churned into a foam that can stick to the lip and face. Progressive paralysis leads to death.

#### **6.3 Paralytic form**

The paralysis of the throat and masseter muscles is the initial symptom, which is typically accompanied by excessive salivation and the inability to swallow. Dogs tend to drop their lower jaw. These animals aren't violent and only bite occasionally. The paralysis spreads quickly to all regions of the body and may lead to coma, and many die within a few hours.

#### **7. Variations in signs and symptoms in different species**

#### **7.1 Cattle**

Incubation takes about 3 weeks on average, although it can take anywhere from a few weeks to several months. Early indications of paralysis include knuckling of the hind fetlocks, sagging and swaying of the hindquarters while walking and typical deviation or flaccidity of the tail to one side. In this species, yawning is a common phenomenon. Soon after yawning, the animal begins to bellow, which continues until it reaches paralysis. One of the most common symptoms is saliva drooling. The penis of bulls in this stage is paralysed. Animals may attack other animals or inanimate objects with ferocity. Lactation in dairy cows ends abruptly. Sexual arousal is common. These symptoms linger during 24–48 hours, after which the animal collapses in a paralysed state and dies within a few weeks.

#### **7.2 Sheep**

The signs are comparable to those of cattle. Sexual arousal, attacks on humans or each other and intense wool pulling have all been observed. There are twitches in the muscles, and salivation is observed. There is no excessive bleating. Most sheep are quiet and anorectic.

#### **7.3 Goat**

Aggressive and continuous bleating seen.

#### **7.4 Pigs**

Excitement, a tendency to strike, dullness and incoordination are some of the indications that have been identified. There is nasal twitching, quick chewing movements, profuse salivation and clonic convulsions.

#### **7.5 Horses**

Show signals of anguish and agitation on a regular basis. These indications are frequently accompanied by rolling. They can bite or strike with ferocity. Abnormal postures, frequent whining, kicking, biting, colic and abrupt onset of lameness in limbs followed by recumbency are all the symptoms. Paddling convulsions and ultimate paralysis are followed by sternal and lateral recumbency.

#### **7.6 Cats**

The symptoms are identical to those seen in dogs. Two to four days after the initial symptoms start, the posterior part of the body is paralysed.

#### **8. Clinical signs in humans**

Incubation, prodromal stage, acute neurological phase, coma and death are the five stages of clinical manifestations.

#### **8.1 Incubation phase**

It takes 30–90 days for rabies to develop, although it can take anything from 5 days to more than 2 years after initial exposure. It may be slightly shorter in children and vary depending on the bite place.

#### **8.2 Prodromal phase**

During this period, the first signs and symptoms appear. Some of the symptoms include fever, fatigue, sore throat, cough, dyspnea, anorexia, dysphagia, nausea, vomiting, abdominal pain, diarrhoea, headache, vertigo, anxiety, irritability and anxiousness. Agitation, photophobia, priapism, increased libido, sleeplessness and depression are all symptoms that could indicate encephalitis, psychiatric problems or brain conditions.

#### **8.3 Acute neurologic period**

This stage starts with symptoms of central nervous system dysfunction, such as anxiety, insomnia, disorientation, agitation, strange behaviour, paranoia, terror and hallucinations and progresses to delirium. During the later stages, significant amount of saliva is produced together with an inability to swallow, resulting in hydrophobia due to paralysed throat and jaw. If hyperactivity is present, the condition is classed as furious, and if paralysis is present, the disease is categorised as dumb. Periods of rapid, uneven breathing may begin near the end of this phase, followed by coma and death.

#### **9. The virus and its genome**

Rabies virus is a single-stranded, negative-sense, unsegmented, enveloped RNA virus with a rod or bullet shape. Five proteins are encoded by the viral genome. In the cytoplasm of infected cells, viral RNA uncoils. A virion-associated RNA-dependent RNA polymerase transcribes the genome. Individual viral proteins are subsequently translated from viral RNA. The creation of progeny negative-stranded RNA begins with the synthesis of positive-stranded RNA templates [10]. The RNA is responsible for coding five genes: *N*, Nucleoprotein, 1424 bp; *P*, Transcriptase associated, 991 bp;*M*, Matrix, 805 bp; *G,* Glycoprotein, 1675 bp and *L,* Transcriptase, 6475 bp while one pseudogene intron of approximately 700 bp makes total genome size of ≈ 12Kb. *N* gene is responsible for the nucleic acid, so it holds more importance for the diagnostic and evolutionary tracking of the disease.

#### **9.1 Important strains of the virus**

*Pasteur*—Pasteur passaged the virulent 'street' virus of rabies in the rabbit by intracranial inoculation. After several passages in the rabbit, virus has modified several characteristics and started giving similar kind of only paralytic forms in rabies and similar incubation period and without producing intracytoplasmic Negri bodies. The virus is also identified as the 'fixed' virus. The virus is used to produce vaccine.

*CVS*—International bodies have approved and recommended a variety of vaccine strains for rabies vaccine production around the world. The rabies challenge virus standard (CVS-11) strain is one of these strains that has been licenced for vaccine manufacturing, is recommended for use in (Rapid Fluorescent Foci Inhibition Test) RFFIT and is utilised as a challenge virus around the world. It is a well-characterised strain that was adapted in mice from the original Pasteur rabies virus discovered in 1882.


#### **9.2 Difference in the street and fixed viruses**

#### **10. Need of the genetic study of the virus**

A case of human rabies is described in Siberia's polar region by Kuzmin [11] In the year 1999. The victim had been bitten by a wolf. Monoclonal antibodies revealed that the isolate was from arctic fox virus strain. This finding reaffirmed the importance of strain typing rabies virus isolates in areas where it has not yet been done: such characterisation is important for identifying the reservoir host, learning about the virus's natural history in the reservoir and planning future surveillance, post-exposure treatment and public education in the area.

#### **11. Epidemiology of rabies**

Epidemiology is the study of distribution and the determinants of the disease. For the better understanding of the topic, epidemiology is given in two separate sections.

#### **11.1 Distribution of the disease**

Rabies is found everywhere across the planet, except for islands. Except for Australia and Antarctica, rabies is endemic in many of the countries. Bahrain, Cyprus, Hong Kong, Japan, Malaysia, Maldives, Qatar, Singapore, Lakshdweep, India's Andaman and Nicobar Islands and Timor-Leste are among the Asian countries free of rabies. Antigua and Barbuda, the Bahamas, Barbados, Belize, Falkland Islands, Jamaica, Saint Kitts and Nevis, Trinidad and Tobago, Uruguay of the Americas subcontinent, and Albania, E.Y.R. of Macedonia, Finland, Gibraltar, Greece, Iceland, Isle of Man, Malta, Portugal, Norway (except Svalbard), United Kingdom and Spain (except Melilla and Ceuta) have all been declared rabies-free. Cape Verde, Congo, Libya, Mauritius, Reunion and Seychelles are the only African countries free of rabies. Fiji, Cook Islands, Vanuatu, Guam, French Polynesia, New Zealand, New Caledonia, Solomon Islands and Papua New Guinea are among the Oceana group of islands that are rabies-free [12, 13]. Bangladesh and India are the most affected, followed by Nepal, Myanmar, Bhutan, Thailand and Indonesia. Nepal is one of the countries in the world with the highest number of human rabies deaths [12, 13].

#### **11.2 Determinants of the disease**

Rabies is a unique disease as it can contract a wide range of all the warm-blooded hosts.

#### *11.2.1 Age*

Children lack fundamental ethology understanding about dogs, children are more vulnerable to the sickness and animal bites. When children disturb dogs while they are feeding, resting, mating or terrified, dogs get violent and bite them. According to research, the disease claimed the lives of 37% of children aged 5–14. [14]. Although the people from all the age groups are susceptible to the disease. The common site of bite in case of children is the face, and often children tend to hide the animal bite marks due to fear of scolds from the parents [15].

#### *11.2.2 Gender*

Males are more prone to contract to the disease as they are usually accessed to go out of the homes for earning or playing. In a study it was found that the ratio of men to women suffering from the disease was 4:1 [16].

#### *11.2.3 Area*

Awareness plays a major role in the succession of the disease. In urbanised area, availability of the medical facilities and awareness is a factor which may show reduced cases of the disease contrary; in rural areas, many socio-economic and religious factors are responsible for the disease spread as in many part of Gujarat, India, there are temples of 'Hadkai mata', mythologically protecting the people bitten by dogs from the rabies. The bite of a rabies-infected dog causes over 95% of human cases, which disproportionately afflict rural people, particularly children, in economically challenged countries of Africa and Asia [17].

#### *11.2.4 Dog population*

Majority of the rabies cases are occurring in the Southeast Asia and that too from the dogs. More the dogs are the factors significantly contributing to the spread of the disease. Stray dogs are generally naive towards the disease while only scanty dogs are vaccinated against the disease. The unvaccinated stray dog population is the biggest factor for the spread of the disease. At least 70% vaccination in the canine population will be taking care of spread of the disease in the animal population [18].

#### *11.2.5 Type of the exposure*

#### *11.2.5.1 Animal bite exposure*

The disease occurs in two phases. First phase of the disease occurs once rabid dog bites any animal or human. The live viruses travel from the site of the bite to the brain in centripetal manner. The second phase starts when the virus after reaching the brain starts travelling from the brain to the peripheral nerves and induces the clinical signs. The course of the occurrence is directly related to the site of bite. If the site is nearer to the head, disease progression is rapid.

#### *11.2.5.2 Non-bite exposure*

The rabies virus is spread by direct contact with saliva or brain/nervous system tissue from an infected animal (such as through broken skin or mucous membranes in the eyes, nose or mouth). Aside from bites and scrapes, there aren't many injuries. One non-bite form of exposure is inhalation of aerosolised rabies virus, although most people, except for laboratory personnel, will not meet an aerosol of rabies virus. Rabies has been transmitted through corneal and solid organ transplants, but these cases are extremely rare [19].

#### *11.2.6 Host susceptibility range*

Although all warm-blooded animals are susceptible to rabies and can transmit the RABV, there is significant interspecies heterogeneity in the ability of mammals to act as reservoirs. Rabies is mostly spread by carnivores all over the world [12]. Main cause for the transmission of the virus is wildlife or stray animals, lesser than 10% cases are reported from the domesticated animals such as dogs or cats [20]. Equine and bovine are generally susceptible to the disease, but they are considered as the dead end hosts as they generally do not transmit the disease [21].

There are two types of epidemiological cycle for the occurrence of the disease. Urban and Sylvatic cycles, both the cycles are overlapping to each other and interrelated. Dog, cat, fox, raccoon, jackal, wolf, badger, etc. are the reservoir of the disease while bats are the vector of the disease. In Asian subcontinent, majority of the cases are dog-mediated rabies while in American and European countries, bat-mediated rabies is seen [12]. In India, there are some factors which promote the growth of the stray dogs.


#### **12. Diagnosis of rabies**

Accurate and timely diagnosis is very important for proper management of the post-exposure prophylaxis and application of the public health control efforts. The disease is diagnosed using a variety of techniques. However, adequate proper collection and submission of post-mortem materials, particularly brain tissues from animals suspected of having rabies, can provide basis for rabies confirmatory diagnosis [22]. Rabies can be difficult to diagnose because, in the early stages, it is easily confused with other diseases or even with a simple aggressive temperament. The reference method for diagnosing rabies is the fluorescent antibody test (FAT), an immunohistochemistry procedure, which is recommended by the World Health Organisation (WHO).

Primary diagnostic methods, such as the direct fluorescent antibody (DFA) test, the direct rapid immunohistochemistry test (dRIT) or pan-lyssavirus polymerase chain reaction (PCR) assays, are used to identify agents. If a proper conjugate or primer/probe is employed, the DFA test, dRIT and PCR offer an accurate diagnosis in 98–100% of cases for all lyssavirus strains. In highly equipped facilities, conventional and real-time PCR may produce speedy results for a large number of samples. Histological procedures such as Seller staining (Negri bodies) are no longer suggested for diagnosis. In the incidence that main diagnostic tests (DFA test, dRIT or pan-Lyssavirus PCR) give unsatisfactory findings, further confirmatory testing (molecular tests, cell culture or mice inoculation tests) on the same sample or repeat primary diagnostic tests on different samples are recommended. Virus isolation in cell culture should be used instead of mice inoculation testing whenever possible. In specialised laboratories, the agent can be characterised utilising monoclonal antibodies, partial and whole genome sequencing and phylogenetic analyses. These approaches can tell the difference between field and vaccine strains, as well as the geographical origin of the field strains. These extremely sensitive tests should only be performed and evaluated by highly experienced experts.

Pre-exposure vaccination and boosters are necessary for all persons and laboratory workers engaged in the management of rabies suspected cases. These individuals are at risk of contracting rabies in a variety of ways. As a result, personal protection equipment (PPE) must be always worn, beginning with the necropsy procedure.

#### **12.1 Identification of the agent**

Because the rabies virus inactivates quickly, the specimens should be delivered on ice to the laboratory as soon as possible. Various approaches are used to diagnose rabies, with a focus on brain tissue, although other organs such as salivary glands are also used. Both the cerebellum and the brain stem are recommended for laboratory testing since the virus will be abundant in them and will help in laboratory detection. These portions of the brain can be acquired when the complete brain is removed during necropsy using the skull open approach.

#### **12.2 Collection of samples**

The virus can be found in the brain, spinal cord, saliva and salivary glands of a rabies-infected animal. B rain tissue is the preferred specimen for rabies diagnosis, the animal suspected of having rabies should be euthanised in such a way that the brain is not damaged. Only vaccinated and well-trained veterinarians or animal control personnel should remove the animal heads.

#### *Rabies: Incurable Biological Threat DOI: http://dx.doi.org/10.5772/intechopen.105079*

Brain sample collection for the accurate diagnosis of rabies is very difficult work and that can be dangerous in the field or if the person is not properly trained. The occipital foramen route of brain sampling is an alternative way of collecting brain samples that does not need open the skull.

#### **12.3 Brain sample collection through the occipital foramen**

The brain sample is collected through the occipital foramen by inserting a 5 mm drinking straw or a disposable plastic pipette with a capacity of about 2 mL or by inserting an artificial insemination sheath about 10 cm long into the foramen in the direction of the eye. Brain stem and cerebellum samples can be obtained through the juice straw or artificial insemination sheath (**Figure 1**). This technique of collection should be user-friendly, quick and risk-free for reliable rabies diagnosis [22]. This technique speeds up the more number of brain samples collection simultaneously.

#### **12.4 Animal rabies diagnosis**

Laboratory procedures for diagnosing rabies were developed as early as 1800 BC. Adelchi Negri discovered the Negri bodies in 1903, and their diagnostic significance was proved by his wife Lina Negri-Luzzani in 1913 [22]. This cleared the way for the development of a multiplicity of laboratory procedures for rabies confirmation, which are described in the WHO book 'Laboratory Techniques in Rabies' [23] as well as the 'OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals' [24].

#### **12.5 Sellar's staining under direct microscopy**

Seller's staining method is a quick and easy test. It is a histological test used on brain impressions to show the unique cell lesions known as 'Negri bodies'. These are viral particle aggregates visible as intracytoplasmic inclusion bodies ranging in size from 3 to 30 m in infected neural cells. The Negri bodies are round or oval structures that include basophilic granules in an eosinophilic matrix. This technique has relatively poor sensitivity for the diagnosis of rabies, that's why nowadays this test is no longer recommended [23].

**Figure 1.** *Brainstem collection through the foramen magnum technique in a dog (captured by the authors).*

#### **12.6 Direct fluorescent antibody assay (DFA)**

The World Health Organisation (WHO) and the World Organisation for Animal Health (OIE) both endorse the direct fluorescent antibody assay as the most extensively used test for post-mortem confirming diagnosis of rabies. Goldwasser and Kissling created this gold standard test in 1958. The 'Nucleoprotein antigen' (N) of the rabies virus is shown here to be present in fresh brain impressions of rabies suspect animals (**Figure 2**). Such rabies viral inclusions do not exist in the brain impressions of non-rabid animals (**Figure 3**). Furthermore, in a normal laboratory, the DFA has a specificity and sensitivity of about 99% [22].

The DFA is accurate and sensitive. The sensitivity of this test is determined by the quality of the sample (how carefully the brain is sampled as well as the degree of autolysis), the type of lyssavirus and the diagnostic staff's expertise. Impressions are obtained from a composite sample of brain tissue that includes the brainstem. It is air-dried before being immersed in 100% high-grade cold acetone for 1 hour to set the impressions. The impression is withdrawn from the acetone, air-dried and stained with a drop of the appropriate conjugate.

The impression is then incubated for 60 minutes at 37°C. Anti-rabies fluorescent conjugates are commercially available as polyclonal or monoclonal antibodies (MAbs)

#### **Figure 2.**

*Rabid animal brain impression, counterstained with Evan's blue and stained with rabies virus antinucleocapsid IgG-FITC conjugate (rabies DFA III, light diagnostics, cat # 6500, captured by authors).*

#### **Figure 3.**

*Non-rabid animal brain impression stained with rabies virus anti-nucleocapsid IgG-FITC conjugate (rabies DFA III, light diagnostics, cat # 6500, captured by authors).*

*Rabies: Incurable Biological Threat DOI: http://dx.doi.org/10.5772/intechopen.105079*

that are specific to whole virus or the N protein of the rabies virus and have been conjugated to the fluorescing dye, fluorescein isothiocyanate (FITC). The DFA slides should be inspected under a fluorescent microscope with a filter that corresponds to the wavelength of the fluorescent conjugate employed. FITC, which is stimulated at 490 nm and re-emits at 510 nm, is the most often used fluorescent dye. The presence of nucleocapsid protein aggregates can be seen by the fluorescence of associated conjugate in an apple green colour. When fresh brain tissue is used, this test is reliable. Bacterial contamination of partially decomposed brains causes nonspecific fluorescence that is difficult to differentiate from specific fluorescence owing to N antigen, making it inappropriate for this test.

#### **12.7 Direct rapid immunohistochemistry test (dRIT)**

The Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, developed dRIT, which is one of the most important breakthroughs in the diagnosis of Rabies. This test also detects the N protein of the rabies virus in rabies brain impressions. A suspected animal brain smear is fixed with buffered formalin before being processed further. Following appropriate viral fixation, the antigen was treated with a biotinylated monoclonal antibody cocktail that was highly concentrated and purified (to N protein). After that, an indicator and streptavidin peroxidase are added. The aggregation of viral clusters is seen as brick red clusters within the cell, along the axons and throughout the brain impression (**Figure 4**). Negative brain impressions show no such brick red inclusions.

This 1-hour test method is helpful in field conditions since the results may be examined with an ordinary light microscope. It has been tested in several nations and confirmed to be 100% as sensitive and specific as DFA. This simple, low-cost test will be extremely useful in enhancing rabies epidemiology monitoring, particularly in underdeveloped countries where expensive fluorescence microscopes and cold storage facilities may not be accessible [22].

#### **12.8 Lateral flow assay (immunochromatography)**

The lateral flow assay is a simple and quick immunochromatographic technique. The rabies virus nucleoprotein is recognised by this test kit, which was produced utilising monoclonal antibodies. It has been tested as a quick rabies screening test.

**Figure 4.** *Rabid animal brain impression tested by dRIT, captured by authors.*

This assay is an immunodiagnostic test that provides quick findings in the field by detecting RABV antigen in post-mortem samples without the need of laboratory equipment. In summary, the detector antibodies are coupled to a membrane at two separate zones, and when the processed material is added to the device at the appropriate slot, coloured lines appear, indicating the presence of viral antigen [25].

In the case of rabies-virus-positive brain samples, coloured lines may be observed in both the 'C' (Control) and 'T' (test) zones; however, in the case of negative samples, only the 'C' zone displays colour development (**Figure 5**). Furthermore, this assay might be used to successfully identify rabies virus in cell culture [26].

#### **12.9 Other assays for antigen detection**

Other less common antigen detection techniques are as follows:

A quick sandwich ELISA is used to identify lyssaviruses belonging to all seven genotypes that circulate in Europe, Africa, Asia and Oceania [27]. Dot-blot immunoassay for brain tissues and enzyme immunoassay (EIA) for quick diagnosis in humans and animals [28].

Various PCR-based tests are now being developed for ante-mortem and postmortem rabies diagnosis. Because the nucleoprotein (N) gene is extremely conserved, most of these PCR variants amplify it. This method has shown to be quite efficient in detecting rabies ante-mortem.

#### **12.10 Reverse transcriptase PCR (RT-PCR)**

RT-PCR tests based on gels are also used to identify rabies virus RNA in clinical samples [29–32]. The amplicons produced in these tests, notably those targeting N, G and G-L intergenic regions, have been sequenced in order to characterise the virus and analyse its phylogeny [33]. However, these assays are vulnerable to cross-contamination, which is a major problem that prevents them from being used routinely for rabies diagnosis [27].

**Figure 5.** *Lateral flow test of rabies-positive brain sample suspensions (captured by authors).*

#### **12.11 Real-time PCR**

Real-time PCR is used to identify and quantify genome copies while reducing the probability of cross-contamination. The SYBR Green real-time PCR technique is applied for rabies ante-mortem diagnosis [34] as well as finding lyssaviruses [35]. TaqMan real-time PCR tests have been shown to have high specificity [27, 36]. This was shown to be 100 times more sensitive than typical nested RT-PCR [36].

#### **12.12 Demonstration of antibodies**

Although they have certain drawbacks, the rabies virus neutralisation test, notably FAVN or RFFIT, is the test of choice for determining neutralising antibodies [37]. Various varieties of ELISA (enzyme-linked immunosorbent assay) are also utilised as an alternative since they are safe, simple and quick. Furthermore, because these tests do not involve the handling of live virus, they do not require use of high-containment facilities. The ELISA findings are shown to correspond well with the RFFIT results. ELISA based on N and G protein Mab was developed to the specially trap the rabies antigen during ante-mortem diagnosis [38].

A second-generation ELISA kit, the Platelia Rabies II, was designed to detect antibodies against the glycoprotein in blood and CSF samples. This ELISA was tested and shown to correlate well with RFFIT, making it suitable for use in laboratories without cell culture facilities [39]. However, when compared with neutralisation tests, ELISA is less sensitive [40].

#### **13. Management of rabies**

#### **13.1 Management in human**

#### *13.1.1 Pre-exposure prophylaxis (PrEP)*

PrEP (vaccination) is the most efficient way of rabies control. It not only saves the budget of the management, but it assures the prevention of the disease. There are several protocols for the prophylaxis of the disease. There are two routes for the vaccination: intra-muscular (IM) and intra-dermal (ID). Intra-dermal vaccine saves the quantity of the vaccine by 80%. The detailed protocol is given below. PrEP is recommended to the people who are associated to specific group vulnerable to rabies such as veterinarians, para-vets, animal welfare activists or people residing in endemic area. The dosage for ID is 0.1 ml at two sides while the dose of IM vaccine is whole vial. The vaccine should not be given at gluteal muscle. The protocol suggests two shots of vaccine on 0 and 7 days.

#### *13.1.2 Post-exposure prophylaxis (PEP)*

PEP is suggested after the exposure of rabies. There are three categories of the exposure listed in **Table 1**. There are three dosage regimes given by different institutions, Institut Pasteur du Cambodge regimen, Essen regimen and Zagreb regimen.

The major between immunologically naïve and previously immunised person with the PEP is no requirement of RIG in previously immunised person. The maximum dose of RIG is 20 (hRIG) or 40 (eRIG). If RIG is not available, thorough, prompt wound washing, together with immediate administration of the first vaccine dose,


#### **Table 1.**

*Suggested PEP according to exposure.*

followed by a complete course of rabies vaccine, is highly effective in preventing rabies. Vaccines should never be withheld, regardless of the availability of RIG. Rabies virus is enveloped virus and so through washing of bite wound with soap solution under running tap water is advised. (Adopted from [41])

#### **13.2 Management in animals**

#### *13.2.1 Pre-exposure prophylaxis*

#### *13.2.1.1 Parenteral prophylaxis*

The rabies vaccine with the potency of RIVM >2 I.U. may be used for the vaccination. The vaccine is approved for the use for the prophylaxis of apparently healthy mammals. The vaccine may be given by the IM or SC route. Generally, a temporary palpable nodule at the site of the SC injection may be noticed, which will disappear by the time. Rarely anaphylactic reaction can be seen which can be managed by SC injection of adrenalin. It is always recommended to give the vaccine a bit earlier than the due date to ensure the protection. Many a times it is possible that the whole dose of vaccine may be failed to be administered to the

*Rabies: Incurable Biological Threat DOI: http://dx.doi.org/10.5772/intechopen.105079*

animals due to faulty administration. Vaccination can begin as early as 3 months of age in dogs, ferrets and livestock. Vaccines for cats can be administered as early as 2 months of age [42].

The schedule is given below in **Table 2**.

#### *13.2.1.2 Oral prophylaxis for dogs and wildlife*

The rabies vaccine bait RABORAL V-RG® contains an attenuated ('modifiedlive') recombinant vaccinia virus vector vaccine that expresses the rabies virus glycoprotein gene (V-RG). Since 1987, when the first licenced recombinant oral rabies vaccine (ORV) was released into the environment to immunise wildlife populations against rabies, over 250 million doses have been distributed globally with no reports of adverse responses in wildlife or domestic animals. V-RG is genetically stable, does not remain in the oral cavity for more than 48 hours after ingestion, is not shed into the environment by vaccinated animals and has been tested for thermostability in a variety of laboratory and field settings. V-RG has been tested in over 50 vertebrate species, including nonhuman primates, and no adverse effects have been reported regardless of method or dose. Immunogenicity and efficacy in a variety of target species have been established in the lab and in the field (including fox, raccoon, coyote, skunk, raccoon dog and jackal). The liquid vaccine is placed within edible baits (such as RABORAL V-RG, the vaccine-bait product) that are released into animal areas for target species to consume. The use of RABORAL V-RG in the field has helped to eradicate wildlife rabies in three European nations (Belgium, France and Luxembourg), as well as the dog/coyote rabies virus form in the United States (USA). With the final case reported in a cow in 2009, an oral rabies vaccination programme in west-central Texas has effectively removed the grey fox rabies virus strain from Texas. In the United States, a long-term ORV barrier effort using RABORAL V-RG is preventing significant geographic spread of the raccoon rabies virus strain. For more than a decade, RABORAL V-RG has been used in Israel to control wildlife rabies [44].

#### *13.2.2 Post-exposure prophylaxis*

PEP of the rabies should include five administrations of the vaccine on the days 0, 3, 7, 14, 28/90 days. If the animal is not immunised previously, eRIG is advised to be administered at the site of bite.


*\*Primary vaccination can be administered at an earlier age, but then a repeat vaccination must be given at the age of 3 or 6 months depending on the species.*

*\*\*Annual revaccination is recommended in endemic areas. Source: [43].*

**Table 2.** *Vaccination schedule for animals.*

#### **14. Control of rabies**

The disease is a classical example of neglected zoonosis. The disease can be well managed by the multi-disciplinary approach. Control of the rabies in the dogs is very important. World Health Organisation (WHO) has strong measures in place to prevent rabies in dogs. These guidelines include:


3.A mass immunisation programme with ongoing boosters

4.Stray dog control and euthanasia of unvaccinated dogs roaming freely

5.Dog registration programmes [45].

### **Author details**

Jitendrakumar Bhogilal Nayak\*, Jeetendrakumar Harnathbhai Chaudhary, Prakrutik Prafulchandra Bhavsar, Pranav Ashok Anjaria, Manojbhai N. Brahmbhatt and Urvish Pravinbhai Mistry

Department of Veterinary Public Health and Epidemiology, College of Veterinary Science and Animal Husbandry, Anand Kamdhenu University, Gandhinagar, Gujarat, India

\*Address all correspondence to: jbn\_anand@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 4**

## Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods

*Timothy J. Tse, Farley Chicilo, Jeffrey Popiel and Martin J.T. Reaney*

#### **Abstract**

Transmission of the severe acute respiratory syndrome coronavirus 2, referred to as COVID-19, has persisted beyond 2020 and led to a global pandemic with far reaching consequences. Many changes in public policy and health measures were developed and implemented with the intention of slowing the spread of the novel virus. Disruptions from the global pandemic created major supply chain consequences due to stockpiling of essential goods (alcohol-based hand sanitizers and surface disinfectants), impacts on trade routes, and limitations on modes of transportation due to border closures. Rapid increase in the use of hand sanitizers and surface disinfectants significantly affected the production capacity of high-quality ethanol (e.g., USP and FCC grade) resulting in regulatory changes in countries facing shortages. Prompt enactment of government policies allowed for use of alcohol with higher impurities to offset heightened demand and increase commercial availability. Changes in monitoring methods were also observed, where many agencies began to track viral shedding through municipal wastewater. In this chapter, we will discuss the impacts of COVID-19 on public policies and health measures, economics as it relates to supply chain disruptions, and the implementation of novel monitoring methods to survey the spread of COVID-19.

**Keywords:** COVID-19, public policy, monitoring methods, hand sanitizer, surface disinfectant, pandemic

#### **1. Introduction**

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; aka. COVID-19) has led to unprecedented global responses in the attempt to limit and slow propagation of the virus. These responses included the shutdown of major manufacturing plants [1], limitations on social gatherings, travel and transportation restrictions, enacting state of emergencies, and public health measures (e.g., social distancing, use of face coverings and hygienic practices, closures of non-essential

businesses and schools, and vaccine mandates) [2]. Even with the development and implementation of safe and effective vaccines, and continued efforts to prevent transmission among the public, COVID-19 has persisted in spreading globally, and new more virulent variants have evolved.

The enactment of public policy restrictions, including social distancing, travel restrictions, access to testing, and contact tracing initiatives decreased COVID-19 infection, morbidity, and mortality rates [3, 4]. Such policies and tools were especially effective in slowing transmission and reducing the strain on healthcare facilities that have been stretched beyond their typical operating capacity [5]. Many governments implemented a variety of technologies, incentives, and practices to track infection, promote vaccination, and enforce restrictions [6]. Biomolecular approaches (e.g., nucleic acid amplification tests) were also implemented to help provide quantitative numbers to investigate spread and infection rates. Altogether, these technologies were implemented to slow the spread of infection and provide strategic advice for informing public health policies.

Unfortunately, economic recovery from the COVID-19 pandemic has been slow, primarily due to supply chain disruptions that have led to low inventories, employment layoffs, and reductions in industrial production and services [1]. Furthermore, as restrictions began to ease, formerly constrained demand for consumer goods surged beyond manufacturing capacity. With diminished inventory and a weakened shipping industry, recovery was slow, and meeting consumer demand became challenging [7]. The demand for antiseptics and medical supplies increased significantly while supply chain constraints intensified. Faced with shortages governments and municipalities implemented impromptu solutions for increasing regional production of much needed hand sanitizers [8]. One effective response was the introduction of legislation that allowed the use of lower-grades of ethanol (often technical-grade ethanol) in the formulation of disinfectant and sanitizing products [8–10].

As the COVID-19 pandemic waned and vaccination limited the severity of viral infection, many governments removed restrictions and opted for more permissive policies that allowed citizens to live with a higher risk of contracting the virus. Health policies designed to reduce transmission among the public were mitigated or ceased altogether. With the implementation of gradual re-opening measures in many countries, policies defining travel restrictions, social distancing, facial coverings, etc. were removed through the 2nd, 3rd, and 4th quarters of 2021, and first quarter of 2022 [2]. Direct monitoring methods for COVID-19 (e.g., contact tracing and biomolecular tests) were also removed during the relaxation of restrictions. For example, Germany ceased free covid testing in August of 2021 with the acknowledgement that testing was both expensive and specifically benefitted the unvaccinated [11]. Currently, many monitoring methods have now targeted wastewater-based epidemiology (WBE) studies to survey the spread of infection in different communities [12–18]. Although these methods can provide early detection [19–22], interpretation of data can be limited in scope when compared with testing of populations, as is discussed below.

Finally, with continued policy changes, the economic recovery due to the COVID-19 pandemic has been slow. GDP dropped sharply across the globe at the start of the pandemic but rebounded somewhat shortly after. Global GDP at the end of 2020 was only a few percentage points less year-over-year than at the end of 2021 [23]. Worldwide merchandise trade decreased significantly, while trade of medical goods increased. Nearly all industries managed to recover by the end of 2021, with transportation & warehousing, tourism, and live entertainment-based industries

*Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods DOI: http://dx.doi.org/10.5772/intechopen.105805*

having yet to return to pre-pandemic levels [24, 25]. Late pandemic supply chain disruptions have shown that pre-pandemic conditions have not returned [26, 27]. With continued risk of future supply-chain catastrophes, some in business are moving to models that develop localized value chains. The purpose of this book chapter is to discuss and review the impacts of COVID-19 on public policy, health measures, economic disruptions, and the importance of surveillance methods for the early detection of infections.

#### **2. Economic disruptions and supply chain shortages, including ethanol-based products**

The economic contraction that occurred during the COVID-19 pandemic affected global markets in 2020, 2021, and into 2022. Prominent among economic challenges were supply chain disruptions, which broadly impacted the delivery of goods and services. For example, manufacturers, builders, and retailers had reduced or delayed access to input materials, building materials, and stock items [9, 26]. Sales sharply decreased as pandemic-related restrictions were introduced in March 2020 which led to an excess of inventory. In some cases, this inventory was written off or liquidated. In later stages of the pandemic in 2021–2022, economic recovery placed additional stress on markets. Manufacturing industries halted or reduced output, canceled orders, and reduced reorders which led to manufacturing that was retooled or refocused to provide goods that were in high demand [26].

Among supply shortages, much of the world's consumers and businesses had challenges acquiring antiseptics such as rubbing alcohol, hand sanitizer, antiseptic wipes, and surface disinfectants at the beginning of the pandemic, which was exacerbated by consumer hoarding [9]. Due to the circumstances of limited world-wide supply of United States Pharmacopeia (USP) or Food-Chemicals Codex (FCC) grade ethanol, Canada modified acceptance criteria to include ethanol that was produced by alternative methods with specific label and usage requirements [28]. Health Canada expedited processing of Site Licenses and Product Licenses for hand sanitizer manufacturing and sales and waived the need for a review of good manufacturing practices (GMP) for new manufacturers, requiring only a signed declaration instead of the usual full GMP documentation [29]. Hand sanitizer supply expanded quickly with the new regulations, and shortages were rapidly addressed. Unfortunately, many producers failed to meet quality standards for ethanol as defined by new regulations [9]. In addition to supporting production of hand sanitizer, Health Canada expedited applications for Drug Identification Numbers (DIN) allowing the sale of surface disinfectants [30].

Worldwide lockdowns contributed to production and acquisition challenges by exacerbating industry down-time and supply-chain shortages, leading to cascading delays [26]. For many businesses the early response to Covid was a strategic long-term decrease in production achieved by layoffs, and a reduction of parts and other inputs (e.g., semiconductors for automakers) [26]. The shipping industry followed this pattern by reducing schedules.

After lockdown restrictions began to ease there was an unanticipated surge of product orders, combined with reduced capacity, making responding to new demand difficult [1]. Many laid off workers decided not to return to their positions through resignation, and retirement. These social factors lead to a labour shortage [31, 32]. In Canada the unemployment rate increased to 9.5%. This represents the loss of

almost one million jobs in 2021 [23]. In the United States of America (U.S.A.) record numbers of resignations occurred in 2021, with 4.4 million workers resigning [33]. Employee resignations occurred for multiple reasons: while some workers planned to avoid potential workplace COVID-19 infection (Delta and Omicron variants), others were faced with lifestyle choices related to the epidemic and other pandemicrelated stresses, such as reduced availability of childcare and elder care services [33]. Indeed, a large cohort of "baby boomers" simply chose to retire. Continuing resignations required extra resources used in hiring, onboarding and offboarding, thereby decreasing the efficiency of businesses and further contributing to industrial disruptions [33]. The job market became increasingly competitive with a new human resource focus on retention strategies [33].

Any business with a complex supply chain was susceptible to production backlogs, which resulted in backorders of inputs and delayed product shipments [23]. Freight costs more than doubled by the end of 2020, with smaller businesses being impacted more significantly, receiving lower priorities due to lower volume orders and higher shipping rates than larger companies with long-term contracts [34]. Tourism-based industries, such as hotels, restaurants, the arts and entertainment, recreation, and travel, diminished quickly when stay-at-home measures were put in place to limit COVID-19 transmission [23]. Once public health measures were lifted, there was a record number of job openings in 2021 due to the quick rise in job availability from impacted industries returning to regular business operations [23]. Through 2021, tourism-based industries exhibited the slowest recovery since the beginning of the pandemic, with transportation and warehousing as the next slowest, showing 16% below pre-pandemic GDP levels in Canada from February 2020 to January 2022, whereas most other industries achieved full GDP recovery [24].

To add to the economic challenges caused by the pandemic, the state of Texas had temperatures dip below freezing with snowfall in late February 2021 [35]. Chemical and petrochemical supply chains were heavily affected, as Texas is the nation's leading producer, and this extraordinary weather system caused major disruptions across the state [35]. Manufacturing facilities in these industries took months to recover [35] and as a result, industries involving plastics, packaging, fertilizers, pesticides, synthetic fibers, cleaners, lubricants, paint, and many more were affected by reduced supply in a market that was already suffering from supply backlogs [35].

In the U.S.A., high demand for import shipments quickly created a shortage of drayage vehicles and drivers while freight value moved by all transport vehicles fell 9.1 percent year over year from 2019 to 2020 [26, 34]. Although this year-over-year decrease is significant, it does not show the extreme swing of GDP in the first three quarters of 2020 as compared between **Figures 1** and **2**. Exports from Canada to the U.S.A. decreased by 70 billion dollars (16%) and imports by 43 billion dollars (11%) [23]. By the end of 2020 the U.S.A. and Canadian economies saw an overall contraction, despite significant recovery in the third quarter, owing to significantly decreased trade between U.S.A. and Canada [23, 25].

Worldwide merchandise trade decreased by 7% in 2020 [38], while the trade of medical goods increased, as demand for PPE (personal protective equipment) and other medical items (ventilators, AEDs, various consumables, drugs) escalated [39]. The first lockdown (and economic contraction) started in China, with lockdowns occurring months before those enacted elsewhere in the world [2]. This afforded China the ability to experience an economic expansion in the 2nd quarter of 2020, as seen in **Figure 2**.

*Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods DOI: http://dx.doi.org/10.5772/intechopen.105805*

**Figure 1.** *GDP growth expressed in % change year-over-year. Reconstructed from [36].*

**Figure 2.**

*GDP growth expressed in % change quarter-over-quarter. Reconstructed from [37].*

Despite the short-term risks of using a lean, or 'just-in-time' approach to doing business, economists see value in maintaining its use [40]. It is possible that the economy may have maintained stability for a longer period if it had used more supply reserves, but the supply required to outlast the continued demand would have been insurmountable in many cases, as any physical product requires a reliable influx of materials to match output; a larger stock merely acts as a longer-lasting buffer to ease supply shock.

Economists have been analyzing and formulating potential solutions to avoid economic contractions like those experienced in 2020 [41]. It has been speculated that putting less reliance on international supply chains and focusing on more local value chains might increase economic loss and create more vulnerabilities in domestic economies [39]. Each country has their own specialized industries and products and continued association to these markets allows for optimal economic gains. In contrast, this interconnectivity also increases the potential negative impacts resulting from global supply chain issues, suggesting a need for more economic self-sufficiency [27]. Relying on a globalized economy may show some benefit, but only in the long-term, and such reliance leaves industries in a vulnerable position in the case of worldwide or specific supplier-affecting disruptions, especially for businesses with complex supply chains.

### **3. Public healthcare policies**

The onset of the COVID-19 pandemic in early 2020 forced governments across the globe to act quickly to reshape public health policy. A major effort to alleviate the stress on health care was described as a "flatten the curve" strategy, but ultimately this approach recognized that the spread of the virus could be slowed but not stopped [42]. Indeed, the spread of the virus continued throughout 2021, and into 2022. In response, governments, health care agencies, and private industries have continued to enact public health measures to mitigate the spread of the virus and its effects. Public health measures have included mandating behavioral practices (social distancing, limited gathering sizes, etc.) [43], use of hygienic products (hand sanitizers, masking) [9], travel restrictions [44], and modifications to the delivery of health care services (online doctors' visits, postponement of elective surgery) [45]. Rates of COVID-associated morbidity and mortality are proportional to the amount of circulating COVID-19 virus within a population, and as of May 2022, total COVID-19 associated deaths are estimated to be more than 6.27 million [46]. This staggering loss of human life highlights the necessity of effective public health policy to minimize infection. Multiple peaks of global COVID-19 deaths were observed from 2022 to 2022. Such waves were often preceded by lower case numbers which, in turn, can cause complacency among the public. However, the emergence of increasingly

#### **Figure 3.**

*Global figures of new deaths from February 1, 2020, to may 15, 2022. New COVID-19 deaths reported show patterns of repeated waves of outbreaks across the world as the pandemic progressed. Reconstructed from [46].*

#### *Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods DOI: http://dx.doi.org/10.5772/intechopen.105805*

contagious strains of COVID-19, such as the Delta and Omicron variants, make the pandemic likely to continue into the foreseeable future (**Figure 3**).

The COVID-19 pandemic has had devastating and lasting effects on the health care system. The resulting increase in hospitalization rates and diminished resources available to treat patients has added significant burden to an already strained system. Policies designed to increase available ventilators [47], intensive care unit (ICU) beds [48], access to COVID-19 testing kits, and vaccination have been important tools that governments have enacted to fight the ongoing pandemic and minimize loss of life. Unfortunately, policies cannot address the immediate need for additional health care workers as it takes many years of training and specialization to care for patients, especially those in critical care settings [49].

To combat avoidable and unnecessary hospitalizations, well-enforced behavioral policies, such as social distancing and face masks, are often quickly enacted, as they do not overly disrupt economic and social systems and have demonstrated effectiveness in reducing transmission [50]. Reducing viral transmission via face-to-face interactions leads to an overall decrease in hospitalization rates. Most critically, this reduction extends to those who are at the highest risk for COVID-associated morbidity and mortality, such as individuals with underlying health care issues and patients over the age of 65 [51]. Public policy involving social distancing has taken various forms, ranging from severe restrictions on personal movement, to limited or no restrictions at all. Importantly, travel restrictions and encouragement of virtual or teleworking, helps limit travel and public contact, something that many in the workforce were able to do effectively during the COVID-19 pandemic [51–53]. Teleworking practices have the added benefit of reducing non-essential travel both internationally and domestically, which delays transmission of the virus. Indeed, there is strong evidence that restrictions on international travel from countries with high infection rates helps in slowing the spread of COVID-19 [44]. To eliminate avoidable public transmission, China imposed drastic lockdowns as outbreaks emerged throughout the country, including restricting travel from other nations, and between regions [54]. Chinese restrictions extended to include the separation of family members in the case of diagnosed infections. India suffered devastating infection rates during April and May of 2021 and imposed district specific restrictions during the second wave of infections to help mitigate the spread through densely populated regions [55]. In the United States and Canada, restrictions and guidelines varied significantly from region to region, owing to local policies, population density, and infection rates. Evidence in the United States suggests that stricter enforcement of public policy measures is likely linked to lower infection rates [56], while sudden, removal of restrictions has led to additional outbreaks [55, 57, 58]. Many governments chose to enact "phases" of restrictions, which lead to gradual policy changes intended to ease the stress on both public and private health care systems by controlling the total number of cases.

Hygienic methods such as hand washing, use of sanitizers, and implementation of personal protective equipment (PPE) have also been shown to be effective at reducing transmission of the COVID-19 virus. Although hand washing is a highly effective practice, the use of hand sanitizers was found to be substantially more convenient than hand washing. The resulting high demand for alcohol-based sanitizers, as well as other essential supplies, led to global shortages [9, 59]. The consequences of these shortages are still being studied, but food and supply scarcities are likely to cause an increase in prices, which disproportionately affect those with lower socioeconomic status [60]. To try and combat shortages, governments have encouraged sourcing from local suppliers while trying to minimize disruptions to essential imports.

Even so, supply chain issues can be particularly challenging in rural populations where food security is already an issue [61].

Large, population-scale testing was implemented as a major intervention strategy to manage COVID-19 infections across the world as community infections increased. Improved access to testing allows for earlier identification of infections, encouraging individuals to self-quarantine and slow the spread of COVID-19. However, difficulties in acquiring testing methods, and significant delays in obtaining results, were frequent criticisms of large-scale testing efforts [62]. If wait times for testing are exceedingly long, individuals are less likely to test. Likewise, the longer the wait between preforming a test and obtaining the results, the less likely an individual will isolate, particularly if they are asymptomatic [63]. Mass testing can be costly, and so testing of health-care workers, symptomatic individuals, and those who are at risk of serious health complications are prioritized. Further exacerbating testing issues was a shortage of reagents, which caused supply chain issues and contributed to the wide disparities of testing rates between countries [64, 65]. A proposed solution to reduce the use of testing supplies is the pooling of samples, allowing for multiple individuals to be tested simultaneously by combining samples and testing with a single reaction. If the result from the pooled samples is negative, then all subsequent individuals are considered negative. However, if a positive result is observed, then individuals are tested separately, reducing the strain on the testing process. Remarkably, Chinese authorities in the city of Qingdao were able to test over seven million people over the course of three days using the method of pooling samples [66]. While the pooling method has demonstrated efficiency, there are limitations to the technique, including the need for relatively low positivity rates, longer reporting delays [63], and a reduction in test sensitivity [67]. Another frequently used method to determine community positivity rates is the testing of wastewater, which can predict general infection rates and is discussed in greater detail below.

Restrictions stemming from public policies can have far reaching impacts, and so constraints and policy changes must be carefully considered to prevent unnecessary disruptions to the economy, crucial supply chains, and earnings by those who are disproportionately affected by the pandemic [68]. Throughout the COVID-19 pandemic, health care experts have advocated for the enactment and enforcement of public health policies, imposing restrictions on social distancing, face coverings in public settings (especially where social distancing may not be possible), respiratory hygiene, and, where necessary, lockdowns [69]. There is evidence that demographic factors such as race, gender, and socioeconomic conditions play a role in transmission, contraction, and overall mortality rates and so not all measures are equally effective [51, 70, 71]. Critically, stay at home orders have adverse effects on supply chain issues, employment, and mental health [72, 73]. Research has shown that the practice of social distancing has caused negative impacts on isolation [74], family stresses [75], domestic violence [76], consumption of alcohol [77], and mental health [78], and so preventative and behavioral policies should be considered before major shutdowns of schools, businesses, and strict stay at home orders are enforced. Many factors play a role in COVID-19 related infections, and government policies should be careful to consider the effectiveness, financial costs, and negative outcomes associated with the policy enforcement. The development and distribution of safe and effective vaccines has helped to reduce the number of deaths and the pressures on hospital systems [79], however higher vaccination rates are concentrated in higher income countries, and vaccination hesitancy, along with the emergence of new more virulent COVID-19 variants, can slow development of broad spread immunity [80]. The consequence of

*Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods DOI: http://dx.doi.org/10.5772/intechopen.105805*

the continued spread of the virus indicates that the COVID-19 pandemic is likely far from over, and public policies will serve as an effective tool in reducing transmission in the future.

#### **4. Infection tracking and surveillance**

A variety of technologies have emerged to alleviate the temporal and social restrictions brought on by the COVID-19 pandemic. These include the use of artificial intelligence (medical tracking), social media platforms (creating awareness of infections and providing real-time updates), virtual and augmented reality communications, blockchain (integration of point-of-care diagnostics for self-testing), additive manufacturing (production of personal protective equipment), 5G cellular technology and smart applications (remote monitoring of COVID-19), geographical information systems (spatial tracking of COVID-19), and autonomous robots (use of drones for disinfection) [6]. These valuable technologies provided critical information regarding COVID-19 and offered alternative communication means for health-related and employment-related meetings.

To manage the spread of COVID-19, other unprecedented techniques were adopted including contact tracing and the use of digital technologies [3, 4] as well as initiatives to provide early detection, monitoring efforts, and surveillance technologies. These technologies were introduced to slow and contain the spread of COVID-19 and provide advisory bodies important details in making informed public health strategies to combat the virus.

Contact tracing involves the identification of individuals who have come into close contact with an infected person, testing them, and, in case of an infection, tracing their own contacts to reduce the spread of an infection throughout a population [81]. Unfortunately, traditional manual contact tracing is labor-intensive, time-consuming, and may not be adequate in monitoring for COVID-19 in real time, especially in the instance of high infection rates [82]. Consequently, the development of digital tracking apps, including contact tracing apps (CTAs), have garnered attention in early detection by combining proximity tracing and contact tracing [3]. These novels CTAs, such as Canada's COVID Alert app [83], rely on self-reporting from infected individuals, as well as the implementation of Bluetooth connectivity to measure and record the spatial proximity between users, and alert nearby persons if they are within proximity to an infected individual [3]. Unfortunately, these applications are technologically limited as they can raise privacy concerns and older smartphones may not be compatible. Digital applications such as CTAs can also exacerbate inequities, such as age and income discrepancies in accessing smartphones, which can ultimately lead to a decline in CTAs effectiveness in preventing the spread of COVID-19 [3]. Another unforeseen occurrence resulting from the use of CTAs comes from a significant increase in the volume of people who receive notifications after being in close proximity of a COVID-19 positive individual. A dramatic surge of notifications was observed by contact tracing apps in the UK in July 2021, where the total number of individuals notified increased by nearly 50% in a single week. This surge in CTA alerts resulted in what was coined the "pingdemic" and required those affected to self-isolate for 10 days [84]. This caused significant consequences for many industries, including manufacturing and hospitality, as hundreds of thousands of individuals were required to stay home, leading to the shutdown of several production lines [84].

With the gradual lifting of social and travel restrictions, and the reopening of borders, access to PCR testing for COVID-19 has subsided and measuring an accurate clinical picture of the spread of the virus has become increasingly more difficult [85]. This has, however, paved the way for wastewater testing to play an increasingly critical role in monitoring for COVID-19 transmission within communities [85]. Currently, there are 5 genes that have routinely been used to screen for the presence of COVID-19. These include the ORF1ab, E-, N-, S-, and the RNA dependent RNA polymerase (RdRp) genes [86–88], encoding for numerous structural and nonstructural proteins. Specifically, the RdRp gene is essential for the replication and transcription of the virus, and is encoded by the open reading frame, ORF1ab gene. In addition, ORF1ab is the largest gene that encodes for several nonstructural proteins [89]. Meanwhile, The E-, N-, and S- genes encode for structural proteins including, envelope proteins, nucleocapsid proteins, and spike proteins, respectively [90–92].

Recently, WBE studies have been employed to monitor the spread of COVID-19. Wastewater infrastructure is an important component of early warning systems to detect disease, due to increased water usage for hygienic purposes (hand washing, disinfection, cleaning, etc.) [19]. As COVID-19 and viral RNA are shed in bodily excreta (saliva, feces, sputum) of infected individuals [93], detection in wastewater [94] can provide early warnings and infer trends for authorities to make informed decisions on public policies and restrictions [19–22].

WBE studies [16, 17] have been used in several countries including Italy, Netherlands, Portugal, Spain, Australia, China, France, Israel, United States, Turkey, and Canada [12–15]. These studies typically involve the extraction of viral RNA material and amplifying the nucleic acid to detect the presence of COVID-19 (i.e., Nucleic acid amplification tests; NAATs, quantitative polymerase chain reaction; qPCR, reverse transcriptase PCR; RT-PCR, etc.) [95], and are important in evaluating the spread, genetic diversity, and geographic distribution of the virus [94, 96]. WBE modeling can be used to provide an estimate on the number of infected individuals in a population based on: (1) concentration of COVID-19 RNA at the inlet of the wastewater treatment plant, (2) volumetric flow rate of the wastewater treatment plant, (3) fecal load, (4) RNA shedding in the stool, and (5) RNA losses in the sewer pipe [97]. For the sensitive detection of viruses in wastewater, samples are often concentrated before quantification [98, 99]. For the surveillance of COVID-19, wastewater samples are often concentrated using centrifugation [100], filtration [101–105], polyethylene glycol precipitation [103, 106, 107], or aluminum flocculation [108, 109]. Unfortunately, RNA extraction efficiency can vary due to co-concentration of organic compounds (e.g., humic substances) [12]. Recent studies of COVID-19 in wastewater have also observed viral recoveries between 3 and 50% [12], although calibration against RNA losses in the wastewater can provide improved accuracy [97]. Nonetheless, these techniques have demonstrated reliability in identifying the true magnitude of infection within a population [97] and have been widely used to monitor for early detection of novel viral pathogens [110–113], including enterovirus, adenoviruses, hepatitis viruses, and more recently COVID-19. As WBE assesses changes in SAR-CoV-2 titres, these studies collectively include asymptomatic individuals, as well as those exhibiting very mild symptoms. Unfortunately, translation of COVID-19 titres in wastewater to actual individual numbers is extremely difficult. Therefore, these analyses are typically used to infer the spread of COVID-19 within a community and monitor for the emergence of related variants.

While PCR tests performed on wastewater samples are identical to those performed at COVID-19 clinics, the N- and E-genes are more commonly targeted as

#### *Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods DOI: http://dx.doi.org/10.5772/intechopen.105805*

they are more well-preserved in wastewater [85]. However, there are challenges with wastewater testing, including variability of the data produced by each sample which can produce a significant margin of error [85]. Furthermore, the operations and designs among different wastewater treatment facilities can result in varying dilutions of the tested samples, thus affecting signals of COVID-19 in the wastewater [114, 115]. For example, in some facilities, rainfall may combine with wastewater, resulting in the dilution of COVID-19. Additionally, residential, and industrial water uses can affect COVID-19 signals in municipal wastewater. Therefore, comparing COVID-19 levels between different communities, cities, health regions, etc. is very difficult and wastewater analyses for COVID-19 should be primarily used to establish trends in COVID-19 prevalence, rather than determining an absolute concentration or comparing to active cases in the community; active cases may not include asymptomatic individuals, whereas wastewater analyses will.

Altogether, wastewater surveillance of COVID-19 provides a powerful tool in evaluating incidences of disease at the community level. However, WBE studies also need to be integrated into other public health studies, such as randomized testing of individuals. Current data on COVID-19 and other viruses suggest that WBE epidemiology is a viable option in assessing and mitigating viral outbreaks [12–17]. The widely used q(RT)-PCR approach enables rapid and strain level RNA/DNA quantification, however, the primers and probes should be chosen carefully, depending on sequence preservation [90–92]. Finally, targeted, and untargeted sequencing of viruses in wastewater has the potential to track the spread of specific sequence variants and identify mutations that could affect detection in clinical settings [12] and provide early detection for emergence of novel strains.

#### **5. Conclusion**

The COVID-19 virus has continued to adapt and persist beyond 2020 and will likely continue in some form for years to come. Learning from the continued spread of this deadly virus is critical, and responses by governments to the global spread of COVID-19 has continuously adapted to new challenges and developing information. The consequences of the pandemic cannot be underestimated and has caused serious impacts on the global economy and healthcare capacity, as well as the physical and mental health of the public. COVID-19 associated morbidity and mortalities continue to climb across the world, even with the distribution of effective vaccines. Indeed, as travel restrictions are slowly lifted across the globe, the implementation of public health policies and expanding access to tracking the spread of the virus are powerful tools for minimizing unnecessary hospitalizations.

The world economy has suffered because of the pandemic, but only in part, as many countries enacted polices to prevent total recession, and some economies have even exhibited financial benefit. Specialized industries have yet to recover fully in 2022, and some businesses have been disproportionately impacted, owing to the challenges of public restrictions throughout 2020 and 2021. As major public restrictions begin to relax, many unrecovered industries can be expected to see continued economic improvements.

Having established efficient ways of tracking the COVID-19 virus through technological and biomolecular methods (e.g., nucleic acid amplification tests and WBE studies), governments around the world will be better prepared in surveying for future diseases of concern. Furthermore, with economists working on restructuring modern practices in supply-chain management, the world economies will be better prepared in the coming years to avoid similar challenges that are still prevalent two years into the pandemic.

### **Acknowledgements**

This work was supported by the Saskatchewan Agricultural Development Fund (20190155, 20190154, 20180281, 20180248, 20180255, 20170133); National Sciences and Engineering Research Council of Canada Discovery Grant (RGPIN-2018-06631); and Mitacs (IT19122, IT16156).

### **Conflict of interest**

Dr. Martin J. T. Reaney is the founder of, and has an equity interest in, Prairie Tide Diversified Inc. (PTD, Saskatoon, SK, Canada: previous company name is Prairie Tide Chemicals Inc.).

### **Author details**

Timothy J. Tse\*, Farley Chicilo\*, Jeffrey Popiel\* and Martin J.T. Reaney\* University of Saskatchewan, Saskatoon, Canada

\*Address all correspondence to: timothy.tse@usask.ca; fhc246@mail.usask.ca; jeffrey.popiel@usask.ca and martin.reaney@usask.ca

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Implications of COVID-19 on Public Policy, Supply Chain Disruptions, and Monitoring Methods DOI: http://dx.doi.org/10.5772/intechopen.105805*

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#### **Chapter 5**

## Zoonotic Parasites and Vector-Borne Parasitoses

*Jasmin Omeragic, Sabina Seric-Haracic and Naida Kapo*

#### **Abstract**

Zoonotic parasites and vector-borne zoonotic parasitoses of humans, especially when affecting immunocompromised persons mobilize researchers' interest and increase parasitological, environmental, and interdisciplinary investigations worldwide. Climate, environmental and anthropomorphic influences had affected the distribution, occurrence, and adaptability of parasites in humans and animals, the level of environmental contamination with parasites and their developing forms, and the surge of vector competency. Knowledge of parasite biology and evolution shows that hybridization phenomena and adaptations may cause genetic diversity, affecting parasite virulence, antiparasitic drug resistance, acclimatization to new host species, and environmental conditions previously not recorded while leading to the emergence of new diseases and changing parasitism epidemiology. Many parasitic infections are emerging or re-emerging and are neglected with deliberating consequences for public and animal health as well as for food safety and security, especially in sub capacitated developing countries. Decrease of exposure of both animals and humans and negative consequences of zoonotic parasitoses requires raising awareness of researchers, policymakers, and the wider public. Modern diagnostic methods, surveillance, monitoring of parasitoses, and early detection systems followed by tailored containment and control actions provide grounds for sane assessments and investigation toward the cost-effective and efficient prevention programs for both human and animal populations.

**Keywords:** parasitic zoonoses, vector-borne parasitoses, prevention, control

#### **1. Introduction**

Parasitism is defined as when one organism (parasite) lives on or within another (host) in close biological and ecological dependence, lasting for a certain period of the parasite life cycle. Zoonotic parasites represent particular parasites to whom mainly animals are hosts, but can as well infect and cause disease in humans. To maintain a parasitic relationship with a host, parasites adapted in different ways as part of their evolutionary development parallel to the phylogenetic development of their hosts. Parasites are recognized for many species of hosts, including plants, vertebrates, and invertebrates, with currently rising concerns of hybridization phenomena as a threat to public health, still not fully understood. The risk posed by hybridization and introgression is recognized based on the biology and evolution of parasites,

#### *Zoonosis of Public Health Interest*

where resulting adaptations may bring significant genetic diversity, affecting parasite virulence, antiparasitic drug resistance, acclimatization to new host species, and environmental conditions previously not recorded while leading to the emergence of new diseases and changing of parasitism epidemiology. Also, research of parasitoses, particularly zoonotic and vector-borne, gains attention in light of enhanced emergence and re-emergence of pathogens affecting humans and animals where many represent a serious threat to the host's health and wellbeing [1, 2].

As shown in **Figure 1** this is primarily caused by anthropogenic influences and continuous modifications of the environment (climate changes, deforestation, disturbance of ecosystems, etc.), practices of food production and consumption (intensive vs. traditional agriculture, global animal movement, and trade), socio-demographic changes and globalization (population growth, urbanization, international trade, tourism, and transportation). Accordingly, our research aimed to provide an overview of the current trends regarding globally most important zoonotic parasites, diseases they cause, and associated influence factors.

**Figure 1.**

*Published research on mammalian zoonoses; color-coded based on geographic region (a), proportional frequency of papers dealing with different hosts (b), different anthropogenic influences (c), and different pathogens (d) [3].*

#### *Zoonotic Parasites and Vector-Borne Parasitoses DOI: http://dx.doi.org/10.5772/intechopen.105120*

Globalization and global warming in the twenty-first-century increase probability of parasitic infections in humans and animals and enable the introduction of most zoonotic parasites in new biotopes thus increasing the risk of epidemics occurrence in different areas [4]. Attempts to control parasitoses by mass treatment or vaccination are changing the environments in which parasites and other pathogens evolve, adapt, or extinct. Advances in diagnostics, especially molecular methods enable better recognition and characterization of pathogens hence improving outbreak detection and predictions. Continuous monitoring of parasites, vectors, hosts, and natural habitats in endemic areas, as well as early recognition systems, provide grounds for sound and timely epidemiological assessment and investigation leading to cost-effective and efficient prevention programs for parasitoses in both human and animal populations.

#### **2. Methodology**

Research inputs were identified through bibliographic database search using keywords: "zoonoses", "zoonotic pathogens", "zoonotic parasitoses", and "zoonotic parasites". In the first run, we excluded case/case series reports, clinical trials (assessment of treatment), and test validation (assessment of diagnostics), as well as a publication based on narrow geographical area, specific pathogen, disease, or hosts. Inclusion criteria for publications were prioritized based on the type of publication (first considered were review papers and global reports) and the topic/subject of a publication (publications reporting and exploring trends, global influences, and epidemiology). More recent publications covering wider geographical areas and multidisciplinary approaches or by author's affiliations were further considered. The selected literature review was oriented toward compiling and summarizing data on causative agents, distribution, life cycle, hosts, pathogenesis, symptoms, diagnostics, and therapy/treatment.

#### **3. Zoonotic parasitoses in humans and animals**

Numerous parasites found in animals, which represent final or intermediate hosts or vectors, are zoonotic or potentially zoonotic thus representing health risks for humans. In addition to direct and vector-borne transmission, an important source of human infections is the contaminated environment (i.e., geo-parasites, waterborne parasitoses), while some zoonotic parasites are foodborne. The majority of the common parasitic diseases of animals caused by helminths, trematodes, cestodes, pentastomids, and protozoa are zoonotic or have zoonotic potential. *Toxoplasma gondii* is the most widespread protozoan parasite worldwide. Estimates are that approximately one-third of the world's population is affected [5]. In developed countries, parasitic water-borne protozoans such as Cryptosporidium and Giardia outbreaks are increasingly reported [6]. In addition to protozoan parasites, the FAO identified *Taenia solium*, *Echinococcus granulosus*, *Echinococcus multilocularis*, Trichinella, Opisthorchiidae, and Ascaris spp. as the main foodborne parasites [7]. Data show that 70% of the helminths population is hosted by 15% of the host population, and these individuals are a prime source of environmental contamination [8]. The tapeworm *T. solium* is a cosmopolitan parasite with global distribution, with most human cases

found in Latin America, Asia, and Africa alongside emergence in recent years in the USA and Europe [9]. In addition to widespread *E. granulosus*, recently *E. multilocularis* has become very important because of its expansion from endemic areas to nonendemic areas in North America, Europe, and Japan, apparently by a displacement of fox populations [10]. Regarding Trichinella spp., during the period 1986–2010, 65,818 new cases were registered in 41 countries. Of these, 87% occurred in Europe associated with boar consumption [10]. Characteristics of selected, most important zoonotic parasitoses are shown in **Table 1**.




#### **Table 1.**

*Zoonotic parasitoses of humans including disease, causative agent, intermediate/definitive host(s), transmission, and distribution.*

#### *Zoonosis of Public Health Interest*

Fascioliasis is caused by parasites of the genus *Fasciola*. In animals, the disease leads to significant economic losses, especially in sheep and cattle farming. Until 1990 it was considered a secondary important disease, however, in the last three decades is on the list of Neglected tropical diseases (NTDs) due to increased incidence of human infections [11]. Adults of *F. hepatica* and *F. gigantica* are found in the liver and biliary system of ruminants, equids, and other herbivores, while humans are accidental hosts for both species. *Fasciola* development starts with eggs excreted in the faces of infected animals that come in contact with fresh water. Miracidia developed from eggs penetrating intermediate host; freshwater snail were through stages of sporocysts, cercaria exit snails and encysts on water plants developing into infectious metacercaria. Ingested by the final host they reach adult form and penetrate through the intestinal wall in the abdomen where they attach to the liver. Estimates are that worldwide between 2.4 and 17 million humans are infected [12]. In humans, an acute form of the disease is manifested by symptoms when parasites migrate through the abdominal cavity toward the liver. Symptoms of the acute and chronic phases of the disease include fever, weakness, abdominal pain, and hepatomegaly. Diagnosis is by direct parasitological or indirect serological tests (i.e., ELISA), magnetic resonance, ultrasound, and computerized tomography. Most people are treated successfully with triclabendazole, even though increased resistance of liver flukes to triclabendazole represents a threat to successful therapy and disease control in endemic areas.

Schistosomiasis is NTD, caused by a fluke of the genus *Schistosoma*. At least five species can infect humans out of which the most important are *S. mansoni*, *S. haematobium,* and *S. japonicum*. Estimates are that currently over 290.8 million people are infected by these parasites, while 779 million are potentially exposed. The disease has a high case fatality rate with 280.000 fatal outcomes and 3.3 million cases with permanently affected health as a consequence of the disease. The largest number of cases is found in areas of sub-Saharan Africa, the Middle East, India, China, Brazil, the Philippines, and Venezuela. In 2013, the disease is confirmed in Corsica. The occurrence and transmission of schistosomiasis are usually related to poor living and sanitary conditions [13]. The life cycle of the parasite starts with excreting eggs found in faces and urine into water. Asexual reproduction of shistoma evolves in snails until the stage of the cercaria, which through water penetrate through the skin into the venous system of the hosts, and parasite in different tissues depending on the species. The S*. hematobium* is found in the bladder and urinary system, *S. japonicum* in the small intestines, and *S. mansoni* parasites in both small and large intestines. Acute schistosomiasis is followed by fever, dermatitis, headache, myalgia, and respiratory symptoms. Infections by the *S. hematobium* are manifested by dysuria and hematuria due to injuries to reproductive organs alongside increased inclination of hosts to other infections. Infections by the *S. japonicum* and *S. mansoni* show symptoms of hematochezia, diarrhea, and obstipation, with ulceration, fibrosis, and hyperplasia of affected tissues in the chronic form of the disease [13]. If the parasite comes to the central nervous system, neuroshistomiasis as the most severe form of the disease develops with granulomatosis lesions of the brain leading to epileptic caesuras, encephalopathies, damaged sight, and ataxia. Diagnosis of schistosomiasis is by confirmation of eggs in feces and urine, by tests such as ELISA and PCR, together with diagnostic imaging techniques. Prevention of schistosomiasis includes snail population control and improvement of sanitary conditions. The vaccine is still unavailable, while praziquantel is used for treatment, efficient only for fully undeveloped forms of the parasite in migrating phase within the host organism.

#### *Zoonotic Parasites and Vector-Borne Parasitoses DOI: http://dx.doi.org/10.5772/intechopen.105120*

Opisthorchiasis and clonorchiasis are diseases caused by species of the family Opisthorchiidae, most commonly by *Opistorchis felineus*, *O. viverrini,* and *Clonorchis sinensis*. The life cycle includes intermediate hosts (freshwater snails and cyprinid fish), while final hosts are humans, cats, dogs, pigs, rats, birds, and fish. Eggs excreted by faces develop through stages of sporocyst, redia, and cercaria, which leave snails to infect fish and become metacercaria. The life cycle ends with the consummation of infected fish by final hosts (raw or undercooked), and metacercaria migrates into biliary ducts, sack, and liver [14]. Currently, 45 million people throughout Europe and Asia are infected with 700 million potentially exposed. Even though estimates vary, clonorchiasis prevalence continues to grow compared to figures in 1990ties, especially in China. Data show that the prevalence in dogs and cats is high (0.8–48.5% and up to 64.1%, respectively). Mild forms of opisthorchiasis and clonorchiasis have nonspecific symptoms including eosinophilia and cholestasis. Chronic disease in humans may be accompanied by cholangiocarcinoma. Diagnosis is by parasitological tests through detection of eggs in host feces, serological tests, and molecular methods. Treatment with praziquantel is very efficient (90–95%), with still no evidence of resistance development.

Cystic and alveolar echinococcosis is caused by larval forms of tapeworms of the genus *Echinococcus* and it is considered one of the most important parasitic diseases in the world. *E. granulosus* s.l. and s.s., *E. ortleppi*, *E. canadensis,* and *E. intermedius* cause cystic echinococcosis (CE). *E. multiocularis* causes alveolar echinococcosis (AE), as well as in rare cases *E. vogelii* and *E. oligarthus* [15]. Most frequently final hosts for *E. granulosus* are dogs and wild Canidae, with ruminants, horses, and pigs as intermediate hosts. Humans can be an intermediate host for both species, infected most commonly by eggs. In 98% of cases, parasite inhabits the liver where cysts are developed. The WHO considers AE as the first of 20 foodborne NTDs, while *E. multiocularis* takes third place. Adult forms of the parasite inhabit the small intestines of the final host with eggs excreted by feces and consumed by intermediate hosts. Through stages of protoscolex, the cestode becomes infectious with the final stage of the cycle represented by the consumption of infected tissues of intermediate hosts by the final host [9]. The AE occurs exclusively in the northern hemisphere. An increase in prevalence is related to the growth of the fox population, especially in periurban areas. The global burden of disease is estimated to be 18.200 new cases annually, out of which 1.600 cases are reported in Europe [9]. The CE is distributed worldwide in both humans and animals, representing a serious threat, especially in the Mediterranean, South America, and Central Asia. The CE and AE are chronic and severe diseases most commonly affecting the liver. The *E. multilocularis* forms multilocular cysts, while *E. granulosus* forms one hydatid cyst. The *E. granulosus* cysts manifest in clinical symptoms correlated with their size and pressure on nearby organs. The prognosis for the CE depends on the parasite location most commonly in the liver or lungs, while 20% of infections are located in the spleen, peritoneum, kidneys, bones, and sometimes brain and spinal cord. Diagnosis in final hosts is by parasitological, serological, and molecular tests. Postmortem examination of small intestines is considered the "gold standard" test because it confirms the presence and enables the identification of the parasite species. In humans' diagnosis is by imaging techniques, serological tests, and by histopathological examination. Benzimidazole is the sole appropriate therapy for the CE, while the AE treatment is by surgery, with limited success due to difficulties in the removal of parasitic cysts. Unfortunately, surgery can be performed only in 20–50% of cases, while in rest treatment is not recommended especially for chronic cases due to developed mass of the parasitic cysts and frequent metastasis of cysts into various other organs.

Hymenolepiasis is caused by cestode; *Hymenolepis nana* and H. *diminuta*, are distributed worldwide with endemic areas in parts of Asia, and central Europe. Central and South America and Africa. The disease is common in children living in poor hygiene and sanitary conditions, wherein some poor community's prevalence can reach up to 58%. Epidemiolocal data show around 175 million people are infected throughout the world [16]. The disease commonly is asymptomatic, while in some cases symptoms such as chronic diarrhea, abdominal pain, anorexia, itching, and slow growth in children are recorded. Infections by the *H. nana* and *H. diminuta* in the final stages develop into severe clinical forms, sometimes life-threatening, especially in people with AIDS. The *H. nana* parasites in rodents, with direct human to human transmission and autoinfections. However, infection by the *H. nana* is still considered zoonotic due to widespread infections in rodents which serve as pathogen reservoirs. Humans can pose both intermediate and final hosts, while in the zoonotic transmission cycle arthropods have the role of intermediate hosts found in flour and grain. Accidental consumption of infected arthropods leads to the development of parasitic worms in humans. Diagnosis is made by confirmation of eggs in feces, while treatment includes praziquantel, nitazoxanide, and nicodamids.

Taeniasis is caused by the parasites of the genus *Taenia*. Species infecting humans are *Taenia solium* (pig tapeworm), *Taenia saginata* (cattle tapeworm), and *Taenia asiatica* (Asia tapeworm). Taeniasis is endemic in some developing countries, especially in Africa, South America, and Asia [17]. In countries of North America and Australia, disease occurs due to an increase in pig meat consumption, migrations, and travel. In epidemic form, taeniasis occurs in Spain and Portugal and sporadically in other countries of Western Europe. People are infected through consumption of undercooked pig or beef meat infected by the development form of the parasite (cysticercus), with the final location of the adult parasite in the small intestines. Also, in cases of feco-oral ingestion of *T. solium* eggs, the cysticercus develops in the human body causing neurocysticercosis (NCC) if development occurs in the central nervous system. The NCC is the most common form of taeniasis and raises great concerns in endemic areas. It causes about 50.000 death annually, and it is considered the most common cause of acquired epilepsy with about 2 million infections worldwide [17]. The symptoms are non-specific and include loss of weight, abdominal pain, vomiting, diarrhea, and obstipation. The symptoms of the NCC depend on the size, number, and location of cysts. The most common symptom of the NCC is epilepsy, followed by remittent headache due to increased intracranial pressure. If cysts are located in chambers of the brain, obstruction of cerebrospinal fluid flow causes hydrocephalus. Diagnosis is by parasitological, serological (ELISA), and molecular (PCR) methods. Albendazole and praziquantel are the most common antiparasitic drugs applied.

Trichinellosis is caused by the parasite of the genus *Trichinella*, transmitted through the consumption of raw or undercooked meat containing larva forms of the parasite [18]. There are at least 13 species/genotypes of Trichinella divided into two groups: incapsulated (*Trichinella spiralis*, *T. nativa*, *T. britovi*, *T. nelsoni*, *T. murelli,* and *T. pathogenesis*, *T. chanchalensis*, T6, T7, T8, and T9) and unencapsulated (*T. pseudospiralis*, *T. papuae*, *T. zimbawensis*). The life cycle starts with the enteric phase after larval ingestion (L1), which after several stages develop within 1–2 days in adult forms. After 30 h post-infection parasite starts to reproduce and newborn larvae start the parenteral phase by penetrating lymphatic and vascular systems. After reaching well-vascularized tissues, (skeletal muscles, myocardium, extraocular and intercostal muscles, and brain) they continue postembryonic development. Trichinellosis even though long known is still widely reported due to disturbances in the ecosystems

caused by humans, where trichinella had successfully adapted and infects wild and domesticated animals, and humans in Eastern Europe, Asia, and South America [18]. Diagnosis is based on clinical examination, blood analysis (eosinophilia and increase in muscle enzyme levels), and epidemiological data. Direct diagnosis is made by PCR, digestion test, and histological examination of tissues collected by biopsy. Indirect diagnostic techniques include serological tests. Antiparasitic treatment includes benzimidazole, mostly albendazole with high therapeutic efficacy. Other antiparasitics such as ivermectin, nitazoxanide, quinfamide, and flubendazole are also good treatment alternatives.

#### **4. Toxocariasis and other soil-transmitted helminthiases**

Toxocariasis is a widely distributed zoonosis with a huge socio-economic impact, especially in poor countries. The disease is caused by the nematode of the genus *Toxocara*, which includes four species; *Toxocara canis*, *T. cati*, *T. malaysiensis,* and *T. vitulorum* able to infect a wide host range. Species *T. canis*, *T. cati,* and *T. malaysiensis* are common parasites of dogs, cats, and other carnivores with importance in veterinary and public health [19]. Toxocariasis in humans is manifested in four main clinical forms: visceral larva migrans, asymptomatic or common toxocariasis, and ocular and neuro-toxocariasis. The largest number of ocular toxocariasis is reported in Japan, Correa, France, Brazil, and the USA, while neuro-toxocariasis is dominant in Europe, Asia, and the Americas, and visceral larva migrans reports are coming from Spain, India, Argentina, and Brazil. In developed countries, humans are most commonly infected with Toxocara spp. Eggs contaminated soil, food, and water. Dogs and cats are the main source of contamination, especially in communities where these animals have free access to public parks and playgrounds. In some countries such as the United Kingdom foxes became a primary contaminant of the environment. Contamination of soil of public parks in most countries varies within a range of 17.4– 60.3% according to reports from Brazil, 14.4–20.6% in the USA, 13.0–87.1% in Europe, 30.3–54.5% in Africa, and 6.6–63.3% in Asia [19]. Also, humans can be infected with embryonated eggs attached to the hair of dogs and cats. In accordance with the wide para-enteritis host range, some human cases are associated with the consumption of undercooked beef, lamb, and chicken. Besides Toxocara spp., other geo-helminths represent a significant problem in tropic and subtropic regions. Most important are *Ascaris* spp., *Ancylostoma* spp., *Uncinaria stenocephala*, *Trichuris* spp*.,* and *Strongyloides stercoralis*. According to the WHO reports almost 1.5 billion people are exposed to these parasites. Infection occurs most commonly by ingestion of eggs, by feco-oral route, or penetration of larvae from the soil through host skin [20]. Geo-helminths in humans causes a range of different, non-specific symptoms, hypersensitivity, small intestine obstruction, volvulus or intussusception, cholecystitis, and pancreatitis. Anemia can occur due to mucosal bleeding from the upper gastrointestinal system. Patients with severe disease demonstrate eosinophilic pneumonia, urticaria, cough, dyspnea, hemoptysis, pleuritis, pleural exudate, hepatic abscesses, diarrhea, dermatitis, asthenia, abdominal pain, tachycardia, tachypnea, edema, hematochezia, and occasionally melena. Diagnosis is by parasitological examination and identification of eggs or adults in feces, sputum, bronchoscopy, endoscopy, basic blood analysis, serological tests, and imaging techniques. Treatment includes the administration of antibiotics and anthelmintics (albendazole, mebendazole, ivermectin). With small intestine obstruction, volvulus, or intussusception, surgical laparotomy is indicated.

Dirofilariosis is a mosquito-borne zoonotic disease caused by the nematode of the genus *Dirofilaria*. Several species of this genus may cause human infection; *D. repens*, *D. immitis*, *D. tenuis*, *D. striata, D. ursi,* and others. Adult forms of *D. repens* are parasites of skin and subcutaneous tissues of animals, while *D. immitis*, known as "heartworms", is usually found in pulmonary arteries and right hearth of dogs and other carnivores. *D. tenuis* infects raccoons, *D. striata* wild felids and *D. ursi* is found in bears [21]. Animals are considered natural hosts while humans are accidental hosts. Increased occurrence of dirofilariasis is reported in Europe related to traveling in endemic areas. Human dirofilariasis is reported in 46 countries from five continents (Afrika, Amerika, Asia, Australia, and Europe). *D. repens* occurs in 39 countries from all continents but America, *D. immitis* is reported in 15 countries from all continents but Africa, *D. tenuis* is reported from USA and India, D. *hongkongensis* from China and Austria, *D. striata* from America and *D. ursi* from Japan [21]. The life cycle of Dirofilaria has five stages developing invertebrate hosts and mosquitos as vectors (dominantly *Culex* spp. and *Aedes* spp.). Mosquitoes transmit third-stage larvae. In the host body nodules are formed at different locations depending on which ocular, subcutaneous and pulmonal dirofilariasis is developed. Since symptoms are absent or non-specific diagnosis is complex. The most common signs are redness of the eye, irritation, and pain similar to allergy conjunctivitis. Diagnosis is by examination of nodules and by x-rays. Therapy consists of surgical removal of nodules from lungs and subcutis. In most cases, treatment with antiparasitic is not necessary.

Capillariasis is a globally distributed zoonotic parasitosis caused by nematode *Capillaria* spp. So far over 300 species of *Capillaria* had been identified with a wide host range, while the following species cause infections in humans; *C. philippinensis*, *C. hepatica,* and *C. aerophila*. Capillariasis is the first time described in rural areas of the Philippines and Thailand, following spread to Indonesia, Japan, Taiwan, India, and Egypt [22]. Cases reported in Europe are mostly imported through travel in endemic areas. The parasite is localized in the liver of mammal hosts, particularly rodents, while humans are accidental hosts. Final hosts—rodents represent a source of environmental contamination. They are transmitted by water or food. In the liver due to parasite migration necrotic lesions, inflammations, and tissue granulation is found. In humans, capillariasis can be intestinal, pulmonal, or hepatic. Symptoms are fever, hepatomegaly, eosinophilia, and an increase in liver enzymes. Complications of infection include lobular pneumonia, pulmonary abscesses, anemia, kidney damage, splenomegaly, and congestion. Diagnosis is made by identification of eggs from stool, liver biopsy, imaging techniques, serological tests such as ELISA, and Indirect immunofluorescence (IFA). Therapy is based on thiabendazole and albendazole.

Trypanosomiasis is caused by species of the genus *Trypanosoma*. Chagas disease (CD) or American trypanosomiasis is caused by protozoa *T. cruzi*, while *T. brucei rhodesiense* and *T. brucei gambiense* are causative agents of African sleeping sickness (African trypanosomiasis). *T. cruzi* is transmitted by insects of the sub-family Triatominiae, while *T. brucei* is transmitted by tsetse flies of the genus Glossina. Both diseases are connected with high morbidity and mortality and are difficult to control since many wild and domestic animals are natural reservoirs. During the life cycle, the parasite undergoes three stages; intracellular amastigote (proliferative form found in invertebrates), epimastigotes (proliferative form from invertebrate intestines), and extracellular trypomastigote. During feeding, hematophagy insects introduce trypomastigote which transforms into epimastigotes [23]. The CD is one of the leading public health issues in most South American countries. Due to continuous migrations

#### *Zoonotic Parasites and Vector-Borne Parasitoses DOI: http://dx.doi.org/10.5772/intechopen.105120*

of people from endemic areas disease is more and more frequently reported in nonendemic areas like North America, Europe, Australia, and Japan. Here transmission occurs through blood transfusion, organ transplantation, or vertical transmission from mother to child. The disease affects about 6–8 million people worldwide, causing 50.000 deaths, while 65–100 million people live in endemic areas. *T. brucei* is an extracellular parasite found in the blood, lymph, lymphatic nods, liquor, and interstitial fluid of the host. The acute form is often fatal to a host, however, if the patient survives, the disease becomes chronic followed by migration of the parasite to cerebrospinal fluid. The patient succumbs to septicemia or meningitis. *T. cruzi* invades macrophages, fibroblast, and epithelial cells. The acute stage of infection is accompanied by high parasitemia with no symptoms or showing as fever, anorexia, and tachycardia. Diagnosis in the acute stage is based on the detection of the parasite in blood or by PCR. In the chronic stage, serological tests are used. Therapeutics (nifurtimox, benznidazole) are efficient in the acute stage of *T. cruzi* infection. For treatment of *T. brucei* infection in acute form pentamidine (*T. b. gambiense*) and suramin (*T. b. rhodesiense*) are used, while for chronic stage melarsoprol and eflornithine.

Leishmaniasis is one of the most important protozoan diseases. Causative agents are of the genus *Leishmania*, within which zoonotic are *L. infantum*, *L. donovani*, *L. peruviana*, *L. braziliensis*, *L. mexicana*, *L. major,* and others. This is a vector-borne disease transmitted by sandflies, insects of the genus *Phlebotomus* and *Lutzomyia*. Most of the species cause disease in many mammals which represent the reservoir of the parasite (rodents, dogs, cats, wolfs, and primates) [24]. Dogs are the main reservoirs in urban areas, while foxes, jacals, and wolfs are important salivatic hosts. Leishmania has a heterosexual life cycle, including two morphologically different forms; amastigote found in macrophages of domesticated mammals and promastigote found in intestines of vectors. In humans, the infection starts when female Phlebotomus inoculates promastigote through the skin. The macrophages then intake promastigote by phagocytosis where the parasite transforms into a non-flageal form—amastigote. This form is further reproduced by binary fission within macrophages. Diseases in endemic in a large number of countries mainly in South and Central America, Africa, Asia, and Mediterranean countries. Annually 1.5 million cases of cutaneous leishmaniasis are confirmed and about 500.000 cases of visceral leishmaniasis alongside 30.000 fatalities [25]. Risk factors for leishmaniasis are related to urbanization and climate changes. An increase in the average temperatures delays the reproduction season of the vector species. Hence endemic areas for zoonotic leishmaniasis had spread to northern Italy, Germany, the United Kingdom, Hungary, and France. There are two clinical manifestations of leishmaniasis in humans. Visceral leishmaniasis in humans and dogs is caused by *L. donovani* and *L. infantum.* The other species most commonly cause cutaneous or mucocutaneous disease accompanied by papulose, muco-papulose, and nodular exanthema. The visceral form is accompanied by fever, hepatosplenomegaly, pancytopenia, weakness, and weight loss. If not treated, severe cases of visceral leishmaniasis are usually fatal, due to direct effects of the disease or due to secondary complications (bacterial infection and hemorrhage). Diagnosis is made based on clinical manifestation, parasitological, serological, and molecular tests. Therapy must be adjusted to individual cases and the most commonly includes amphotericin, pentamidine, pentavalent antimonial, ketoconazole**,** itraconazole**,** fluconazole, and miltefosine.

Giardiasis is a disease caused by *Giardia duodenalis* (formerly called *G. lamblia* or G. *intestinalis*), with at least eight genotypes (A-H) confirmed in humans and other mammals. Species of the genus *Giardia* are found in other hosts; *G. agilis* in

amphibia, *G. ardeae* and *G. psittaci* in birds, *G. microti* and *G. muris* in rodents [26]. Giardiasis is globally distributed, yielding over 280 million cases caused dominantly by genotypes A and B [26]. Epidemics and increases in prevalence are related to exposure to contaminated food and water, public pools, and daycare establishments. The disease is important from a veterinary perspective since it causes serious symptoms in animals as well as death, while diseased animals are a source of infection for humans. The life cycle of *Giardia* includes two phases; trophozoite (replicating stage) and cyst (infectious stage). Infection can occur directly by ingestion of cysts or by the feco-oral route. The following infection in the duodenum, cyst transforms to trophozoite, which reproduces by binary division, forming the cysts then excreted by feces. Cysts are very viable and can maintain infectivity in the environment for weeks and months. The disease can be asymptomatic or in acute form followed by dehydration, abdominal pain, nausea, vomiting, and weight loss. In the chronic form, the disease can manifest as the syndrome of irritable colon and chronic fatigue. Laboratory diagnosis of *Giardia* spp. Is mainly based on the detection of cysts or trophozoite in fecal samples by serological and molecular methods. Treatment is adjusted to anamnesis and clinical findings and includes metronidazole, tinidazole, nitazoxanide, paromomycin, quinacrine, and furazolidone.

Malaria is a disease caused by the parasites of the genus *Plasmodium*. Species found in humans are *P. malariae*, *P. falciparum*, *P. vivax*, *P. ovale,* and *P. knowlesi*. The disease is transmitted by mosquitoes of the genus *Anopheles* which transmit disease to humans and other vertebrates [27]. Malaria is still one of the most severe diseases affecting hundreds of million people worldwide causing over 400.000 deaths annually. *P. vivax*, in most cases considered the cause of re-emergent malaria occurrence, is an ancient and common zoonosis originating from apes. The occurrence of other zoonotic malaria agents (*P. knowlesi*, *P. cynomolgi,* and *P. simium*) additionally accentuates the severity of this disease. Malaria is the most common in Africa and some Asian countries. Species found in America and Europe are *P. vivax* and *P. malariae*, while in Africa dominant species is *P. falciparum*. The life cycle is very complex and evolves in two stages; sexual in mosquitoes and asexual in vertebrates including humans [27]. Clinical symptoms of malaria; fever, nausea, and weakness are related to every cycle of merozoite exiting and leaving erythrocytes. Diagnostic tests for malaria include microscopic analysis of blood smears (golden standard), PCR, IFA, and ELISA. Treatment of malaria is based on anti-malaria drugs; chloroquine phosphates, with increasing reports of resistance to this drug from around the world. Other drugs are used in addition such as primaquine, and quinine sulfate alongside doxycycline and mefloquine.

Toxoplasmosis is an important disease in animals and humans globally, especially due to resulting in stillbirths and miscarriages in humans [28]. The causative agent, *Toxoplasma gondii* can be found in many species of animals and humans. More than a billion people in the world are infected by *T. gondii*, with very high seroprevalence in some countries (Brazil, 77.5%; St. Thomas and Principe, 75.2%; Iran, 63.9%; Columbia, 63.5%; and Cuba, 61.8%). Only in the USA, the annual cumulative incidence is 9.832 new cases; out of which 2.169 are ocular form and 1.399 cerebral forms of toxoplasmosis as the most common form of the disease [28]. Humans and most warm-blooded animals and intermediate hosts, while domestic and other cats are final hosts. In the final host's intestines, parasites reproduce sexually, resulting in forming of the oocyst, which matures by sporulation to an infectious form. People get infected by consumption of raw or undercooked meat (mainly lamb and pork) containing bradyzoites or ingestion of the sporulated oocysts found on vegetables,

#### *Zoonotic Parasites and Vector-Borne Parasitoses DOI: http://dx.doi.org/10.5772/intechopen.105120*

water, in cat feces, transmission from mother to a child, or by organ transplantation. In most patients, primary infection or mild form when parasites are found in different organs, mainly the heart and skeletal muscles, brain, and retina. Alongside three standard forms of toxoplasmosis (ocular, congenital, and cerebral), a latent infection occurs characterized by behavioral changes and neurologic symptoms. Diagnosis is made by imagining techniques, histopathology, and serological test. Dormant parasites in tissues are the main obstacle to successful treatment since no drug available can reach the parasites encapsulated in cysts. Currently available drugs are efficient for acute and reactivated infections caused by tachyzoites. If treatment is not timely, a fatal outcome is inevitable in immunocompromised individuals. Therapy includes derivates of pyrimethamine in combination with sulfadiazine or clindamycin.

Cryptosporidiosis is caused by the species of the genus *Cryptosporidium* resulting in intestinal infections in a large number of vertebrates including humans, wildlife, reptiles, birds, amphibian, and fish [25]. Species the most commonly found in humans are *C. parvum* and *C. hominis,* causing over 90% of cases of cryptosporidiosis, and also *C*. *meleagridis* along with other parasite species. *C. parvum* has a range of hosts that includes over one hundred mammal species demonstrating the excellent adaptation of the parasite [29]. *Cryptosporidium* can be found in water, food, and surfaces contaminated with feces. The infection comes with ingestion of contaminated water, food, or by direct contact (community and hospital infections). The *Cryptosporidium* due to its morphological features can persist for longer periods outside the host and is very resistant to many desificants. Development of the *C. parvum* starts with sporulated oocytes, which after ingestion begin asexual (merogonial) and sexual (gametogonia) reproduction in small intestines. The significance of this infection reflects in high incidence especially in children, immunocompromised parsons (AIDS patients) with the highest case fatality rate in younger individuals. The most common symptom is diarrhea followed by dehydration, nausea, vomiting, increased temperature, and weight loss [29]. All domestic and wild animals, as well as humans, can serve as potential reservoirs resulting in contamination of food and water, while feco-oral transmission is also possible. The disease is globally distributed and, in the USA, Canada, Australia, and Europe it is considered one of the most common water borne pathogens. Diagnosis is established by examination of dyed fecal smears, serological tests, and PCR. The USA Food and Drug Administration approved nitazoxanide for human therapy.

Babesiosis is a tick-borne disease caused by the parasites of the genus *Babesia*. Over 100 species of *Babesia* are described, most causing high morbidity in animals, while only some are competent human pathogens. Disease transmission occurs by bite of an infected tick, blood transfusion, or via the placenta. Babesiosis is confirmed on all continents with *B. microti* (rodents) found in North America, *B. divergens* (cattle) most commonly found in Europe, and some infections by *B. duncani* and *B. venatorum* [30]. The occurrence of babesiosis is related to tick distribution and competent vector species of ticks are *Ixodes scapularis, I. ricinus,* and *I. persulcatus*. *Babesia* can be found also in tick species *Dermacentor reticulatus*, *D. marginatus*, *D. silvarum*, *Haemaphysalis longicornis*, *H. punctata*, *H. concinna*, *H. leporispalustris*, *H. japonica*, *H. sulcata*, *Hyalomma marginatum*, *Amblyomma variegatum*, *Argas (Carios) vespertilionis*, *Rhipicephalus simus*, *R. turanicus*, *R. bursa*, *R. microplus,* and *R. sanguineus*. Global annual prevalence is 12.45%; largest in North America (27.81%), Europe (9.88%), Asia (9.30%) and Africa (8.55%) [30]. Human infection is mostly asymptomatic, sometimes with fever, headache, lethargy, loss of appetite, nausea, and dyspnea. Older and immunocompromised individuals are at greater risk of developing more severe

symptoms such as hepatomegaly and kidney failure. Diagnosis is made by macroscopical examination of blood smears. Patients with mild disease receive therapy of atovaquone and azithromycin, while in severe cases clindamycin and kinin are used. Since currently there is no vaccine available, recommendations are to avoid tick bites using repellents and appropriate clothing. Babesiosis gains more priority for control due to the risks of its spread influenced by climate changes, vector distribution, and a huge impact on public health.

Amebiasis is a disease caused by *Entamoeba hystolitica* leading to dysentery in humans. It is transmitted by contaminated food, and water and results in a high case fatality rate especially in children from poor countries [31]. In addition to humans E. *histolytica* can be found in primates, cats, dogs, and other animals such as mice and pigs serving as reservoirs. Besides *E. hystolitica* other parasitic species are recorded; *E. dispar*, *E. moshkovskii*, *E. coli*, *E. hartmanni. E. histolytica* is globally distributed, with the highest occurrence in tropical and sub-tropical regions of South America, Africa, and Asia, especially in rural areas with poor sanitary conditions and malnutrition. Amebiasis follows giardiasis and campylobacteriosis is the leading cause of gastrointestinal disease in humans. The life cycle of *E. histolytica* is relatively simple and has two stages; cysts and vegetative trophozoite. Mature cysts as an infectious form of the parasite are found in feces, while trophozoites invasive form are in epithelial cells of the intestine. By feco-oral route and ingestion by food and water infectious cysts of *E. histolytica* passage through the stomach, mature in the ileum into trophozoite which colonizes the large intestine and destroys epithelial cells causing inflammation and dysentery. Parasites can by portal vein reach the liver and cause extraintestinal infection followed by liver, lung, or brain abscesses [32]. Clinical symptoms vary from diarrhea to severe dysentery accompanied by abdominal pain, and watery or bloody stool. Diagnosis by symptoms is difficult, hence parasitological, serological, and molecular tests are used. The ELISA antigen test is available, while out of molecular assays conventional and multiplex PCR are used as well as Loop-mediated isothermal amplification test (LAMP). Treatment includes amebicides such as metronidazole, emetine, chloroquine, diloxanide-furoate, and some antibiotics (tetracycline, paromomycin, erythromycin).

#### **5. Prevention and control of parasitic diseases**

The constant increase in numbers of human parasitoses is being reported worldwide, while zoonotic parasites are among the most important causes of human infectious diseases, especially in undeveloped and developing countries [8]. Parasitoses make up the majority of the WHO/FAO lists of the NTDs, affecting 1000 million people in endemic areas, including 149 countries [7]. Causes for a surge of zoonotic parasitic infections in humans and the emergence of zoonotic parasites are various, such as overpopulation, migrations due to natural or man-made disasters, inadequate food and water supplies, encroachment leading to human interaction with new animal and/or parasite species and global warming influencing distribution and survival of parasites with resultant overflow infections [32, 33]. The consideration that parasitic diseases are exclusively associated with tropical and/or undeveloped countries with deficient hygienic and sanitary conditions in recent years has been widely challenged. The developed countries have witnessed an unprecedented increase of some parasitosis due to migrations, tourism, changing alimentary customs, and internationalization of commerce [34]. Parasitic infections are even more a threat to immunocompromised people due to genetic, iatrogenic, or infectious causes.

#### *Zoonotic Parasites and Vector-Borne Parasitoses DOI: http://dx.doi.org/10.5772/intechopen.105120*

The surveillance of zoonotic parasites is important for common health and begins with an investigation of the presence of known and potentially zoonotic parasites in both human and animal populations and the environment. Estimating the extent of the parasites worldwide is hampered since in many countries they are not notifiable diseases, while in addition, the parasitosis can be asymptomatic or with an unspecific symptom that makes its diagnosis difficult [34]. The traditional approach to the prevention of parasitic infection in animals is based on chemoprophylaxis and treatments are commonly not scheduled, nor they are regular or specific and rely on owners' awareness and initiative. In humans particularly in endemic areas regular and mass treatment is considered the main approach for infection control [4]. However, costs associated with diagnosis and prevention in animals and animal origin food are lesser than the mass treatment and diverse consequences of parasitic infections in humans [35]. Unselective treatment with anti-parasitic drugs has also brought to the light issue of resistance. According to Moleto [36] use of the broad spectrum anthelmintics started in the early 60s had superior outcomes, but the present situation is worsening with alarming consequences arising from the development of the multidrug-resistant parasite population. Currently, other means of parasitic infection control in animals are developed such as vaccination, breeding for resistance, biological control, and grazing management [36].

Since the animals and the environment are the main sources of infection for humans, control of zoonotic parasitoses needs to be primarily addressed at these levels. Rapid, simple, and available diagnostic methods are available for the detection of parasites in both companion and food animals and environmental samples, thus enabling early detection and specific treatment. Alongside investigations of parasitic infection in hosts, vectors require investigation and control (i.e., ticks, mosquitoes, sand flies, etc.). The trends toward an increase in vector populations are, in part, due to landscape fragmentation and an increase in the abundance of hosts. This, along with warming temperatures, has enabled the gaining vector competency, development, and survival of many vector species not as earlier limited by the season (temperatures and precipitation), altitude, and geographical distribution [37]. In the past dominant source of parasite infection in humans was infested animal origin food, which still is important but the majority of human infection nowadays is linked to companion animals and outdoor activities (contaminated environment and vectors).

Further down the food chain control of food-borne parasitoses in animal origin food needs to be part of sanitary and quality control in food processing establishments (i.e., slaughterhouses) [35]. In addition to regulated meat inspection, other methods have become available such as commercial serologic detection kits (for screening antibodies in milk) and near-infrared hyperspectral imaging (for animal carcasses inspection) [35, 38]. Besides direct consequences on human health through parasite-infested food, parasitic diseases such as gastrointestinal parasitoses in food animals are the single most important cause of production losses [36]. Parasite infections are shown to significantly affect milk yield, lower milk protein content, impair fertility, and contribute to a more frequent onset of metabolic disorders in animals as well as cause condemnation of affected organs (i.e., liver) [38]. Considering traditionally low animal productivity in undeveloped and developing countries, simultaneously struggling with many animals health issues, further decrease in the availability of animal protein due to parasitism is a serious threat to food security, nutrition-related deficiency, and both the health and economic wellbeing of humans (**Figure 2**). Also, in developed countries, changes in production due to animal welfare


#### **Figure 2.**

*Impact of parasite infection in food animals [39].*

perspectives (i.e., pasture access) and an increase in organic farming led to altered patterns of parasite prevalence in farmed animals. For example, an increase in *F. hepatica* prevalence and/or an increase in the geographical spread of this parasite alongside recognition of its zoonotic potential has been observed in some European countries during recent years [38].

Control of parasitic infections is difficult for various reasons. First, many of these parasitoses are zoonosis, which requires collaboration between the human and animal health sector. It was long recognized that many emerging zoonoses arise from complex, diverse, and constantly evolving factors related to the environment, people, and animals. Zoonotic parasitoses with emergence and adaptability, wide host range, and various means of transmission all highly influenced by the environment need One Health approaches in both investigations, health regulations, prevention, and control measures [40]. On the other hand, the socio-economic conditions of developing countries make it difficult to apply measures to prevent or combat these diseases. Research on vaccines is yet expected to produce applicable results, while sophisticated molecular diagnostics on a routine basis are not even done in developed countries.

#### **6. Conclusion and recommendations**

Parasitoses of humans and animals contribute significantly to a global burden of infectious diseases, public health, animal health, and production, especially considering current trends of disease emergence and re-emergence and the high and increasing dominance of zoonotic pathogens. Research shows that exposure and increased risk of zoonotic pathogens are influenced by global environmental, social, and economic trends mainly man-made. Understanding, predicting, addressing, and preventing diseases with fast-evolving virulence, host range, pathogenesis and epidemiology require multidisciplinary approaches and reactions. Genesis as well as

#### *Zoonotic Parasites and Vector-Borne Parasitoses DOI: http://dx.doi.org/10.5772/intechopen.105120*

consequences of novel and re-emerging pathogens is complex, hence it needs to be addressed in its entirety to be proactive. Researchers, international bodies, governments, and the entire global community are called to adopt and adapt in their efforts to combat common health and wellbeing threats either current or those inevitably looming over the horizon.

#### **Author details**

Jasmin Omeragic, Sabina Seric-Haracic\* and Naida Kapo Veterinary Faculty, University of Sarajevo, Sarajevo, Bosnia and Herzegovina

\*Address all correspondence to: sabina.seric-haracic@vfs.unsa.ba

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### **Chapter 6**

## The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications for Vector Borne and Neglected Tropical Disease Control

*Moses Adriko*

#### **Abstract**

Tungiasis is a neglected parasitic inflammatory tropical skin disease affecting the world's poorest people caused by a female flea called *Tunga penetrans*. It is potentially endemic in 88 countries worldwide, with an estimated community prevalence of 60%. The national prevalence is estimated at 50% with recent epidemics re-emergence dimensions in Uganda. The disease burden continues to escalate with high-school dropouts, absenteeism, and poor performance. This study was geared toward assessing the prevalence and risk factors in communities in Uganda. Overall, there is prevalence of 40.6 and 28% among households and individuals. Our findings further indicate prevalence of infection was the highest at household level compared to infected individuals observed; (Jinja; 73.3% vs. 50.0%), (Namutumba; 53.2% vs. 33.3%), (Iganga; 41.1% vs. 25.3%), (Bugiri; 24.4% vs. 27.1%), (Namayingo; 20.5% vs. 12.6%) and (Mayuge; 13.6% vs. 6.2%). Physical examinations revealed the most affected body parts were the toes (6.5%), sole (1.2%), and the heel (0.8%). The common method of prevention and treatment used is self-removal (49.4%), removal by a family member (32.7%), support from medical personnel (14.4%), and use of ointment (1.9%). The findings have implications for the prevention and control of Tungiasis as a public health concern in Uganda. This requires strengthened health education aimed at improved household sanitation and hygiene with community empowerment as a long-term measure.

**Keywords:** prevalence, risk factors, Tungiasis, Uganda, implications, control

#### **1. Introduction**

Tungiasis is a neglected tropical parasitic inflammatory tropical skin disease (NTD) affecting the world's poorest people [1] caused by a female flea called *Tunga penetrans* [2]. It is described as "the greatest curse that has ever afflicted Africa" [3] and is potentially endemic in 88 countries worldwide with an estimated prevalence

in community based-settings 60% [4–9]. It is predominantly a health problem in the tropical areas of Latin America and Africa [10, 11]. It is more common in places with poor hygiene and is closely associated with domestic animals (mainly pigs, dogs, and cattle) [12]. Tungiasis commonly known as *emvunza* or *Nyende* in eastern Uganda has reemerged as the national prevalence in Uganda is estimated at 50% and recently reemerged to epidemic dimensions in many countries [13] including Uganda with an estimated prevalence of 50% reported [14, 15].

Tungiasis is a neglected disease of marginalized populations [16] and has been associated with a number of potential reservoirs from pigs, dogs, goats, mice, rats, and wild animals [17–20]. Studies have shown significant levels of infestations of goats in Uganda with Tungiasis as a serious health concern in domestic animals in Uganda including goats [21], pigs, and dogs [22]. Tungiasis is estimated to affect over 6,000,000 million people who are at risk and an estimated 3 million Ugandans infested with Tungiasis, 50% of whom, are confined to eastern Uganda especially the Busoga sub-region, the rest distributed in other regions of Karamoja and central sub-regions [23].

The ranging disease burden continues to escalate with high school dropouts, absenteeism, poor performance, and low esteem have continued to ruin the areas of Busoga region. There has been no study done to establish the magnitude of this problem and yet resource allocation and interventions can only be appropriately sought when such estimates are made. This study was geared towards assessing the prevalence and risk factors that will help provide the cornerstone for controlling future infections in communities in Uganda.

#### **2. Materials and methods**

#### **2.1 Study area and design**

This was a cross-sectional and multistage sampling study design that utilized semi-structured questionnaires combined with an observation-checklist to collect quantitative data from 983 individuals and 288 households from Bugiri, Iganga, Jinja, Namutumba, Namayingo, and Mayuge districts in eastern Uganda. The study sites are shown in **Figure 1**. The study was conducted in Bugiri, Iganga, Jinja, Namutumba, Namayingo and Mayuge districts (**Figure 1**). These districts were chosen due to the highest epidemiological reports by the Ministry of Health (weekly epidemiological reports). A sampling frame was established and randomization of the villages was performed to generate a proportional number of participants per District.

#### **2.2 Survey methodology**

The study utilized a census-style survey conducted across all the six districts survey. Overall a total of 983 individuals and 288 households were surveyed and interviewed over an eight-week period beginning February 2018. Before interviews began, an advocacy meeting was held with all the district officials to discuss the study and obtain district approval and support for the survey. Meetings were also held with the local council, chairpersons from the two villages, and the village health teams (VHTs). During mobilization meetings, community members were asked to provide information when the researchers arrived in their homes but were informed that they had no obligation to do so. Households were visited door-to-door; if residents were absent, teams returned to the house at least twice for follow-up. Informed consent

*The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications... DOI: http://dx.doi.org/10.5772/intechopen.104444*

**Figure 1.** *Location of study area.*

from the head of the household and adults present during the interview was obtained. The main interviewers were Ministry of Health Vector Control Officers or the District Health Drug Distributor and each team had a member of the Village Health Team from the respective village. There were three teams performing interviews; team members rotated between groups to ensure uniform questioning across the community.

#### **2.3 Case definition**

*A short description of Tunga penetrans* as an inflammatory of the skin characterized by a white patch with a black spot at the center of a swollen red lesion causing a painful itching constituted a case definition the survey team based on to determine and score observed cases. Individuals were included in the study based on the criteria that they were aged six years and above who had lived in the selected districts for a period of one year and above and excluded in the study when found of unsound mind (very sick, unconscious, mental disturbed).

#### **2.4 Data tools and analysis**

One week of training was conducted for all the research assistants involved in this study and deployed on the basis that was able to speak the native language. The data collection tools and questionnaires were pretested in one of the areas known for Tungiasis infections and corrected for errors before use in the study sites. The data collected was entered daily in the field for all the individuals into the computer and cross-checked for consistency and validity of results. A daily data review audit was performed by research to ensure compliance with the standards set.

Household and individual survey data were cleaned and checked for consistency using custom scripts in R v. 3.2.1. Chi-squared tests were used to compare categorical data using the base R function chisq.test. Multivariate logistic regressions were created with the function glm using the binomial family to evaluate two outcome variables.

#### **2.5 Ethical clearance**

The methods in the study were reviewed and approved by the Vector Control Division Research Ethic Committee (VCDREC/090) and the graduate of the Nexus International University (VUU-PGDPH-2016-037).

#### **3. Results**

#### **3.1 Demographic characteristics of the study respondents**

The demographic characteristics of the respondents are presented in **Table 1**. Overall, a total 983 respondents were interviewed. The majority of 657(66.8%) were male and only 326 (33.2%) were female. The mean age (26.13) years (standard deviation (SD) 22.56). Regarding age, the majority 500 (50.9%) were in the age bracket of 5–17 years, 187 (19%) were above 50 years of age, 120 (12.2%) were 30–39 years, 87 (8.9%) were 40–49 years of age and the least number of respondents were 18–29 years of age. concerning occupation, the majority of the respondents 376 (38.3%) were farmers, 61 (6.2%) were doing business as their occupation and a least respondents 14 (1.4%) were engaged in other activities in order to earn a living. The biggest proportion of the respondents 449 (45.7%) were Moslems, 260 (26.4%) were Catholics, 156 (15.9%) belonged to other religions and only 118 (12%) were Pentecostals.

Regarding the water source, the majority of the respondents 373 (37.9%) obtained water for household use from the rivers/lakes/streams/pond, 328 (33.3%) used piped/ protected water as a source of water, 141 (14.3%) used open well water. Concerning education, the majority 526 (53.5%) had a primary level of education, 284 (28.9%) had none as the education level, 159(16.2%) had a secondary level while the least 14 (1.4%) number of respondents had obtained tertiary education. Furthermore, the majority of 557 (56.7%) were single, 225 (22.9%) were married, 161 (16.4%) were separated/divorced and only 40 (4.1%) were widow/widower. This implies that the study was mainly dominated by single respondents.

#### **3.2 Prevalence of Tungiasis in Busoga region**

The overall prevalence of Tungiasis amongst households surveyed was 40.6% (288/984) while 28% (276/984) individuals were found infected with Tungiasis during the study as shown in **Table 2**. The prevalence at the household level was much higher than at the individual level with some villages having 100% as the case with Butangula-A in Jinja district. The findings further indicate the highest prevalence of infection at the household level versus infected individuals were observed in Jinja (73.3% vs. 50.0%), followed by Namutumba (53.2% vs. 33.3%), Iganga (41.1% vs. 25.3%), Bugiri (24.4% vs. 27.1%), Namayingo (20.5% vs. 12.6%) and Mayuge (13.6% vs. 6.2%). The study findings show that the greatest age group affected by this scourge in all the districts surveyed was 5–17 years as shown in **Table 2**.

#### **3.3 The risk factors, morbidities, and management of Tungiasis infestations in the Busoga region**

The major environmental risk factors associated with Tungiasis as reported by the respondents were; poor hygiene and sanitation. Other causes reported were;


*The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications... DOI: http://dx.doi.org/10.5772/intechopen.104444*

*Location of Study area 15.*

*Tungiasis infestations of the toes, finger-nails and buttocks 17.*

#### **Table 1.**

*Demographic characteristics of the study population.*

dirtiness, uncommented house, disposal of household wastes, and people sleeping in houses with bare soils. The study findings revealed that 344 (35.0%) agreed that poor hygiene is the most commonest cause of Tungiasis since some just dispose of household wastes outside their compounds. About 6.9% of the respondents reported sharing a residential house with domestic animals while 93.1% reported having a separate shelter for domestic animals. The type of floor material for suspected cases


**Table 2.**

*Prevalence of Tungiasis infestation in Busoga region.*

of Tungiasis reported was bare soil, clay, and sand. These observations were seen in zoonotic nature in Uganda [21, 24]. Our findings also show that disposal of household wastes was significantly associated with (*p* = 0.002) with outside disposal contributing the greatest percentage of 52.3%. The presence of domestic animals at home was also significantly associated with Tungiasis infestations (*p* = 0.002). The study also noted that knowledge concerning the causes of Tungiasis infestations was equally significantly associated with Tungiasis infestations (*p* = 0.002) with poor hygiene the

*The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications... DOI: http://dx.doi.org/10.5772/intechopen.104444*

biggest contributor accounting for 35%. Similar observations were reported by studies on the knowledge among animal keepers [25] as shown in **Table 3**.

**Table 3** presents the commonest methods of prevention and treatment used by the infected individuals; self-removal accounted for 49.4%), removal by a family member



#### **Table 3.**

*Risk factors and management of Tungiasis infestation in Busoga in region.*

**Figure 2.** *Tungiasis infestations of the toe, finger-nails and buttocks.*

(32.7%), support from medical personnel (14.4%), and use of ointment (1.9%). As concerns the methods of treatment for infected individuals, a bigger percentage acknowledged self-removal, 35.1%, by health workers, 15.1%, removal by relatives 19.9% and 29.9% had no idea of any interventions.

Physical examination of the respondents showed 27% (266/983) which was significantly associated with Tungiasis infections (*p* = 0.001) as shown in **Table 3**. The highest cumulative number of Tungiasis infections recorded was 8.35% on the toes, 2.5% on the sole, 2.5% on the heel, and 2.5% on the dorsal area. Other body parts localized with infections were the fingers (2.5%), hands (4.3%), and forearm (4.3%).

*The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications... DOI: http://dx.doi.org/10.5772/intechopen.104444*

The commonest body parts affected by Tungiasis infections as shown in **Figure 2** are the fingernails, toes, buttocks, and knees.

#### **4. Discussions**

The overall prevalence of Tungiasis amongst households surveyed was 40.6% (288/984) while 28% (276/984) (95%CI, 0.0001–0.0290, *p* < 0.0001) individuals were found infected with Tungiasis during the study as shown in **Table 2**. The study findings further show that females were 2.4 times more infected with Tungiasis compared to males as observed in other studies from studies by [6, 26]. The prevalence at the household level was much higher than at the individual level with some villages having 100% as the case with Butangula-A in Jinja district. The findings further indicate the highest prevalence of infection at the household level versus infected individuals were observed in Jinja (73.3% vs. 50.0%), followed by Namutumba (53.2% vs. 33.3%), Iganga (41.1% vs. 25.3%), Bugiri (24.4%vs. 27.1%), Namayingo (20.5% vs.12.6%) and Mayuge (13.6% vs. 6.2%). The results of this study indicate that Tungiasis is a major public health problem amongst households in rural communities in eastern Uganda. The present-day study areas had previously been known as a hot spot and problematic for Tungiasis infestation in humans [15, 27] and animals [21, 22, 24, 25, 28, 29]. This could have been due to repetitive infestations of the affected households. These findings were in conformity with similar studies [28, 30].

Previous studies [26, 31] have shown that the prevalence of Tungiasis amongst 5–14 years was higher during the dry season similar to the trends observed in our study as indicated in **Table 2**. The study further points out that the prevalence of Tungiasis varied across different age groups though more significantly amongst 5–17-year-olds in almost all villages surveyed. This trend has been observed in similar studies by [8, 32], mostly attributed to the poor hygiene and exposure behaviors of these youngsters. This is made worse with the limited knowledge to take good care of themselves, frequently playing in dusty environments where the parasite thrives most.

It was a common observation that the majority of those suffering from Tungiasis infections had problems with walking because they had multiple infections on the toenails, fingernails and even to the extent some buttocks of the elderly were severely affected. Similar levels of morbidities were reported in many studies both in animals [21, 22, 29] and humans [18, 32–35] and a common cause of serious secondary bacterial infections [36].

The major environmental risk factors associated with Tungiasis as reported by the respondents were; poor hygiene and sanitation. Other causes reported were; dirtiness, uncemented house, disposal of household wastes, and people sleeping in houses with bare soils. The study findings revealed that 344 (35.0%) agreed that poor hygiene is the most commonest cause of Tungiasis since some just dispose of household wastes outside their compounds. About 6.9% of the respondents reported sharing a residential house with domestic animals while 93.1% reported having a separate shelter for domestic animals. The type of floor material for suspected cases of Tungiasis reported was bare soil, clay, and sand. These observations were seen in zoonotic nature in Uganda [21, 24]. Our findings also show that disposal of household wastes was significantly associated with (*p* = 0.002) with outside disposal contributing the greatest percentage of 52.3%. The presence of domestic animals at home was also significantly associated with Tungiasis infestations (*p* = 0.002). The study also noted that knowledge concerning the causes of Tungiasis infestations

was equally significantly associated with Tungiasis infestations (*p* = 0.002) with poor hygiene the biggest contributor accounting for 35%. Similar observations were reported by studies on the knowledge among animal keepers [25]. These observations were made on studies of zoonotic nature in Uganda [21, 24]. Our findings also show that 55.4% were knowledgeable about Tungiasis infection with 23.8% reporting poor hygiene, 23.9% reporting sleeping on the floor, 24.0% stating too much sunshine, and 22.0% reporting uncemented floors as the major causes of Tungiasis infestations. Similar observations were reported by studies on the knowledge among animal keepers [25]. Only 4.5% had reported using regular footwear. The majority reported bathing with soap (73.3%) as a good strategy for the prevention of infections although only 11.5% reported having good personal hygiene as one of the prevention strategies. Physical removal of *Tunga penetrans* using manipulation with safety pin/needles accounted for 14.4%.

#### **4.1 The National elimination Policy for Uganda**

In Uganda, the disease outbreak came to light in 2010 when deaths were reported in the Bugiri district. This has resulted in a series of activities that have led to the proper understanding and recognition of Tungiasis is a neglected tropical disease. The disease is endemic in the whole country, with an estimated 6 million people are at risk and at least 2.4 million infected with Tungiasis [23]. However, 50% of total cases in Uganda come from Busoga and Karamoja Subregions. This has been included as a priority disease under the NTDs by the year 2020 through mapping to assess the distribution, Capacity building on vector control treatment and rehabilitation, Advocacy and community mobilization, Personal and Environmental hygiene, and identifying partners to support the program [23]. The warm dusty weather and environment of these regions have certainly played an amenable role in breeding Tungiasis. More so, exposed dirty floors, walls, and compounds mean Tungiasis-eggs can incubate inside homes. There are many rural families who keep animals and chickens inside their houses at night as a measure of theft. This close proximity of animals enables the transmission of eggs from animals to humans to happen with much ease.

The Ministry of Health has proposed the use of Benzyl-benzoate emulsion (BBE) combined with petroleum jelly as the medication for treating and managing cases. These have been provided to health facilities for use by the affected communities. This will be incorporated and run alongside the national control program implemented through the community-based village health teams (VHTs) geared towards community involvement and ownership. The government has proposed to strengthen and enforce the current public health act on household sanitation and hygiene, which will include smearing, cleaning, and prohibiting sharing of human dwelling houses with domestic animals. Also, strengthen community social norms with community engagement.

#### **5. Conclusions**

Based on the study findings, it's noted that Tungiasis infections present a serious health hazard to communities living in Busoga where many people live and suffer quietly under poor housing conditions. This is worsened by sharing housing and accommodation with domestic animals that are reservoirs for the infection. The following lessons have been learned during the study and recommended for further studies to advance solutions as regards the need to make a sound decision as *The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications... DOI: http://dx.doi.org/10.5772/intechopen.104444*

to which drug to use during the community treatment intervention for Tungiasis. We have to choose between the scientifically backed Dimethicone (BBE) and the locally recommended interventions but data lacking on the Country's use of BBE for Tungiasis Control and elimination. There is a need to develop a training manual, IEC Materials, and Community/Civil Societies Organizations Materials for sensitizations to support those affected and the need for integrated coordinated community disease surveillance mechanisms with a comprehensive approach. Vector-Borne and Neglected Tropical Disease control division will be critical in providing solutions to this problem.

#### **6. Recommendations**

It is therefore suggested that countrywide studies are required to establish the exact prevalence and magnitude of Tungiasis infections in Uganda, assessing the epidemiological, socio-cultural context, behavioral and ecological risk factors. There is a need to assess the impact on school-age children (SAC) attendance 5–14 years and the disability-adjusted life years associated with the infections.

#### **Acknowledgements**

The authors would like to thank in particular the research assistants who were involved in the data collection. We are also grateful for the contribution of District NTD focal Persons for their efforts in mobilizing the communities for the study. Approval for the surveys was gratefully received from the Ethics committee of the Virtual University of Uganda (VUU-PGDPH-2016-037) and Vector Control Division Research Ethics (VCDREC/090) and Uganda National Council of Science & Technology (UNCST). Individuals who participated in the study provided written consent and assent before the study took place.

#### **Authors contributions**

Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing all by the author.

#### **Funding**

This study was a student lead study supported by primary healthcare funds from the Ministry of Health, Republic of Uganda.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Zoonosis of Public Health Interest*

### **Author details**

Moses Adriko1,2,3,4

1 Vector Control Division, Ministry of Health, Kampala, Uganda

2 Uganda Institute of Allied Health and Management Science (UIAHMS), School of Medical Entomology and Parasitology, Kampala, Uganda

3 Ministry of Health, Kampala, Uganda

4 The Virtual University, Uganda, Kampala, Uganda

\*Address all correspondence to: adrikomoses@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Prevalence and Risk Factors Associated with Tungiasis Infestations in Uganda: Implications... DOI: http://dx.doi.org/10.5772/intechopen.104444*

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[13] Kehr JD, Heukelbach J, Mehlhorn H, Feldmeier H. Morbidity assessment in sand flea disease (tungiasis). Parasitology Research. 2007;**100**(2):413-421

[14] Sentongo E, Wabinga H. Tungiasis presenting as a soft tissue oral lesion. BMC Oral Health. 2014;**14**:112

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[18] Pilger D, Schwalfenberg S, Heukelbach J, Witt L, Mehlhorn H, Mencke N, et al. Investigations on the biology, epidemiology, pathology, and control of Tunga penetrans in Brazil: VII. The importance of animal reservoirs for human infestation. Parasitology Research. 2008;**102**(5):875-880

[19] Pampiglione S, Trentini M, Fioravanti ML, Onore G, Rivasi F. On a new species of sand flea from Ecuador and tungiasis, a problem of Public Health in many developing countries. Annali di Igiene. 2003;**15**(5):747-752

[20] Clyti E, Couppie P, Deligny C, Jouary T, Sainte-Marie D, Pradinaud R. Effectiveness of 20% salicylated vaseline in the treatment of profuse tungiasis. Report of 8 cases in French Guiana. Bulletin de la Societe de pathologie exotique. 2003;**96**(5):412-414

[21] Mutebi F, Krucken J, Mencke N, Feldmeier H, von Samson-Himmelstjerna G, Waiswa C. Two severe cases of Tungiasis in Goat Kids in Uganda. Journal of Insect Science. 2016;**16**

[22] Mutebi F, Krucken J, Feldmeier H, Waiswa C, Mencke N, von Samson-Himmelstjerna G. Tungiasisassociated morbidity in pigs and dogs in endemic villages of Uganda. Parasites & Vectors. 2016;**9**:44

[23] MOH. Uganda Master Plan for National Neglected Tropical Diseases Programmes: 2017-2022. 2017

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[31] Muehlen M, Feldmeier H, Wilcke T, Winter B, Heukelbach J. Identifying risk factors for tungiasis and heavy infestation in a resource-poor community in northeast Brazil. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2006;**100**(4):371-380

[32] Ugbomoiko US, Ariza L, Babamale AO, Heukelbach J. Prevalence and clinical aspects of tungiasis in southwest Nigerian schoolchildren. Tropical Doctor. 2017;**47**(1):34-38

[33] Klimpel S, Mehlhorn H, Heukelbach J, Feldmeier H, Mencke N. Field trial of the efficacy of a combination of imidacloprid and permethrin against Tunga penetrans (sand flea, jigger flea) in dogs in Brazil. Parasitology Research. 2005;**97** (Suppl. 1):S113-S1S9

[34] Heukelbach J, Costa AM, Wilcke T, Mencke N, Feldmeier H. The animal reservoir of Tunga penetrans in severely affected communities of northeast Brazil. Medical and Veterinary Entomology. 2004;**18**(4):329-335

[35] Wiese S, Elson L, Reichert F, Mambo B, Feldmeier H. Prevalence, intensity and risk factors of tungiasis in Kilifi County, Kenya: I. Results from a community-based study. PLoS Neglected Tropical Diseases. 2017;**11**(10):e0005925

[36] Nyangacha RM, Odongo D, Oyieke F, Ochwoto M, Korir R, Ngetich RK, et al. Secondary bacterial infections and antibiotic resistance among tungiasis patients in Western, Kenya. PLoS Neglected Tropical Diseases. 2017;**11**(9):e0005901

#### **Chapter 7**

## Exosomes Therapy in Zoonoses

*Fernando Ojeda, Gabriela Barreto and Sinforiano J. Posadas*

#### **Abstract**

Exosomes are smaller extracellular vesicles (EVs) involved in complex intercellular communication, which were first discovered in sheep reticulocytes. Exosomes include two subpopulations, large (Exo-L, 90–120 nm) and small (Exo-S, 60–80 nm) exosome vesicles. Recently studies of RNA viruses including SARS-CoV-2 have demonstrated that exosomes release regulatory factors from infected cells and deliver other functional host genetic elements to neighbouring cells, and these functions are involved in the infection process and modulate the cellular responses. This review provides an overview of the biogenesis, composition, and some of the most striking functions of exosome secretion in zoonoses and identifies physiological/pathological areas in need of further research as well as potential therapeutic agents in zoonotic disease.

**Keywords:** RNA virus, exosome, infection, miRNA, active proteins, lipids, and nucleic acids

#### **1. Introduction**

Zoonotic diseases are estimated to cause 60% of infections in humans. Treatments are mainly based on the use of antibiotics and antimicrobials; this creates resistant strains, searching for new therapeutic approaches of paramount importance [1]. Cellbased therapy, and especially stem cell therapy, has become a promising therapeutic field in which many see opportunities to treat incurable diseases. Among the various cell types, MSCs have attracted attention due to the source of origin, a high proliferation rate, low-invasive and ethically unproblematic procurement procedure [2].

The therapeutic effect of MSCs seems to rely on the modifications they exert on their microenvironment through paracrine interactions, secretion of soluble factors, cytokines, and trophic factors. It is possible to simplify treatment by using only the components secreted by MSCs, constituting the so-called secretome, which includes immunoregulatory factors (e.g., IL-6 and IL-10), prostaglandin E2, hepatocyte growth factor, indolamine 2,3-dioxygenase, nitric oxide, TGF-ß, and human leukocyte antigen, as well as extracellular vesicles. In fact, these cells can be considered potent pharmacotherapeutics that release biologically active substances [3].

Once released, EVs and soluble proteins interact with target cells (by ligand-receptor interaction or by internalisation) and modulate cellular responses. The secretome can activate endogenous stem cells and progenitor cells, suppress apoptosis, regulate the inflammatory response, stimulate extracellular matrix remodelling and angiogenesis, reduce fibrosis and mediate chemoattraction [4].

#### *Zoonosis of Public Health Interest*

Exosomes are nanoscale extracellular vesicles with a lipid bilayer of endocytic origin and are secreted by almost all cell types and physiological states [5]. They are small with a diameter of 40–100 nm [6] and can be permeable to biological barriers.

Exosome formation takes place by internal plasma membrane budding to form multivesicular bodies (MVB) [7], which can also originate from the trans-Golgi network [8]. Within the MVB, exosomes are formed by further internal budding and then released by fusion of the MVB membrane with the plasma membrane [9].

Exosomes contain a large number of parental cell proteins, and their membrane is abundant with proteins of the tetraspanin family (CD9, CD63, CD81, and CD82), which are widely used as exosome markers. They also have adhesion surface proteins to facilitate their internalisation by other cells [10].

They have a defined composition, depending on cell type, pathology, and activation state, thus exerting their role on specific target cells to release their protein content, mRNA, and, importantly, specific microRNA molecules [11].

Exosomes are considered safe because they lack the potential for endogenous tumor formation as they cannot self-replicate, have low immunogenicity and, when injected intravenously, lead to low embolism formation [12]. The application of exosomes in therapy also has technological advantages: they can be managed and stored easily, and they are a suitable product for use in emergency interventions [13].

Exosomes can be isolated from cell culture supernatant by different methods (each with different limitations). Current techniques are based on exosome size (30– 100 nm), density (1.13–1.21 g/ml), and exosome-specific markers (such as CD63). The general method is based on ultracentrifugation of the cell culture supernatant. However, this method often entrains impurities from microvesicles or other cellular detritus. In addition, the high centrifugal force and duration of centrifugation can cause damage to the exosomes [14].

Summarising, with a conglomerate of cytokines, growth factors, mRNAs, and microRNAs having anti-inflammatory, immunomodulatory and regenerative functions; exosomes play a role as paracrine and endocrine mediators; a fact that, together with their safety profile, stability, and scalability, make them a valuable treatment option for zoonotic diseases either as vehicles or as vaccines themselves (see **Table 1**) [15].

In view of the above, the objectives of this chapter are as follows:

	- a.Possibility of altering target cells by acting as molecules in intercellular communication.

b.Potential to act as a vehicle for the delivery of desired therapeutical targets.

#### **2. Methodology**

The study presented here follows a qualitative methodology, as it pursues the description and interpretative understanding of exosome therapy for diseases of zoonotic origin. Specifically, we will stick to documentary research to approach the aforementioned object of study. Thus, both review and research articles, as

*Exosomes Therapy in Zoonoses DOI: http://dx.doi.org/10.5772/intechopen.105121*



*This table describes the pathogens and their origin, as well as the function of exosomes in the organism. Source: Compilation based.*

#### **Table 1.**

*Overview of the different pathogens and how exosomes work as therapy.*

well as governmental websites will be used. In all cases, the types of documents are electronic. As this is documentary research of an exploratory nature, the aim of this exploratory documentary research is fitting the above-mentioned objectives.

The studies have been reviewed in different databases:


The search for documents was carried out based on keywords such as zoonosis, exosome, vaccine, infection, intercellular communication, rabies, Ebola, HIV, SARS-CoV-2, influenza, brucella, salmonella, mycobacterium tuberculosis, toxoplasma gondii, and cryptococcus neoformans.

For the development of the documentary work, a total of 108 bibliographic sources were found, based on: (1) year of publication, except for the study by Pan BT (1985), and (2) relevance of the study associated with our objectives, as some of them, despite addressing the subject, did so from a more general perspective.

For all these reasons, the sample includes information of both a qualitative and quantitative nature, which allows us to have a bigger knowledge range to argue properly our work.

#### **3. Exosome-based therapy for zoonotic diseases**

#### **3.1 Rabies**

Rabies virus is a single-stranded RNA belonging to the Rhabdovirus family. They are bullet-shaped, with a flat and a rounded end, an envelope with spicules

#### *Exosomes Therapy in Zoonoses DOI: http://dx.doi.org/10.5772/intechopen.105121*

surrounding the genome, and a helical capsid. The Rhabdovirus family includes the genus Vesiculovirus, which causes vesicular stomatitis virus, and the genus Lyssavirus, which causes rabies [48].

The receptor of the rabies virus is the nicotinic acetylcholine receptor. It enters the cell by endocytosis and replication takes place in the cytoplasm. It has RNAdependent RNA polymerase. Transcription of the viral RNA produces five individual mRNAs that will give rise to five proteins, a process that takes place in the Negri corpuscles. Negri bodies are cytoplasmic inclusion bodies that correspond to aggregates of viral nucleocapsids and are formed as a result of the replication process (diagnostically useful) [49, 50].

Rabies is a zoonosis whose reservoir is wild animals, mainly bats, and dogs (in 99% of cases) [48]. The virus is excreted in the saliva of an infected animal and enters other animals through bite wounds or scratches. The virus is very labile, so transmission through contaminated objects is rare. Human-to-human transmission is not confirmed [51].

Pre-exposure prophylaxis is based on an inactivated vaccine in at-risk personnel. As the incubation period is long, post-exposure vaccination is feasible. The original vaccine designed by Pasteur was an attenuated virus vaccine (obtained from neural tissue of infected animals) and had the disadvantage of producing adverse reactions with allergic encephalomyelitis. Post-exposure prophylaxis is based on wound lavage, passive immunisation with human rabies immune globulin and active immunisation with inactivated vaccine (five intramuscular doses) [52].

It is known that infected cells release exosomes into the environment [53, 54]; however, the role of exosomes in infections is not entirely clear. Therefore, Wang et al. evaluated the role of exosomes in rabies virus infection. After isolation of exosomes by density gradient, they characterised them by transmission electron microscopy and western blotting. The results were that, after infection, the release of exosomes increased. They also used treatment with two inhibitors of exosome secretion, GW4869, and si-Rab27a, and found not only that exosome secretion decreased, but also that the presence of intra- and extracellular viral RNA was reduced. This finding provides a better understanding of the role of exosomes in rabies virus infection and proposes it as a new research target for the development of therapeutic strategies [16].

Research groups such as Yang et al., Alvarez-Erviti et al. and Kumar et al. highlight the role of rabies virus glycoprotein-modified exosomes (RVG-modified exosomes) for, in addition to being loaded with the desired content to tackle the condition, the ability to cross the blood-brain barrier and bind specifically to the acetylcholine receptor of neurons [17–19].

Yang et al. conducted a study with the human diploid cell line Medical Research Council-5 (MRC-5), which is used to develop vaccines. In the case of rabies, a vaccine based on this cell line exists, but with low efficacy due to the limitation of infection on the cells. These researchers demonstrated that, following rabies virus infection in the MRC-5 cell line, exosomes have a dual function: (I) to interfere with the type I interferon signalling pathway to increase its production and (II) through this regulation, to inhibit rabies virus replication [20].

#### **3.2 Ebola**

Ebola virus is a filamentous, enveloped, helical nucleocapsid, single-stranded negative RNA genome. It belongs to the Filovirus family where the Marburg virus is also found. The genome has the information to encode seven structural proteins that form the virion. It replicates in the cytoplasm similar to Rhabdoviruses [55].

The Ebola disease outbreak in West Africa, which began in March 2014, was the largest viral haemorrhagic epidemic in history. Nearly 40% of people who contracted Ebola during this outbreak died. The natural reservoir is unknown. Transmission is by direct contact with infected blood and secretions; there is no airborne transmission. There is no vaccine or specific treatment. Favipiravir, an antiviral against RNA viruses, has been used; in addition, passive immunisation is carried out by the administration of sera [56].

Exosomes released by the Ebola virus, called VP40+, cause cell death and apoptosis, eventually destroying immune cells [21]. Because exosomes play a role in intercellular communication and influence cellular responses, they may be targeted for therapy development, specifically for vaccine production [22].

CD8 T cells play a central role in antiviral immunity and are also involved in the immune response generated against other intracellular pathogens, such as intracellular bacteria. Destruction of virus-infected cells requires the T-lymphocyte receptor to recognise peptides associated with MHC class I molecules. This triggers the activation of lymphocytes to (I) destroy infected cells and (II) produce inflammatory cytokines [57]. This immune response has been seen in Ebola survivors [58] and in non-human primates [59].

Exosomes are vesicles released by all cell types of the organism [60, 61]. By developing intramuscular DNA vector vaccines, namely NEFmut, scientists Anticoli S. *et al*. incorporated exosomes to study the immune response against Ebola virus (based on those discussed above). They were able to see an increase in the levels of cytotoxic T-lymphocyte response and cope with the disease [23].

#### **3.3 HIV**

Human Immunodeficiency Virus (HIV) belongs to the retrovirus family. It is a virus with two identical single-stranded RNA molecules enveloped. They are called *Retroviridae* because they possess an enzyme with reverse transcriptase activity (retrotranscriptase) that allows RNA to be transcribed into DNA, making it an RNAdependent DNA polymerase. There are four families of retroviruses: oncornavirus (human T-lymphotropic virus), spumavirus (only in animals), alpharetrovirus (Rous sarcoma virus), and lentivirus (HIV) [62].

Replication begins with the binding of viral glycoproteins to the primary receptor, the CD4 molecule, and to the co-receptors CCR5 or CXCR4. They infect CD4 T cells and other cells that express the CD4 molecule on their surface, such as monocytes, macrophages, or dendritic cells. They penetrate the host cell by fusion of the envelope with the cell membrane. Binding to the co-receptor brings the envelope into contact with the plasma membrane and the glycoprotein gp41 promotes membrane fusion. The genome is released into the cytoplasm and undergoes a reverse transcription process, which uses the transfer RNA as a primer [63].

To avoid the development of HIV resistance, a combination of three drugs from two different classes is recommended. The recommended antiretroviral treatment in naïve patients (those who have not had previous antiretroviral treatment) is outlined below [64, 65]:


• 2 NRTIs (nucleoside reverse transcriptase inhibitors) + 1 INI (integrase inhibitor).

The above-mentioned therapy has side effects such as decreased life expectancy and the virus may develop resistance. Shrivastava et al. developed an HIV promoter targeting the ZPZ-362 protein that fuses with DNA methyltransferase domains capable of long-term HIV suppression. This promoter is introduced into exosomes acting as a transport medium and allowing delivery to act in epigenetic regulation. Analysing the results, they found that this transport medium performed its function perfectly, as once inside, the methylation machinery acted, leading to viral suppression [24].

More than half of HIV-infected people suffer from cognitive problems due to prolonged inflammation and disruption of the blood-brain barrier (BBB). The problem is that not all treatments are able to cross the BBB. Therefore, exosomes have been proposed as drug delivery vehicles since, among their many characteristics, is the ability to cross the BBB [66].

Among the essential genes for viral replication that form a regulatory protein is Tat (Trans-Activator of Transcription). It increases the level of HIV double-stranded RNA transcription; in its absence, there is little RNA transcription. On this premise, Tang et al. introduced the Tat protein into exosomes, enabling the reactivation of HIVinfected CD4 T cells. This makes it possible to deal with latently infected cells [25].

#### **3.4 SARS-CoV-2**

SARS-CoV-2 belongs to the coronavirus (CoV) family, named after its characteristic morphology, which resembles a solar corona when viewed under the electron microscope. CoVs are classified into four different genera according to their phylogeny and genomic structure: alpha, beta, gamma, and delta [67]. They are a family of viruses that can cause multiple systemic infections or damage in various animal species [68]. Genomic analyses show that SARS-CoV-2 is from the same beta coronavirus (βCoV) family as SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV), and they have high sequence homology [69]. In 2003 SARS-CoV-1 caused an epidemic with 8273 cases and 775 deaths [70]. The MERS-CoV epidemic, however, caused 1139 cases and 431 deaths in 2013 [71].

Coronaviruses are composed of a single-stranded positive-sense RNA, with a genome ranging from 26.2 to 31.7 kb [67]. It has mainly three viral proteins in the virion envelope: spike protein (S), membrane protein (M), and envelope protein (E). The spike protein mediates virus entry and determines the range of potential hosts, cell tropism, and pathogenic disease [72].

SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor to infect bronchial epithelial ciliated cells and type II pneumocytes [73], which explains the severity of lung involvement. In addition to the lungs, the receptor is widely distributed in the gastrointestinal, hepatic, renal, nervous, cardiovascular, and other systems. This can lead to pathologies beyond the respiratory system [74]. After binding to the receptor, the viruses fuse their envelope with the host cell membrane and the nucleocapsids reach the target cell [75].

At the end of 2019, several cases of acute respiratory infection were discovered in the Chinese province of Wuhan. Those affected had in common pneumonia of unknown aetiology and exposure to the Wuhan market [76]. Due to its virological similarity and clinical picture with Severe Acute Respiratory Syndrome (SARS)

caused by the SARS-CoV-1 coronavirus, the World Health Organisation (WHO) named the coronavirus SARS-CoV-2 and the disease it causes COVID-19 [77].

On 11 March 2020, the WHO declared the disease a pandemic because of the increase in the number of people affected since the discovery of the virus [78]. At the time of writing (25 March 2022) and according to the Ministry of Health, the total number of COVID-19 cases worldwide is 47,465,969,674 [79], affecting more than 200 countries. It has therefore become a global health problem and many researchers are currently seeking to eradicate it.

Fortunately, scientists have succeeded in developing vaccines to tackle COVID-19. These are composed of mRNA or adenoviral vectors that encode the virus and are enveloped by lipids [80]. Millions of lives have been saved thanks to these vaccines, but issues such as the use of booster doses, the origin of SARS-CoV-2 variants, and whether the vaccines can cope with the side effects of the disease remain unresolved.

Multiple preclinical studies have demonstrated favourable therapeutic effects of intravenously administered MSC-derived exosomes in animal models of acute lung injury [26], acute respiratory distress syndrome (ARDS) [27], asthma, and other inflammatory diseases, with analyses revealing reduced alveolar inflammation, enhanced oedema clearance, restoration of permeable epithelium, membranes and other sequelae of cytokine storm (**Figure 1**) [28].

Taking advantage of the benefits provided by exosomes, scientists Jiang et al. studied the feasibility of an exosome-based vaccine. They introduced the spike protein-binding domain into *Salmonella typhimurium* exosomes. Once the animals

#### **Figure 1.**

*Pathogenesis of SARS-CoV-2 and stem-cell-based therapy and exosomes. (1) SARS-CoV-2 enters the human body via droplets. In human cells, SARS-CoV-2 binds with the ACE2 receptors present on host cells and produces a cytokine storm. This storm results in a severe lung injury. (2) MSCs. (3) MSCs-Exo or EVs are considered a possible future treatment due to many of their properties, such as ACE2—(lack of ACE2 receptors) which prevents a cytokine storm and immune modulation and restoration of damaged cells due to their essential growth factors and metabolites. Source: Compilation based.*

#### *Exosomes Therapy in Zoonoses DOI: http://dx.doi.org/10.5772/intechopen.105121*

were vaccinated (first group), they tested the control group (unvaccinated animals infected with the Delta variant). The first group had less virus replication, less alveolar damage, a slight or no decrease in body mass, and a high titre of IgG antibodies measured in serum and bronchoalveolar lavage compared to the control. This demonstrates the feasibility of an exosome-based vaccine against COVID-19 [29].

One of the side effects of COVID-19 is how it can affect the nervous system. There are several reasons for this. First, because of the cytokine storm producing neuroinflammation which is the basis of numerous neurological diseases such as Alzheimer's, Parkinson's, multiple sclerosis [30], or even psychiatric conditions [31]. Secondly, the direct neuroinvasive capacity of ACE2 receptors, which are also found in the nervous system and are considered potential targets [32]. The third is the indirect action on the nervous system due to the already demonstrated relationship between the intestinal microbiota and the nervous system, as the virus invades the intestinal mucosa and causes inflammatory processes that can lead to neurological damage [31]. Therefore, exosomes could be used as a therapy for this side effect, as intranasal administration not only offers the benefits mentioned above but is also a direct route of entry into the nervous system and also has the ability to cross the blood-brain barrier [29].

#### **3.5 Influenza**

The Orthomyxovirus family has a helical capsid, is enveloped and the negative single-stranded RNA is segmented into eight fragments. Influenza viruses or influenza viruses stand out. There are three types: A, the most important; B, the endemic type; C, very rare [81].

The influenza virus transcribes and replicates its genome in the nucleus of the target cell. Replication begins with the binding of haemagglutinin to the sialic acid of cell surface glycoproteins. They replicate in the nucleus because they cannot synthesise their own mRNA. Transcriptase uses cellular RNA as a primer to initiate viral mRNA synthesis (cap-snatching) [82]. The mRNA is synthesised using 5′-CAP ends of heterologous nuclear RNA as a primer (mRNA cap-stealing). It is assembled in the cytoplasm and exits by budding through the plasma membrane [83].

Virus transmission is airborne via respiratory secretions. Its genetic diversity is based on its segmented genome structure and its ability to infect and replicate in humans and many animal species, such as birds and pigs. Influenza virus type A is characterised by high antigenic variability, much higher than in type B and C [84].

Antigenic variations can be of two types:


For at-risk personnel, possible immunoprophylaxis is a vaccination with inactivated viruses. Other therapeutic options include amantadine, oseltamivir, and zanamivir, which should be administered early within 48 h of symptom onset [81].

miRNAs are single-stranded RNAs that are approximately 22 nucleotides in length and have the ability to regulate the expression of various genes that play a role in development, cancer, defence against organisms, immunity, homeostasis, etc. Scientists Liu et al. studied the role of miRNAs in influenza virus, focusing their research on the functional role of hsa-miR-1975 in the defence of the infected organism. The methodology was based on assessing the antiviral effects of this miRNA by RT-PCR, Western Blot, and plaque assays. The results obtained were not only that virus replication is inhibited, but also that the release of hsa-miR-1975 occurs via exosomes [33]. This indicates evidence of the importance of investigating the therapeutic possibilities of exosomes due to their ability to harbour content that modifies cellular communication [10].

One notable function of exosomes is in cell-cell communication in the immune system, aiding the body's defence against pathogens. Exosomes carry proteins, and mRNA and, as mentioned above, can carry miRNA. An investigation was carried out to look at the performance of exosomes against influenza virus infection. Among the miRNAs studied, miR-483-3p emphasised its role in defense. The researchers were able to demonstrate its capabilities in the release of pro-inflammatory cytokines and the overexpression of type I interferon. They were able to demonstrate the role of exosomes in the inflammatory reaction when a microorganism is present in the body [34].

Influenza virus is acquired via the respiratory tract through inhalation of aerosolized viral particles. Initially, local infection of the upper respiratory tract is established and can lead to acute lung injury. MSCs, specifically umbilical cordderived MSCs (UC-MSCs) and their derived exosomes, which mediate paracrine transport, have the ability to restore the lung microenvironment. They restore the permeability that characterises lung epithelial cells and removes alveolar fluid from impaired cells [35].

#### **3.6 Brucella**

The most clinically relevant species are *Brucella abortus*, *Brucella melitensis*, and *Brucella suis*. They are responsible for classical zoonoses and the most prominent reservoirs are cattle and wild animals; cows (*B. abortus*), goats (*B. melitensis*), and pigs (*B. suis*) [86]. The zoonosis in humans is known as brucellosis, Bang's disease, Malta fever, or undulant fever [87].

They are Gram- coccobacilli, non-flagellating (hence not motile). They grow only under aerobic conditions, and are non-fermenting and slow-growing. They are facultative intracellular pathogens [88].

Brucellosis is a globally distributed zoonosis, is an occupational disease, and is a reportable disease in most countries of the world. *B. melitensis* infections are more frequent in Mediterranean countries, Latin America and Asia. The main prophylactic measure is to avoid exposure and prevent consumption of unpasteurised dairy products. Isolation of infected persons is not necessary, as the infection is not transmitted from person to person [87].

Attenuated *B. abortus* and melitensis vaccines have been successful in preventing infection in cattle [88]. The absence of an effective human vaccine is a cause for concern, because Brucella could be used as an agent of biological terrorism. Current *Exosomes Therapy in Zoonoses DOI: http://dx.doi.org/10.5772/intechopen.105121*

treatment in humans is based on doxycycline with streptomycin or gentamicin; the alternative is co-trimoxazole. Antibiotic therapy should be prolonged for 3–4 weeks. For children and pregnant women, co-trimoxazole and rifampicin are used [87].

As mentioned above, exosomes can function as vehicles and deliver various molecules. This ability is exploited by macrophages to transport interferon-induced transmembrane protein 3 (IFITM3) from uninfected to infected macrophages once the organism is exposed to the Brucella pathogen [36]. IFITM3 is a critical protein for the immune system as it prevents the replication of foreign agents when they enter the body [37]. In this study by Yi et al., they found, in addition to the transmembrane protein mentioned above, that exosomes transport multiple proteins after infection including those involved in the immune response. This ability of exosomes represents a breakthrough in the development of a vaccine to tackle brucellosis [36].

In the research and development of an effective vaccine for Malta fever, a group of scientists led by Solanki KS treated mice inoculated with a virulent strain of *B. abortus* S544 with exosomes. The exosomes were outer membrane vesicles extracted from *B. abortus* S19Δper an attenuated strain, OMVs S19 Δper. After analysis of the results and comparison between the control group (inoculated with the strain, but not treated) and the vaccinated group (inoculated with the strain and vaccinated with OMVs S19) they were able to conclude that there was an increase in the Th1 and Th2 immune system response, with an increase in IgG antibody titres, and cytokines such as IL-2, IL-4, TNF, among others [38].

#### **3.7 Salmonella**

Typhoid salmonellosis is caused by *Salmonella typhi* and *Salmonella paratyphi* serotypes A, B, and C. S. typhi has a capsular antigen that does not form a true capsule because it does not completely cover the cell wall. Adherence of the bacteria to jejunal cells (M cells) facilitates invasion by endocytosis-transfer-exocytosis. Dissemination via blood and lymph from the intestinal tract occurs. Cases of typhoid salmonellosis in Europe are imported by travellers and occur as a circumstantial epidemic. Humans are the only reservoir; they can survive in the gallbladder, generating asymptomatic carriers [89, 90].

Enteric salmonellosis is caused by *Salmonella enteritidis* and *Salmonella typhimurium*. The bacteria gain access to the gastrointestinal tract through food (animal reservoir). Adhesion to enterocytes of the ileum and colon facilitates mucosal invasion mediated by bacterial surface invasions. Endotoxin production is the main cause of food-borne toxic-infection. Enteric salmonellosis occurs both endemically and epidemically. The main focus of infection is livestock; it is a zoonosis [91, 92].

Typhoidal salmonellosis should be treated with antibiotics. Third-generation cephalosporins are recommended. Other antibiotics such as ciprofloxacin or cotrimoxazole may be treatment alternatives. In typhoid salmonellosis, elimination of chronic carriers presents a problem but can be achieved with high doses of antibiotics (4-quinolones or ampicillin) [89, 93].

In enteric salmonellosis, symptomatic treatment is sufficient, loperamide to decrease intestinal activity and fluid and electrolyte replacement. Antibiotic treatment is reserved for exceptional cases [91, 94].

Macrophages or mononuclear phagocytes are cells of the immune system, derived from blood monocytes that migrate to tissues where they differentiate into mature macrophages that can live for years. Their main function is phagocytosis of pathogens and cellular debris, although they also participate in inflammatory

processes by chemotaxis of other cells of the immune system. They are antigenpresenting cells (APCs) and possess an extraordinary cytokine-producing capacity (TNF-α, IL-1, IL-6, IL-12, etc.) in response to pathogen-associated molecular patterns (PAMPs) [95].

Hui WW et al. studied the ability of infected macrophages to trigger immune responses and thus "alert" inactivated macrophages. This communication is carried out by exosomes; this allows macrophages to perform their function and, in addition, due to the possession of lipopolysaccharides by the exosomes, causes an inflammatory reaction to be exerted [39].

Years later, this researcher and his group, due to the lack of an approved vaccine for humans, delved deeper into macrophage exosomes. They studied the proteome of the exosomes of Salmonella-infected macrophages. They observed that, once the exosomes are administered, the body's innate and adaptive response is triggered, leading to a release of the aforementioned cytokines and an increase in the production of IgG antibodies. Likewise, when exosomes are administered intranasally, mucosal defences are activated [40].

#### **3.8** *Mycobacterium tuberculosis*

The genus *Mycobacterium* is characterised by aerobic, non-sporulating, non-motile bacilli. The most important bacteria in this group are *Mycobacterium tuberculosis* and *M. bovis*, the aetiological agents of tuberculosis, and *M. leprae*, the aetiological agent of leprosy [96].

Many of the special characteristics of TB bacteria are due to their cell wall chemistry. It has a murein coat, numerous lipids such as glycolipids (cord factor being trehalose dimycolate), mycolic acids, mucosides, and waxes [97].

Primary TB infection is localised in the lungs. In most cases, pathogens enter the lung via respiratory droplets (airborne transmission), where they are phagocytosed by alveolar macrophages (facultative intracellular pathogen). Bacteria are able to reproduce in macrophages due to their ability to inhibit phagolysosome formation (prevents fusion of the phagosome with lysosomes). In about 10% of cases, the primary infection can reactivate in immunocompromised individuals and progress after months or years to a secondary stage characterised by tissue necrosis [98].

TB is an endemic disease. Although it is much less common in developed countries, from a global perspective it remains a priority medical problem. The major reservoir is the human (except for *M. bovis*). The main source of infection is the human carrier; there are no healthy carriers. Transmission of the disease is usually direct, via respiratory droplets [98, 99].

An attenuated vaccine is available that reduces the risk of infection by 5% and contains Bacillus Calmette-Guerin (BCG), which is an attenuated strain of *M. bovis*. Vaccination provides temporary immunity, for a period of 5–10 years. In persons at risk of developing the disease who are: contact tuberculin-positive, immunocompromised tuberculin-positive, or radiologically confirmed residual tuberculosis, isoniazid prophylaxis for 6 months is recommended [98, 99].

The exosomes shed by the cells into the medium, which allows intercellular communication, can be used as potent immunotherapeutic agents to tackle TB. First, it is possible to add immune cell exosomes to the current vaccine against *Mycobacterium tuberculosis* to enhance the immune response and thus make the defence against subsequent infections effective. This possibility as an adjuvant has been tested in hepatitis and has given good results [41]. And secondly, the ability of exosomes to

#### *Exosomes Therapy in Zoonoses DOI: http://dx.doi.org/10.5772/intechopen.105121*

harbour molecules inside them in order to administer the desired drugs, which are unable to cross biological membranes on their own [42].

In the study conducted by Cheng and Schorey, the main objective was to evaluate the therapeutic capabilities of macrophage-derived exosomes in mice infected with tuberculosis bacteria. The researchers were confronted with the fact that, for the vaccine that exists, the protective efficacy decreases over time and the lungs are exposed to the infection. They concluded that both exosomes applied as vaccines, as a booster with the currently available vaccine, exert an immune response via Th1 and Th2, although the latter is more limited. Finally, an increase in IFN-γ and IL-2 levels in lung cells after vaccination was determined by ELISA [43].

#### **3.9** *Toxoplasma gondii*

It is an obligate intracellular parasite that causes toxoplasmosis. It has several life forms:

Tachyzoites: the result of asexual multiplication by endopolygeny or multiple fusion. They are arranged in clusters or pseudocysts. They characterise the acute phase of infection in which rapid multiplication of the parasite occurs [100].

Bradyzoites: asexual reproductive forms formed by endodiogeny or binary fission. They group together to form spherical tissue cysts. They constitute the chronic (latent) phase of infection [100].

Oocysts: form after sexual multiplication in cells of the host (cat) intestinal epithelium. They are excreted in the faeces and to be infective they need to continue sporulation outdoors, which, depending on external conditions, will occur between two and 21 days. In a warm, humid climate, oocysts can persist viable for more than a year [100].

Humans can become infected by ingesting the tissue cysts contained in the meat of infected animals or by ingesting mature oocysts in contaminated food and water. When a woman's primary infection coincides with her pregnancy, the parasite can cross the placental barrier and infect the foetus, resulting in congenital infection [101, 102].

Pyrimethamine, sulphadiazine, and folinic acid are generally used as treatments. In children with congenital toxoplasmosis, pyrimethamine alone is used. In cases of HIV with toxoplasmic encephalitis, if sensitivity to sulphonamides develops, clindamycin is given instead of sulphadiazine. For HIV patients, trimethoprim and sulfamethoxazole (co-trimoxazole) are used as prophylaxis. In pregnant women spiramycin [103–105].

Dendritic cells immunised with *Toxoplasma gondii* producing antigens are effective in coping with the infection and producing an effective immune response. Based on this premise, Aline F and her team developed a vaccine based on exosomes derived from dendritic cells that had been exposed to *T. gondii*. They were able to prove that the response generated is mediated by Th1 lymphocytes. These secrete IL-2 and IFN-gamma, activate macrophages and NK cells. They also promote the function of cytotoxic T-lymphocytes that activate the cell-mediated immune response to intracellular pathogens such as *Toxoplasma gondii* [44].

A woman infected with *T. gondii* is capable of transmitting it to her foetus. In the study by Beauvillain et al., they focus on how the use of exosomes for this pathology can protect the offspring. They tested both parasite-exposed and non-parasiteexposed dendritic cells and exosomes as vaccines. They concluded that, in addition to triggering an effective immune response, it increases fertility, and this is because the

immune response is type 2 (Th1-mediated response leads to non-viability of pregnancy due to poor implantation and maintenance of the placenta) [45].

#### **3.10** *Cryptococcus neoformans*

It is a unicellular yeast with a size of 3–5 μm surrounded by a polysaccharide capsule. It inhabits soils rich in organic substances. The most common route of entry in humans is respiratory; organisms are inhaled and reach the lungs. Pulmonary cryptococcosis may develop [106].

From the primary pulmonary focus, pathogens spread via the blood to other organs. *C. neoformans* shows a major affinity for the central nervous system, where it develops very severe meningoencephalitis. The treatment of choice for this disease is amphotericin B and 5-fluorocytosine [106–108].

Oliveira et al. investigated the role of *C. neoformans* exosomes upon entry into the organism. They were able to prove in vitro that these vesicles play a modulating role in infection and the generation of the immune response. The complement system is activated, leading to inflammation, phagocytosis, and cell lysis. Furthermore, when exosomes come into contact with macrophages, they release antimicrobial compounds such as TGF, TNF, and IL-10 [46].

Due to the lack of knowledge about fungal exosomes, they wanted to study them in-depth. They used advanced techniques such as cryogenic electron microscopy and tomography, proteomics (random access liquid chromatography in tandem with mass spectrometry), and nanoscale flow cytometry. They were able to conclude that exosomes can function as stand-alone vaccines and elicit an immune response to confront the pathogen [47].

#### **4. Conclusions and future perspective**

Exosome therapies are a major breakthrough in preventive and therapeutic medicine. There are currently 259 ongoing studies involving exosomes according to the clinical trials website ClinicalTrials.gov. In this review, exosomes derived from different cell types are proposed as a therapy for zoonotic infections. The rationale for the use of exosomes, the benefits involved and the fact that MSCs are not used have been outlined above. Due to their immunomodulatory capacity, exosomes will help the immune system to cope with pathologies. They can also be used as vehicles by introducing the desired molecules inside them due to their permeability to biological barriers.

Delivering exosomes intranasally provides faster action, allows smaller doses to achieve the same effect as injection therapy, is non-invasive, avoids the pain typically associated with parenteral therapy, and the potential for side effects is minimal.

Since exosomes trigger the immune system's defence against a variety of zoonotic diseases, further development of their use as vaccines would be important for clinical trials. If finally viable, one option to consider is the creation of a bank of exosomes so that they can be available for both prevention and disease control.

Finally, one option to study would be the possibility that exosomes could fight not just one disease but a spectrum of diseases by activating the immune system and thus boosting the body's defenses. This would make it a universal tool for tackling different pathologies.

#### **Acknowledgements**

We want to thank Ramón Wahl for his contribution to the performance of figure and table.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Fernando Ojeda1,2, Gabriela Barreto2 and Sinforiano J. Posadas1,2\*

1 Instituto Biotecnológico en Medicina Integrativa y Terapias Avanzadas (INBIOMITER), Promalaga I+D, Malaga, Spain

2 DIBIOTHER ORGANIZACION, Promalaga I+D, Malaga, Spain

\*Address all correspondence to: sposman@uma.es

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 8**

## Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention and Intervention

*Andrew W. Taylor-Robinson and Olaitan O. Omitola*

#### **Abstract**

A propensity to re-emerge is a characteristic of bacterial zoonoses, diseases caused by bacteria that can be transmitted to humans from animals. Research shows that their transmission occurs in Nigeria, the most populated nation in Africa. However, due to insufficient epidemiological surveillance of bacterial zoonoses, the magnitude and burden of these infectious diseases is not fully acknowledged. They are therefore not a priority target of the national public health policy. This lesser concern is regardless of their likely role in the extensive prevalence of non-malarial undifferentiated fever in Nigeria. Several animal reservoirs and arthropod vectors of transmission have been identified for these diseases, Yet, the increase in cases of undiagnosed febrile illness emphasizes the imperative to undertake an extensive evaluation of other possible reservoirs, vectors and transmission cycles that may raise the local risk of zoonotic bacterial infections. Animal health interventions have been advanced as an economically viable and practical approach. Further, facilitating the operation of a community-based One Health program is essential to providing the comprehensive epidemiological information that is required in order to improve prioritization of bacterial zoonoses. This would generate impetus for much-needed investment in relevant public health interventions.

**Keywords:** bacterium, emerging, zoonosis, vector, reservoir, transmission, infectious disease, fever, public health, Nigeria, One Health

#### **1. Introduction**

Diseases that are transmitted directly or indirectly from wildlife to humans are a major cause of morbidity and mortality globally, including in Nigeria, which has the largest population and economy in Africa [1]. Around 60% of the 1500 or more infectious microorganisms known to be human pathogens are recognized as zoonotic, i.e. they normally exist in animals but they can also infect humans [2, 3]. While approximately 73% of emerging and re-emerging pathogens cause zoonotic diseases [2, 3], even more prevalent infectious diseases of major public health importance

worldwide, notably malaria and HIV/AIDS, are known to be of zoonotic origin [2]. It is therefore speculated that future generations may face a higher risk of exposure to zoonotic diseases, requiring us to acknowledge the potential impact of this on life expectancy and quality of health [2, 3].

Zoonotic bacterial diseases such as bubonic plague and bovine tuberculosis inflicted enormous damage on mankind during the medieval period, an age in which sanitary measures, vaccines and antibiotics did not exist. In this context, the increasing occurrence and spread of zoonotic bacteria is of concern worldwide, with animals frequently identified as the reservoir host of a wide variety of potential pathogens [3]. The livelihoods of more than 600 million people globally are thought to depend directly on livestock. These communities represent 70% of the poor and marginalized population who are most at risk of zoonotic diseases but are often isolated from adequate health care provision [4].

Bacterial zoonoses are a category of much neglected human infections that may account for a substantial proportion of febrile illnesses without focal features, especially in malaria-endemic hotspots of sub-Saharan Africa, where they are often misdiagnosed as the more familiar protozoan infection [5]. While there are no reported estimates of the prevalence of fever of unknown origin (FUO) in Nigeria records suggest both its common occurrence and incorrect determination of the etiology [6, 7]. Despite the incidence of FUO and although humans have obvious contact with animal reservoirs and vectors of zoonotic disease, potentially important pyrogenic pathogens have not been rigorously investigated in many low- and middle-income countries, particularly in rural areas [8]. A deeper knowledge of the preventable and treatable infectious causes of severe febrile illness is critical to achieving a high level of disease control in developing countries and improving outcomes of affected patients [8].

This chapter discusses the neglected zoonotic bacterial pathogens of Nigeria, West Africa [9]. The focus is on commonly occurring emerging and re-emerging zoonotic diseases, presenting key developments in the field from recent worldwide research, highlighting findings from Nigerian investigations to date and identifying pivotal epidemiological features that have not been described in local studies. Adopting the One Health concept to combat bacterial zoonoses in Nigeria invokes a collaborative, interdisciplinary and multi-sectorial strategy to human and animal health management and interventions. The knowledge gleaned from implementing these principles can be applied in similar West African settings as well as low-income contexts elsewhere.

#### **2. Bacterial zoonoses of public health relevance to Nigeria**

As they are frequently associated with high case fatality rates, zoonoses dominate Nigeria's register of notifiable infectious diseases for which emergency declaration is required [10]. Notable zoonotic diseases in Nigeria include Lassa fever, Ebola virus disease, rabies, influenza, yellow fever, anthrax, plague, tuberculosis, salmonellosis and trypanosomiasis, most of which are endemic [1, 10, 11]. Cryptosporidiosis and food-borne *Campylobacter* and *Escherichia coli* O157:H7 infections also constitute important national zoonotic diseases [1]. Leptospirosis, scabies, pentastomiasis and African histoplasmosis occur sporadically [1]. Considered endemic throughout the developing world, neglected zoonoses are inherently capable of causing local outbreaks and larger epidemics [12].

Zoonotic bacterial infections show tremendous potential to re-emerge once they are considered eradicated or under control, and therefore pose grievous, enduring

#### *DOI: http://dx.doi.org/10.5772/intechopen.106142 Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention…*

threats to public health [3]. Although re-emerging across sub-Saharan Africa bacterial zoonoses are mostly neglected and under-reported in low-income nations [12]. However, they are acknowledged to be common and widely distributed in Nigeria [13]. Their emergence and re-emergence have been attributed to a combination of climatic, ecological, agricultural and socio-economic factors that create an uncertain public health situation [1].

In a recent investigation, a trend towards disease outbreak in Nigeria was reported for zoonoses of *Leptospira*, a Gram-negative, obligate aerobe spirochete [14]. Leptospirosis is an important bacterial zoonosis, especially in northern Nigeria, with a significant level of sporadic occurrences [1]. A national average incidence of six clinical cases of leptospirosis is reported annually, which is considered to be an underestimate [15]. Research during the past two decades in different regions of Nigeria have detected by serology and urinalysis various serovars of *Leptospira interrogans*, including Canicola and Hardjo, which are considered pathogenic in other continents [14, 16–19].

Possibly the first report of the Gram-negative coccobacillus *Yersinia pseudotuberculosis* in the tropics was from Plateau State, Nigeria, and gastrointestinal yersiniosis due to infection with the pathogenic *Yersinia enterocolitica* is also known [20, 21]. Various serotypes of the Gram-negative, motile bacillus *Campylobacter jejuni* emerged in Nigeria decades ago as prominent causes of human gastroenteritis, inflammation of the stomach and small intestine [1]. Infection due to *C. jejuni* and the other primary zoonotic agent of campylobacteriosis, *Campylobacter coli*, have been on the increase worldwide and often exceed salmonellosis and shigellosis in national notifications [22]. Although comprehensive information on zoonotic campylobacteriosis in Nigeria is limited, both *C. jejuni* and *C. coli* have been isolated [22–24]. Globally, campylobacteriosis and non-typhoidal salmonellosis constitute the most prominent and significant enteric zoonoses [24].

*Salmonella enterica* serovars Typhimurium and Enteritidis are the main causative agents of sporadic outbreaks of salmonellosis among Africans, with which observations in Ibadan, the capital city of Oyo State, Nigeria, are consistent [25–27]. However, other less common serovars of the Gram-negative, flagellate, facultatively aerobic bacillus have a more geographically restricted distribution. For instance, the rare *S. enterica* Hidudiffy was the predominantly detected serovar in a study in northern Nigeria but was absent in a similar investigation in the southern region [25, 27]. This was attributable to factors like variation in climate or farming systems between the two regions and may need verification [25]. Other rare serovars that have been detected in Nigeria include *S. enterica* Apapa, Mouschaui and Vinohrady [25, 28]. In a recent large-scale surveillance program in Nigeria, *S. enterica* Eko was identified as a major serovar, one of 17 different serotypes that are potentially being transmitted locally within the country [27].

Brucellosis also remains a major neglected zoonotic disease of low-income nations. While assessment of existing data suggests ongoing transmission of human brucellosis in Nigeria, information on the causative *Brucella spp.* Gram-negative, facultative coccobacilli is not sufficiently clear from the limited bacteriological studies [12, 29]. Other common zoonotic bacterial infections, such as bartonellosis, borreliosis, Q fever and rickettsiosis, are also on the rise globally, especially in developing countries like Nigeria [3, 8]. Another Gram-negative coccobacillus, *Coxiella burnetii*, which causes Q fever in humans, has been reported at high serological prevalence in West African countries and has also been detected in veterinary studies in Nigeria [30]. Species of the Gram-negative *Bartonella* such as *B. elizabethae, B. grahamii*, known

to cause human diseases in Peru and Thailand [31, 32], were recorded in a Nigerian study [33]. Another investigation identified *Bartonella spp*. in Nigeria similar to those detected in Ghana and Kenya [7]. Several studies have also detected rickettsiae, Gram-negative, intracellular coccobacilli, as potential agents of zoonoses in the country [34, 35]. *Rickettsia massiliae*, *Rickettsia conorii israelensis* and *Rickettsia africae*like species have been identified as agents of bacterial zoonoses with possible ongoing transmission in Nigeria while *Rickettsia felis*, a prominent emerging rickettsial pathogen that is common in Senegal and Kenya [36], has a largely unknown epidemiology in the rest of the Africa, including Nigeria [30, 34–36].

Together with the isolation of other Gram-negative bacterial zoonotic agents in Nigeria, such as *Anaplasma platys* and *Candidatus Neoehrlichia mikurensis*, its first known description in Africa [34, 35], the scenario presented is of an increasing threat of bacterial zoonotic infections to Nigerian public health. However, fewer studies are conducted to investigate this class of zoonosis than most other infectious agents across a large geographic footprint of the developing world [8]. Plague is an important re-emergent bacterial zoonosis caused by *Yersinia pestis*, one of the most extensively studied pathogenic bacteria. Yet, with current case reports restricted to Africa, there is no known incidence in Nigeria [37, 38]. It is recognized that most zoonotic infections in the country are documented either poorly or not at all, comprehensive efforts to characterize the zoonotic agents are insufficient, and data on important aspects of their epidemiology are also limited [1, 13].

#### **2.1 Infection risks associated with common transmission routes of zoonoses**

Close contact with animals due to a person's lifestyle choices or occupation is often associated with the re-emergence and heightened risk of zoonotic bacterial infections. Among others, this subjects farmers, hunters, wildlife workers, veterinarians, pet traders, families with pets, butchers and slaughterhouse workers to an increased risk of transfer of infection from animals [3, 10]. Therefore, bacterial zoonoses are generally considered occupational diseases in Nigeria [10, 14], where intimate proximity to animals as well as exposure to their tissues and body fluids are principal risk factors for zoonotic disease transmission. A prime example is that of leptospirosis during livestock slaughter and processing in abattoirs [14].

Infections with *Brucella* and *Leptospira* have been associated with handling of wild and domestic animals, through which direct transmission may occur [29, 39]. Association with livestock and pets in northern Nigeria increases the risk of *Leptospira* infection acquired through abraded skin when carelessly handling infected animals and their fluids or tissues [14, 15]. However, a significant link between a person's intimate proximity to livestock or other animals and their contracting leptospirosis is not corroborated by inconsistent observations from other countries, thereby suggesting a complexity of region- and context-specific factors in infection risk [40]. Since studies of leptospirosis in Nigeria are limited [40], concentrated in the north and performed on standard risk groups [14, 15], whether such disparity occurs across varied settings in all regions of the country requires further investigation.

Indirect transmission routes for leptospirosis include soil and water contaminated with urine or other body fluids from infected animals via which *L. interrogans* may enter the human body through mucous membranes of the eyes and nose during activities such as bathing [14, 41]. Globally, heavy rainfall and flooding are associated with leptospirosis outbreaks in overcrowded locations with deficient waste disposal and poor sanitation [41, 42]. These conditions prevail in Nigeria among socioeconomically

#### *DOI: http://dx.doi.org/10.5772/intechopen.106142 Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention…*

disadvantaged communities living in shanty towns, squatter settlements and relief camps [43]. Zoonotic bacterial agents like *Salmonella*, *Campylobacter*, *Shigella*, *Yersinia* and *Listeria* may also be acquired from contact with animals, their dung and droppings, as well as via indirect transmission by ingesting contaminated food [3]. Although known to occur predominantly in temperate zones, sporadic infections with pathogenic serotypes of food-borne *Yersinia enterolitica* as well as the rare *Y. pseudotuberculosis* have been reported in Nigeria [20]. However, aspects of the epidemiology of food-borne yersiniosis in developing countries, such as contamination routes in food, remain poorly understood and require clarification [21].

While leptospirosis may also be acquired through food [14] *Salmonella* and *Campylobacter* are regarded as the leading and most frequent zoonotic agents of human food-borne bacterial gastroenteritis in both developing and developed regions globally. Research performed on food products from markets in the Nigerian States of Sokoto, Plateau and Oyo identified bacteria of both genera to be associated with, and commonly transmitted via, contamination of poultry meat and eggs [3, 22, 24, 44]. A recent investigation in the north-east of the country also identified vegetables as a potential source of salmonellosis transmission, corroborating reports of increasing frequency of *Salmonella* outbreaks elsewhere in the world [28].

Consumption of raw or unpasteurized milk constitutes an important transmission route for *Campylobacter spp.*, *C. burnetii* and *Brucella spp*. [3, 24, 29]. In Nigeria, *C. jejuni* was quite recently isolated from raw cow's milk in Sokoto [45], while shedding of *C. burnetii* was detected in milk from cattle in Zaria in the 1980s [46–48]. Q fever is a devastating zoonotic disease that is associated with dairy farming, especially of goats, even in industrialized nations like the Netherlands, where it was epidemic between 2007 and 2010 [3, 49]. Among Fulani pastoralists in Nigeria it is important to assess the risk of *C. burnetii* infection due to Q fever outbreaks [50–52].

Inhalation of aerosolized organisms, one of the ways to contract the plaguecausing *Y. pestis* that is endemic to Africa, is also regarded as the most important transmission route for *C. burnetii* infection in humans [53, 54]. Aerosols containing *C. burnetii* result from infected animals shedding bacteria, usually during parturition and lactation, which are inhaled from placental fluid, vaginal mucus, milk, urine and environmental dust [48, 49]. Q fever contracted by humans inhaling contaminated aerosols or ingesting raw milk or raw milk products has been reported elsewhere but not yet in Nigeria [54, 55]. A nationwide assessment of the risk of *C. burnetii* contamination of aerosols and dairy products may be justified in light of the fact that 90% of milk produced in rural areas is consumed raw [13].

Q fever poses a chronic health risk to immunocompromised individuals [48]. Immunosuppression from such varied causes as cancer treatment, pregnancy, organ transplant, diabetes, alcoholism and even infancy is also an important risk factor for other bacterial zoonoses including salmonellosis, bovine tuberculosis and bartonellosis, with *Salmonella* being a leading cause of bacteremia in this at-risk population across sub-Saharan Africa [3, 10, 26, 33, 56].

#### **2.2 Animal reservoirs and the potential role of arthropods as transmission vectors**

Livestock and animal reservoirs are recognized to contribute substantially to the continued transmission of bacterial zoonoses. This involvement ranges from passive to active roles including passive transmission of infection through bites and scratches, contamination of the environment and active transmission as vectors [3, 41, 57, 58]. The widespread distribution of zoonotic pathogens in domestic and

wild animal populations represents a large reservoir of these disease-causing agents. Consequently, there is a perpetually high risk of infection between infected and susceptible animals with the potential for spread to human hosts [13].

It is estimated that approximately 20% of animal bites or scratches become infected, which is an important transmission route to humans for *Bartonella henselae*, the causative agent of cat-scratch disease. This is also transmitted by cat fleas (*Ctenocephalides felis*) that are found on both cats and dogs [3, 53, 59]. Cats are under-studied as potential reservoirs of locally acquired *Bartonella* infection despite their relative popularity as companion animals and the frequent occurrence of strays [60, 61] even in hospital premises in northern Nigeria [62]. However, a first report of bats as reservoirs of *Bartonella* in Nigeria identified four species as well as bloodfeeding bat flies as possible contributors to local transmission of bartonellosis [7], similar to findings from Kenya, Ghana and Algeria [63–65]. While bats are thought to host numerous pathogens, most research has focused on viral zoonotic agents. Accordingly, the main aim of the recent survey overseen by the Nigerian Ministry of Health was to catalog new and existing viruses in the bat population [7, 66]. These flying mammals live near humans in many communities in Nigeria, where they are used for food, cultural practices and rituals. They may therefore play hitherto unrecognized roles in transmission of *Bartonella* and other zoonotic bacterial agents [7].

The past decade has seen reports of fleas, which are commonly known to transmit *Y. pestis* plague and likely contribute to the transmission of zoonotic pathogens such as *Rickettsia typhi*, *R. felis* and *B. henselae* [53, 67]. Therefore, it is necessary to investigate this hematophagous insect vector in Nigeria, a location where information about the possible role of fleas in zoonotic transmission is scarce. Conducted in 2011, the first known examination of rodents and their ectoparasites for *Bartonella* in Nigeria detected species in fleas, ticks and earwigs; some isolates represent known strains while others are of uncertain identity and require further characterization and evaluation for possible pathogenicity [34]. Meanwhile, human fleas (*Pulex irritans*), which have been found to infest Nigerian pets [68], and cat fleas have each been linked with recently re-emerged *Bartonella quintana* infections in some developed countries [53]. Cat fleas and several other flea species are also considered to be major reservoirs and biological vectors of *R. felis*, capable of transmitting this pathogen horizontally and vertically. However, conflicting reports from Senegal suggest that, despite the high prevalence of human infection, cat fleas do not contribute to local transmission of *R. felis* [53, 69]. Canine fleas such as *Ctenocephalides canis*, associated with transmission of *B. henselae* in other global regions, have a high prevalence in Nigeria where pet dogs are ubiquitous and in close contact with humans, yet the potential role of this flea in transmitting zoonoses locally is not well understood [68, 70, 71]. It is also thought that any species of flea is capable of transmitting *Y. pestis* under suitable conditions, and that *P. irritans* may play a crucial role in the transmission of plague from person to person [53]. Often considered a mere nuisance because of prior reports of vector incompetence for *Y. pestis*, cat fleas are suspected of causing an outbreak of plague in Uganda [53]. However, although human and other flea species are found on Nigerian pets there is currently no documented association between cat fleas and local transmission of *Y. pestis* [38].

In addition to hosting *Y. pestis*, rodents are reservoirs of *R. typhi*, the causative agent of murine typhus, as well as other zoonotic bacteria like *Bartonella* [32, 53]. *Y. pestis* has been detected in over 200 species of wild rodent in natural plague foci in Africa and across the globe [32, 53]. Small mammals such as rodents are common natural *Bartonella* reservoirs and close associations with humans due to conditions like

*DOI: http://dx.doi.org/10.5772/intechopen.106142 Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention…*

overcrowding in rural communities enhance infection transmission [31, 33]. Rodents, particularly rats, are also widely recognized as prominent reservoirs of *L. interrogans*, typically spreading leptospirosis via their infected urine [42]. A variety of wild and domestic animals that are considered reservoirs of *Leptospira* have been extensively studied for leptospirosis in Nigeria. Dogs, cattle, pigs, sheep and goats are recognized to excrete leptospirochetes in their urine, thereby contaminating the environment for many months or even years after infection [19, 39, 42]. Yet, in Nigeria very little effort has been made to investigate the contribution of rodents to the epidemiology of this disease, with the last known report being published in 1990 [42, 72].

Livestock are principal reservoirs of zoonotic infections such as brucellosis and Q fever, with ruminants being the main source for transmission to humans [29, 48, 55]. For food-borne zoonotic pathogens like *Y. pseudotuberculosis* and *Y. enterocolitica*, pigs, sheep, goats and cattle are the main reservoirs of the pathogenic serotypes causing human infection in Nigeria [20]. *C. jejuni* and other human campylobacteriosis agents are also food-borne bacteria for which chicken has frequently been identified in Nigeria and elsewhere as a common reservoir [23, 24]. A higher prevalence of *C. burnetii* was observed in feeding *Rhipicephalus evertsi* ticks than in questing ticks collected from cattle in Oyo State, indicating that cows may be reservoirs of Q fever in Nigeria [30]. Wild birds, dogs, cats and monkeys are also natural reservoirs of *Campylobacter*, with certain species showing association with specific animal hosts [23]. The increasing consumption of camel meat and its other products in northern Nigeria prompted investigation that identified camels as potential reservoirs of *Campylobacter* zoonosis [23]. Genomic analysis of *S. enterica* Eko isolates collected from various sources in Nigeria also demonstrated an association between camels and non-typhoidal *Salmonella* zoonoses, implicating camels, together with cattle, as a principal reservoir for infection of humans [27]. In low-income nations, where sources and routes of transmission of salmonellosis are poorly defined, common food-producing animals are considered to be major reservoirs of *Salmonella*. An example is that of poultry in Nigeria, the studies on which corroborated research performed elsewhere in identifying chickens as a major reservoir of a broad range of *Salmonella* serotypes such as Hadar known to colonize flocks [26, 28]. However, transmission of *Salmonella* has also been linked to pet and indoor-dwelling reptiles such as wall geckos in Nigeria and worldwide, pointing to a potential role for captive reptiles as reservoirs of disease [25]. A pet lizard was implicated as the source in the first report of human infection with *S. enterica* Apapa [73]. Infections of Apapa and other rare serotypes such as Jukestown, Mouschaui and Oritamerin were identified in Ibadan, where these bacteria were not detected in chickens screened for salmonellosis. This suggests local transmission via unverified sources of infection such as household lizards, as these serovars have previously been associated with reptiles and amphibians [25].

The number of known animal reservoirs and vectors of *Bartonella* also continues to increase; as with fleas, other hematophagous arthropods such as sand flies, lice, mites and ticks transmit bartonelloses between the reservoir and final mammalian host, including humans [3, 34]. Tick-borne bacteria and other pathogens are recognized as significant causative agents of human and animal disease [33]. Considered a carrier of infectious disease second only to mosquitoes [33, 74], ticks were identified as a potential vector of Q fever in the 1930s following the first isolation of *C. burnetii* from *Dermacentor andersoni*, the Rocky Mountain wood tick [55]. Because of the frequent detection of *C. burnetii* in ticks collected from the wild as well as experimental evidence of their vectorial capacity, ticks are now considered to act as vectors of

Q fever transmission [55]. The tropical bont tick, *Amblyomma variegatum*, is adept at supporting transmission of *C. burnetii*, for which it is considered a reservoir, as well as of *R. africae*, in Nigeria and Uganda [54, 75]. The largest tick species in Nigeria, *A. variegatum*, is the most common, providing a significant risk of Q fever transmission in Nassarawa, Oyo and Plateau States, where *C. burnetii* has been isolated from fieldsampled ticks [54]. Detection of *C. burnetii* in ticks should be carefully interpreted until a method to directly distinguish between *C. burnetii* and *Coxiella*-like bacteria is developed. However, while following currently recommended procedures for screening for *C. burnetii*, these findings point to a role for tick reservoirs in transmitting Q fever in Nigeria [55].

Tick-borne rickettsiosis also occurs frequently in West Africa and *R. conorii israelensis*, the etiological agent of Mediterranean Spotted Fever which has been reported in Senegal [76], was first detected in Nigeria in the brown dog tick, *Rhipicephalus sanguineus* [34]. *R. africae*, the cause of African tick-bite fever, was identified in the cattle tick, *Rhipicephalus microplus*, from Nigeria in a study screening fed and questing ticks [30]. This rickettsial species is often associated with *Amblyomma* ticks and less commonly with other possible vectors including *Rhipicephalus annulatus* [77]. *R. africae* was isolated from feeding ticks only, so was likely acquired by ingesting blood from an infected host [30, 77–79]. From these reports it is unclear which tick species are potential vectors and thus further elucidation of their vector competence is required. A further Nigerian study in which dogs and brown dog ticks were free of *R. africae* may indicate a specific association between zoonotic bacteria and ticks of cattle and game animals [33], as reported in South Africa [80]. Detection of *Rickettsia massilae* in unfed ticks but not in their cattle hosts implies that ticks serve as both an important vector and reservoir of this pathogen in Nigeria [30]. Similarly, in Plateau State, *Bartonella spp.* was identified in *R. sanguineus* but not in rodent hosts, suggesting that the brown dog tick, whose role in transmission of *Bartonella* has not been previously shown, may be a local reservoir [33].

Other agents of bacterial zoonoses that have been associated with ticks in Nigeria include *Candidatus N. mikurensis* and *A. platys*, which were first detected in dogs, *Ehrlichia spp*., and a possibly novel form of the *Borrelia burgdorferi sensu lato* group that differs from known forms and which is associated with the *Rhipicephalus* ticks that can parasitize humans [30, 34, 68]. Comparing prevalence of pathogen bacteria in Nigerian ticks reiterates that detection in feeding ticks does not establish vectorial competence, i.e., the capacity of a tick to acquire, maintain, and transmit a bacterial species [30]. This highlights the need to demonstrate experimentally the vector capacity of ticks to sustain transstadial transmissibility of major zoonotic bacterial pathogens [30].

While the *in vitro* vector capacity of ticks, from which *Leptospira spp.* were isolated, was demonstrated several years ago, a link between arthropods and transmission of leptospirosis is not widely acknowledged [39, 81]. However, *Leptospira* was detected recently in *Ixodes* ticks from a wetland in Poland, eastern Europe [81]. This hints at a switch of *Leptospira*, aided by environmental fluxes, to adapt to novel hosts and maintain transmission through them, as previously documented for *L. interrogans* Hardjo serovar [41]. This finding requires confirmation from other global locations where ticks are recognized to contribute to transmission of bacterial zoonoses. However, *Ixodes* ticks of medical and veterinary importance are not a common presence in those regions of Nigeria that are prone to flooding [33].

Recent research suggests that mosquito species have emerged as transmission vectors for *R. felis* in West Africa. *R. felis* was detected in the tiger mosquito, *Aedes*  *DOI: http://dx.doi.org/10.5772/intechopen.106142 Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention…*

*albopictus*, in Gabon, which lies to the south of Nigeria, at a similar infection load as found in the cat flea, *Ctenocephalides felis*, currently considered as the primary vector [82]. An invasive species to Nigeria, *Ae. albopictus* is now dominant over the native yellow fever mosquito, *Ae. aegypti*; first discovered in Delta State, analysis suggests a broader distribution across the southern part of the country [83]. Although originally identified in Nigeria in 1991 and first reported in Gabon as recently as 2006, the role of *Ae. albopictus* in arbovirus transmission is a major focus of investigation in Nigeria [83], yet its possible association with *R. felis* is less of a research priority. In Cote d'Ivoire, Gabon and Senegal, West African countries in which *Ae. albopictus* is not known to occur, the major malaria vector in Africa, *Anopheles gambiae*, presents a threat of rickettsial infection as *R. felis* and a new *Rickettsia* species were detected in *An. gambiae* and also *An. melas* [84].

Mosquito transmission may be implicated in the high risk of *R. felis* infection that has been reported in Senegal, where fleas are not involved [36, 69]. However, the possible role of mosquito species in transmitting rickettsial zoonoses in Nigeria remains poorly understood or not described. This also applies to other arthropods, particularly the housefly, *Musca domestica*, which has been identified as a potential mechanical vector able to transmit zoonotic infectious agents such as *C. burnetii* and *Campylobacter* in other parts of the world [58, 85].

#### **2.3 Zoonosis surveillance and public health interventions**

Infection rates in surveillance indicators such as arthropods and other host animals are commonly used to determine the risk of local transmission of pathogens to humans. Thus, within a defined area, the abundance and distribution of ticks and other hematophagous vectors are considered determinants of the epidemiology of vector-borne infections [33, 86]. Nigerian investigations showed that ongoing transmission of emerging and re-emerging bacterial zoonoses is associated with several animal reservoirs and vectors, while preliminary assessment of the risk of infection has also been made [13]. Human infection data are also a valuable surveillance indicator of infection risk [86]. However, in Nigeria this information is vanishingly scarce for bacterial zoonoses such as brucellosis, of which little is known about its prevalence. Further studies are needed to provide comprehensive profiling of clinical cases [13, 29]. Serological evidence of human brucellosis has been recorded but no details are available on the isolation of *Brucella* from patients in Nigeria [29].

Estimates of vector-borne infectious disease burden in low- and middle-income countries focus primarily on malaria and dengue, while zoonotic bacterial infections are largely ignored [8]. This is irrespective of reports from Nigeria justifying an assessment of the human disease burden imposed by *C. burnetii*, *R. conorii israelensis* and other zoonotic pathogens, plus a lack of attention to the public health impacts related to different vectors and animal reservoirs [30, 33]. This neglect of zoonotic bacterial infections is explained partly by under-reporting resulting in a reduced estimation of their disease burden and health impacts, which downgrades their relevance to politicians, policymakers and other interested parties [12]. In Nigeria, brucellosis is often confused with malaria [29], which frequently occurs in the reporting of bacterial zoonoses in other malaria-endemic areas [87]. Recent research conducted in malaria-endemic northern Tanzania showed that leptospirosis, brucellosis, rickettsioses and Q fever are often excluded or misdiagnosed as the parasitic disease [5]. After the gradual reduction of malaria incidence in sub-Saharan Africa this century, there is raised awareness of bacterial zoonoses as significant causes of FUO [5, 88, 89].

In the capital city of Nigeria, the centrally located Abuja, where historical overdiagnosis of malaria is suspected, non-typhoidal *Salmonella* infections were reported in the etiological diagnosis of febrile illnesses [90]. In contrast, for a case of FUO in southeast Nigeria, plausible causes were overlooked in favor of a presumptive malaria diagnosis, a practice common in this region that is also reported for management of febrile pediatric cases [91, 92]. Patients in Africa infected with bacterial zoonoses are likely to be discharged from hospital without receiving a correct diagnosis and thus the appropriate specific treatment. Focus on a wide range of potential causes of FUO, especially zoonotic infections, has been recommended for patient management and disease control in resource-limited settings [5].

While public health interventions for zoonotic infections in Nigeria have been proposed, prioritizing a disease for investment and funding will depend on impact assessments on both humans and animals [12, 13]. Initial reports identified how important joint efforts of medical and veterinary professionals are to controlling zoonoses that affect Nigerian public health and animal welfare [1]. Subsequently, the key role of the Ministries of Agriculture, Health and Information to promote the health of human and animal populations was emphasized [10, 13]. The complex interdependent relationships between human, animal and environmental health have given rise to the concept of 'One Health'. This promotes collaboration of experts from diverse fields, such as physicians, veterinarians and environmentalists, working at state, national and international levels to achieve improved public health outcomes [2]. Despite growing global support for countries to embrace a One Health approach, in Nigeria the interdisciplinary similarities, especially between clinical and veterinary medicine, have not yet been recognized. This remains a major challenge to progress in addressing zoonotic diseases in the country despite increasing awareness of misdiagnosed undifferentiated fever [2, 13]. In 2009, the US Centers for Disease Control and Prevention launched the Animal-Human Interface Project (AHIP), providing technical training to facilitate progress on One Health in Nigeria [66]. Several collaborative projects have been promoted by AHIP together with partner agencies in Nigeria to investigate a wide range of zoonoses; however, attention has mainly focused on viral diseases. This may reflect the assertion that zoonotic viruses have the potential to influence stronger political and economic responses, as exemplified by recent Ebola outbreaks in Nigeria and the Democratic Republic of the Congo [93, 94].

A key recommendation of the One Health strategy for food-borne zoonoses is onfarm intervention. This includes routine vaccinations, immunostimulants and probiotic feed additives to manage animal health, as well as implementing animal welfare policies and measures to limit antibiotic resistance [3]. However, the successful adoption of these interventions in Nigeria is restricted by sustainability issues resulting from the discontinuation of disease control programs [13]. Furthermore, culling livestock and compensating farmers, a strategy that has helped to control zoonoses in industrialized nations, has not proved effective in Nigeria. This is because farmers, especially Fulani pastoralists, are unwilling to cooperate when infectious disease control involves the intentional loss of their herds [13]. However, changing lifestyles among settled Fulani communities, including healthcare attitudes and practices, may lead to greater receptivity of this influential group to interventions in future [51].

Among food-borne zoonoses such as salmonellosis conspicuous antimicrobial resistance of public health concern has been reported in Nigeria [25, 95]. Curbing the indiscriminate use of antibiotics as animal growth promoters that is commonly practiced requires the imposition of strict regulations. *S. enterica* Typhimurium isolates bearing close similarity to the multidrug-resistant ST313 strain that circulates in

#### *DOI: http://dx.doi.org/10.5772/intechopen.106142 Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention…*

sub-Saharan Africa, as well as other strains resistant to tetracycline and sulfamethoxazole, have been identified in Ibadan [25]. This is attributed to the non-selective use of antibiotics at therapeutic and sub-therapeutic doses, which was observed in cattle examined in the same location where residual doses of oxytetracycline and penicillin-G were found [96]. Of associated concern, an alarming trend in the use of fluoroquinolones, tetracyclines, beta-lactams/aminoglycosides and macrolides for questionable purposes including disease management and growth promotion of livestock was recently highlighted for southwest Nigeria [95]. Meanwhile, other countries led by the United States have banned quinolones as a growth promoter in poultry feed due to the public health impact of pharmaceuticals used to treat both human and infections [3, 95]. In Nigeria, there are no strict laws governing antibiotic residues in animal tissues, while local food and drug regulatory authorities do not pay much attention to veterinary drug safety regulations [97].

Vector-borne diseases are also an important target of the One Health approach. It is expected that better national surveillance and reporting will improve disease control strategies, whereby clinicians play an important role in the effective management of vector-borne zoonoses with enhanced differential diagnoses [3]. The multiple causes of fever are difficult to distinguish clinically and hence many cases of FUO in low-resource contexts may be attributed to either lack of access to or limited provision of suitable medical microbiology laboratory services [8]. As an example, it was reported that Nigerian abattoir workers who eventually received a correct diagnosis of *Brucella* infection frequently complained of continued treatment for malaria despite their condition failing to improve [29]. It is evident that clinicians often lack information on the local epidemiology of causes of severe febrile illness. Consequently, internationally set management guidelines and disease control programs currently have insufficient data to set local priorities for prevention [8].

In sub-Sahara Africa, where hospitals and clinics typically are not readily accessible to affected people, accurate statistics on morbidity and mortality resulting from bacterial zoonoses are difficult to obtain [12]. Food-borne yersiniosis caused by the pathogenic *Y. enterolitica* that is commonly found in developed nations has been associated with chronic gastrointestinal illness, glomerulopathy and other disease symptoms in Nigerians [21, 98]. While *Bartonella spp.* are linked with endocarditis and neuroretinitis in Peru [32], for identical strains isolated in Nigeria a similar association to human disease has yet to be made [34]. In Senegal, where there are lower rates of detection of *C. burnetii* in reservoir cattle than those in Nigeria, seroprevalence rates in humans are as high as 51% [48], suggesting that these may be even surpassed in Nigeria [30]; however, this requires to be substantiated through further investigation. While a case of human leptospirosis recently occurred in Plateau State, no survey of leptospirosis as the cause of febrile illness has been conducted in Nigeria [42]. In 2006, the zoonotic bacterial infections leptospirosis, brucellosis, bovine tuberculosis, campylobacteriosis and salmonellosis were acknowledged as less recognized and under-reported [99]. The true extent to which these zoonoses exert an impact on health, especially at the population level, is unknown. In the following decade, the situation remained generally unchanged for most of these diseases, including brucellosis [29]. Therefore, the underestimation of zoonotic bacterial pathogens in Nigeria contributes to a dearth of integrated approaches to preventing morbidity and mortality from febrile illnesses. For example, this relative neglect stands in stark contrast to pneumonia and diarrhea, each of which is the focus of coordinated global control and prevention initiatives across most of its pathogen range [4, 5].

Determining the spatiotemporal distribution of an infectious disease is an important step in planning and implementing effective infection control and prevention measures [100]. However, in developing countries coordinated epidemiological systems for national surveillance of zoonotic infections are generally inadequate despite indications of a substantial burden of disease [22, 26]. The first comprehensive laboratory-based surveillance of human and animal salmonellosis in Nigeria was targeted at the north-east of the country [101], while another more recent attempt that employed whole genome sequencing to identify sources of *Salmonella* infection from isolates collected across Nigeria was focused solely on the *S*. *enterica* Eko serovar [27]. Reports from the country on human brucellosis similarly focus on standard at-risk populations and thus ignore other potentially susceptible groups. As a result, a century since its initial identification in Nigeria, little is still known about *Brucella* in regard to accurately assessing its zoonotic potential and hence informing establishment of appropriate control measures [29].

Many endemic diseases have increased in global incidence in the past two decades and a large number of vector-borne infections have also emerged in new regions [3]. For Nigeria, this growing public health concern underscores the need for up-to-date, accurate information on bacterial zoonoses, particularly with respect to arthropodborne zoonotic pathogens that have recently emerged in novel vectors, such as *R. felis* in mosquitoes [68]. There is a correlation between the epidemiology of *R. felis* infection and increased risk of dengue in sub-Saharan Africa but not in other regions [78]. Mosquito species identified as potential vectors of *R. felis* in other West African countries, and which may be responsible for its transmission in Senegal [84], are known to be endemic to Nigeria [69, 82–84]. Although human rickettsial infections have yet to be confirmed in Nigeria, as a precautionary measure they are highlighted as a source of potential disease for travelers to the country [102]. Other pathogenic agents of bacterial zoonoses such as *Candidatus N. mikurensis* and *Y. pseudotuberculosis* were described recently for the first time in Nigeria [20, 33], which indicates an extension of their respective geographic ranges into the country.

The risk of contracting zoonotic bacterial infections is elevated among rural communities and for individuals who otherwise come into close contact with livestock or wild animals. Unfortunately, zoonoses that mainly affect subsistence farmers and low-income residents of regional and remote regions do not have a designated control or prevention scheme within Nigeria's national healthcare program [12, 13]. Misreporting of cases and undervaluation of the clinical impact of a disease are factors for a lack of prioritized investment in tailored health interventions [12]. Applying a global burden of human disease methodology, Nigerian policymakers rely on unsubstantiated, incomplete data from other regions, an extrapolation that contributes to the systematic depreciation of zoonotic diseases nationwide [12]. The consequent paucity of resource commitment to public health issues by Nigeria and other developing countries poses a continuing challenge for One Health interdisciplinary collaborations and partnerships to enhance public health surveillance and disease control [13].

As an alternative criterion to total disease burden, appraising the cost-effectiveness of an intervention is a way to identify investment priorities for infection control [103]. The existence of multiple reservoir hosts is highlighted as a major hindrance to the elimination of zoonoses in Nigeria. Thus, interventions primarily targeting animal reservoirs and accompanied by promoting national public awareness are considered cost-effective strategies to constrain zoonotic bacterial and non-bacterial diseases [10, 13]. Investing funds in monitoring and treating animal populations is

*DOI: http://dx.doi.org/10.5772/intechopen.106142 Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention…*

rarely supported strongly in most developing countries despite the potential benefits of improving food security and reducing poverty [12]. Interventions for zoonotic diseases may seem expensive in proportion to the public health benefits *per se*. Evidence of the burden to communities and the cost-effectiveness of integrated control would strengthen the case for a One Health approach to endemic zoonotic diseases [12]. It is argued that by investing in animal health interventions and veterinary care the exposure of a population to locally endemic zoonotic diseases is commensurately reduced [13, 104].

The rewards of a multidisciplinary analysis that covers health and economic factors will easily exceed the outlay and enable the health sector to present a case to policymakers based not on the impact on disability-adjusted life years but rather on the rate of return on public and private investment [12]. Hence, it is advocated that in Nigeria interventions against zoonotic infections should be viewed as a human capital asset and as integral to a poverty reduction plan [12].

#### **3. Future directions**

In order to enhance the security of human and animal health in Nigeria, costeffective strategies are needed to raise the prioritization of bacterial zoonoses in health policies and to encourage investment in health interventions [9]. Current epidemiological surveillance of zoonotic bacterial infections across the country is incomplete, a situation that hinders development of a One Health program. This is an impediment to interdisciplinary collaboration between qualified professionals including environmentalists, veterinarians and clinicians. While different species and strains of common and rare pathogenic bacteria have been identified in vectors and reservoir animals in Nigeria, little is known about their potential impact on human health. Indeed, data on human infection do not exist for some zoonotic diseases. Recent research revealing the emergence of several zoonotic bacterial pathogens in previously unknown vectors and in new geographic locations demands a re-evaluation of their formally recognized national distributions. The knowledge gap regarding bacterial zoonoses in Nigeria is significant, closing of which is critical to the future success of control and preventive interventions. Implementing these public health measures will likely reduce local incidence of FUO.

#### **Author contributions**

Both authors contributed significantly to preparing and writing this chapter.

#### **Funding statement**

No specific funding was received for this work.

#### **Competing interests**

No conflicts of interest declared.

*Zoonosis of Public Health Interest*

### **Author details**

Andrew W. Taylor-Robinson1,2,3,4\* and Olaitan O. Omitola5

1 College of Health Sciences, VinUniversity, Hanoi, Vietnam

2 Center for Global Health, University of Pennsylvania, Philadelphia, USA

3 School of Health, Medical and Applied Sciences, Central Queensland University, Brisbane, Australia

4 College of Health and Human Sciences, Charles Darwin University, Casuarina, Australia

5 Department of Pure and Applied Zoology, Federal University of Agriculture, Abeokuta, Nigeria

\*Address all correspondence to: andrew.tr@vinuni.edu.vn

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Emerging and Re-Emerging Bacterial Zoonoses: A Nigerian Perspective on Control, Prevention… DOI: http://dx.doi.org/10.5772/intechopen.106142*

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#### **Chapter 9**

## Neotropical Echinococcosis: A Review

*Roy D. Meléndez*

#### **Abstract**

*Echinococcus vogeli* (Rausch and Berstein, 1972) and *Echinococcus oligarthra* (Diesing, 1863) (Cestoda: Taeniidae) are the only two species known of Neotropical tapeworms, which cause Echinococcosis Polycystic (EP) and Echinococcosis Unicystic (EU), respectively, in humans and in wild rodents from Central and South America. This review applied a meta-analysis on published research about these diseases during the last decade (2010–2020) with the aim of finding out the new human cases reported on that decade on EP and EU. Several new human cases have been published in these 10 years, and important findings have been carried out on the phylogenetic taxonomy, on the genome of *E. oligarthra*, and on new molecular diagnostic techniques and imagenology applied upon this two neotropical echinococcosis, in particular in Argentina and Brazil. Finally, the life cycle of both *Echinococcus* species appears to be in a dynamic activity, apparently there is an expansion of both zoonotic diseases moving down to Southern zones of Argentina; therefore, a program of epidemiological surveillance on EP and EU is proposed to be carried out in those Patagonic regions.

**Keywords:** *Echinococcus vogeli*, *Echinococcus oligarthra*, echinococcosis, zoonosis

#### **1. Introduction**

Neotropical echinococcosis is a parasitic disease caused by two species of cestodes: *Echinococcus vogeli* (Rausch and Berstein, 1972) and *Echinococcus oligarthra* (Diesing, 1863), which are parasites in the small intestine of their specific definitive hosts: for *E. vogeli* the "bush dog" (*Speothos venaticus*, Lund, 1842), so far the only known natural host (some colloquial names for *S. venaticus* are: "pitoco dog" or "vinager fox" in Argentina; "cachorro do moto" in Brazil; "guache dog" in Venezuela and Colombia), whereas several species of wild cats (Felidae) are hosts for *E. oligarthra*. The life cycle of these two tapeworms follows the "predator-prey" seylvatic patron; thus, a wild rodent the paca (*Cuniculus paca*, Linnaeus, 1776) is the main known intermediate host for *E. vogeli* (the paca is named "lapa" in Venezuela; "guagua" in Colombia) even though it has also been collected from agouties (*Dasiprocta* spp., and from spiny rats (*Proechimis* spp.). On the other hand, metacestodes of *E. oligarthra*<sup>1</sup> have been found in tissues of several intermediate hosts such as the agouties [1] ("picures" in

<sup>1</sup> *Echinococcus oligarthra*: new name given to the former species *Echinococcus oligarthrus*.

Venezuela), spiny rats, pacas, opossums (*Didelphis marsupialis*), and in wild rabbits (*Sylvilagus floridanus*) [2] in tropical forests of Panama, Venezuela, Colombia, Chile, Brazil, and Argentina [3]. Proglotis and many eggs are shed from these tiny tapeworms into the gut lumen of their definitive hosts, passed out with the feces [4, 5], and next, eggs are accidentally ingested by the intermediate hosts, which become infected; in the case of *E. vogeli*, once in the intestine, the oncospheres stages are freed, invading organs such as the liver, lungs, small intestine, spleen, where develop they as protoscoleces, which asexually proliferate forming the hydatid polycystic cyst stage, polycystic for *E. vogeli*. The unicyst for *E. oligarthra* appears to be less erratic, and in three out of four cases diagnosed were found retrorbital. *Echinococcus oligarthra* was reported in its adult strobilar stage before 1860; nonetheless, more than 100 years (yr) have passed from the first report of the adult parasite to the recognition that this species infects humans causing the neotropical echinococcosis [6]. "Bush dogs" (*Speothos venaticus*) are less probably a direct source of infection for humans since it is a wild or seylvatic canid. On the contrary, hunting dogs (*Canis familiaris*), after being fed with raw viscera of pacas, are infected developing numerous Echinococcus *vogeli* cestodes in their small intestine, and thus in this way these dogs are the main responsible sources of infections for humans in rural zones. Therefore, *E. vogeli* and *E. oligarthra* metacestodes can have two transmission kinds of life cycles: (a) seylvatic and (b) rural or domestic to assure its survival as species [7].

A general taxonomic list for of these two *Echinococcus* tapeworms is as follows: Kingdom: Animalia; Phyum: Plathyelminthes; Class: Cestoda; Order: Cyclophylidea; Family: Taeniidae; Genus: *Echinococcus* (Rudolphi, 1801); and Neotropical species: *Echinococcus vogeli* and *E. chinococcus oligarthra* [6, 8]. On October 2019, the World Association of Echinococcosis (WAE) had its 28th World Cystic Echinococcosis Meeting at Lima, Peru, where it was updated the current nomenclature for the genus Echinococcus as follows: (a) it approved the names of Cystic Echinococcosis (for *E. granulosus*), Alveolar Echinococcosis (for *E. multilocularis*), and Neotropical Echinococcosis (for *E. vogeli*, and *E. oligarthra*), (b) the word "hydatid" from now on is used only for cysts caused by *E. granulosus sensu lato*, and (c) in the genus Echinococcus nine (09) species were officially recognized: *E. granulosus*, (*sensu lato* and *sensu stricto*), *E. multilocularis*, *E. canadiensis*, *E. equinus, E. felidis, E. ortleppi, E. shiquicus, E. vogeli*, and *E. oligarthra* [8].

The metacestodes of these two parasitic diseases are well documented and have been diagnosed in more than 200 people, mostly dwellers of tropical and subtropical areas from several Latin American Countries, (Nicaragua, Costa Rica, Panama, Colombia, Venezuela, Ecuador, Peru, Bolivia, Suriname, French Guiana, Paraguay, Brazil, Chile, Uruguay, and Argentina); these parasitoses are listed by the World Health Organization (WHO) among the 17 neglected tropical diseases and classified as zoonotic diseases [9]. The presence and impact of these neotropical parasitoses on humans in syelvatic and rural areas are directly related to different risk factors such as: (a) agricultural activities and deforestation, (b) continuing urbanization, (c) construction of new roads into syelvatic regions, (d) reduction of natural habits, (e) illegal hunting, plus capture and outlaw trade of wild animals, (f) infection in dogs due to their feeding with raw viscera, (g) possibility of scavenging dead animals, (h) lack of anthelmintic treatment, and (i) that these Neotropical Echinococcosis are not under surveillance and no compulsory official notification, because there is no obligation to report clinical cases in humans caused by these parasitic infections to health authorities in many countries of the region such as Colombia [10, 11] and also in other South American Countries [12–16]. The study of neotropical echinococcosis needs to

#### *Neotropical Echinococcosis: A Review DOI: http://dx.doi.org/10.5772/intechopen.106163*

follow and strengthen the holistic project of "One Health" following the WHO and the Pan American Health Organization (PAHO) plan of actions for hydatidosis for Latin American [9]. Therefore, a joint effort by veterinary and human medicine, environmental sciences, imagenology, and ecology is needed to improve our knowledge; in summary, it is a field that requires a multidisciplinary biomedical team to study its biology, diagnosis, treatment, surveillance, and control [3].

Few cases of human echinococcosis due to *E. oligarthra* infections have been diagnosed: the first case ever was a female patient from Venezuela who suffered a retroocular neotropical unicystic infection [17]; the second and third cases were diagnosed in Surinam showing one retroocular unicyst case, and another abdominal case [14, 18, 19]; the fourth case was a rural patient from Brazil who died of tetanus, and after necropsy an *E. oligarthra* unicystic stage was found at cardiac tissue [20]; and the fifth case was also in Brazil, and this patient had an hepatic neotropical unicyst infection [21]. On the contrary, in the period between 1979 and 2020. *E. vogeli* was responsible for causing more than 240 cases of human EP disease in several countries of Latin America [7, 22], and even few cases of EP have been diagnosed in the Netherlands from Suriname people who had moved to this European country [22]. The diagnosis of this neotropical echinococcosis originally has been carried out by the morphology of the cestodes shape, size, and length of the large and small rostellar hooks of these two Echinococcus cestodes [7]; however, the diagnosis has been widely improved in the last two decades: first, by the use of immunodiagnostic techniques such as ELISA, Western blot, or immunoeletrophoresis; second by molecular techniques (PCR) [22–26] and third by the use of imagenology equipment, i.e., ecography, including ultrasonography, Computerized Axial Tomography (CAT), Magnetic Resonance Imagenology (MRI), and conventional radiography; all are important for the diagnosis of CE; all these techniques are used not only for classification and identification of cysts, but also for monitoring the responses to treatments [7, 27–30]; consequently, the number of human cases diagnosed has increased, not only in new cases, but it has also been reported in countries where it had not been diagnosed, i.e., Peru [30, 31] and Argentina [32, 33]. In addition, in the Peruvian Amazon, a study was carried out in wild pacas looking for EP, and 11.7% of pacas were found to be infected with metacestodes of *E. vogeli*, thus representing these pacas' potential risks for humans living in that Peruvian region and for rural and urban dogs [3, 34].

#### **2. Materials and methods**

A meta-analysis was carried out as follows: articles search was performed by the author (RDM), since February 02, 2021, a systematic literature search was conducted on four databases to identify all publications reporting *Echinococcus vogeli, Echinococcus oligarthra*, Echinococcosis policystic, and Echinococcosis unicystic throughout the world in PubMed, Scopus, Research Gate, Google Scholar, and Medline, which were screened using those four (04) words without language restrictions.

Several inclusion criteria were required to meet articles to be selected: (a) should be scientific studies such as cross-sectional, longitudinal, case report or outbreak studies, published in indexed journals, reporting any natural infection of *E. vogeli* and/or *E. oligarthra*; (b) the study design, sample size, sample type, diagnostic methods, and number of *Echinococcus* infected animals; and (c) species of intermediate or definitive hosts animals for *E. vogeli* or/and *E. oligarthra* infections must be specified.

#### **3. Results and discussion**

The meta-analysis of scientific literature published between 2010 and 2020 showed that several new human cases of either neotropical EU and EP have been published during this decade, i.e.: (1) *Echinococcus vogeli* infection in a hunter from the rain forest of French Guiana was confirmed by imaging and mitochondrial Deoxyribonucleic Acid (DNA) sequence analysis [35]. (2) A case of infection by *E. oligarthra* in a Brazilian man was presented as a first case of Echinococcosis unicystic invasion of liver tissues [21]. (3) Two cases of liver EP were diagnosed by computerized tomography (CT) and ELISA in two female members of a Yanomani ethnic group located in the Amazonas State, Venezuela [36]. (4) Another human case of infection but by *E. vogeli* was reported from Argentina, the female patient was a Paraguayan immigrant who presented jaundice and abdominal pain in the right hypochondriac region. The diagnosis was achieved by abdominal CT, immunodiagnosis techniques (ELISA, immunoelectophoresis, Western blot), histopathologic studies, and molecular techniques (PCR) [37]. On the contrary, a review was recently published on the genus *Echinococcus* spp. [38], but new human clinical cases about neotropical EU and/ or PE were not reported; the main information was about the life cycle and morphology of these two tapeworms [38].

The genus *Echinococcus* was recently studied through phylogenetic reconstructions of the relationship between several species using their mitochondrial DNA (mtDNA); moreover, molecular taxonomic analysis was also performed using short mtDNA sequences of genes for the cytochrome c oxidase subunit 1 (cox1) and for NAHD dehydrogenase subunit 1 (nad1) [39–41]. These studies concluded that the origin of the two species of Neotropical Echinococcus appears to be monophyletic; in other words, both share a common ancestor [42, 43]. This monophyletic result was more recently confirmed for *E. vogeli* after studies on its genetic diversity carried out in Western Brazilian Amazon [44, 45]. In addition, mitochondrial and nuclear sequence polymorphisms carried out with 38 isolates of *E. vogeli* from humans and wild animal hosts from Amazonian Regions revealed that *E. vogeli* is partially synanthropic, with a diverse population near or in association ecologically with humans [44, 45]. The use of molecular tools has shown differences in nucleic acid sequences that reflect phenotypic variation, and the phenotypic and genetic characteristics complement the previous observations published by the descriptive parasitologists years ago [20].

The genome of *E. oligarthra* was recently sequenced and assembled from hydatic unicysts obtained from tissues of an agouti (*Dasyprocta azarae*) [40], and it was estimated that its genome has a size of 86.2 megabases (Mb) and 8753 genes, which unexpectedly showed ~90% identity and 76.3% coverage with *Echinococcus multilocularis*, a tapeworm of Palearctic zones of the Northern hemisphere [46], and the phylogenetic work carried out on this *E. oligarthra* genome also showed that: (a) this neotropical genome is at a higher and farther distance from *E. granulosus*, and (b) *E. oligarthra* is one of the basal species of the genus *Echinococcus*. The genome size of *E. granulosus* was also recently estimated in 151.6 Mb, with 11,325 genes, and 9 pairs of chromosomes [47], therefore, the genome size of *E. oligarthra* is smaller, and almost half-size that of *E. granulosus*. The life cycle of *E. oligarthra* was also completed in the Upper Parana Atlantic Forest, Argentina, by microscopic, histological, and molecular techniques (PCR and nucleotide sequence of *E. oligarthra* DNA), and concluded that the agouti (*D. azarae*) is the main intermediate host (prey), and the felines Ocelot (*Leopardus pardalis*) and the puma (*Felis concolor*) are the definitive hosts of *E. oligarthra* [1, 32, 48].

#### *Neotropical Echinococcosis: A Review DOI: http://dx.doi.org/10.5772/intechopen.106163*

It is considered that the number of human cases of neotropical unicystic and EP could be just "the tip of the iceberg" in relation to its real prevalence in Central and South America due to factors such as: (a) most infections occur to farmers, hunters, and rural people who lack medical assistance in those regions; (b) the development of these EP and EU cysts in human tissues or organs is slow and takes time, and during some years, patients are not aware of being parasitized by those polycysts; and (c) under those conditions patients are prone to suffer other infectious or organic diseases, which often might put an end to their lives. Therefore, the total number of human cases only for EP (232 for the year 2008) is perhaps only a small fraction of the real prevalence in South America countries, where there is lack of cumulative reports, of advanced diagnostic methods, and on-time treatment for EP [44]. In other clinical cases, parasitized farmers are able to obtain medical diagnosis and surgical treatment but with fatal results due to the advanced damage to organs such as the liver [21]. Previous publications showed that 172 human cases of Neotropical EU and EP were well documented from 12 countries in 2007 [7], whereas for the year 2008, a total of 232 similar cases were accounted, and from this last amount, 160 cases alone were diagnosed in Brazil (occurring in the States of Pará and Amapa, located in the Western Amazonian Region [44]. The difference between the 2007 and the 2008 data was 60 new cases, which means a 25.8% increment of new cases/year of Neotropical EU and EP per yr., if this percentage is taken as a reference point, then after 10 years (2010–2020), it may be estimated that at least more than 100 new cases of these parasitic diseases may have occurred in humans in seylvatic or rural regions, which were neither registered nor diagnosed.

The WHO included the EU and the EP among the 17 neglected tropical diseases and classified them as zoonotic diseases because these *Echinococcus* parasites infected humans in rural zones and seylvatic regions of Central and South America, where an early diagnosis and treatment for infected people are a difficult process. In this review it was stated that an exact cumulative annual number of human cases in the American Continent is lacking, due to the rural and remote origin of the patients, adults or teenagers, who get the fecal-oral infection from parasitized rural dogs or due to drinking water contaminated with feline feces. On the bases of the difference between the number of clinical cases of EP, published in 2007 and 2008 [7], it can be hypothesized that each year, between 2010 and 2020, may have occurred at least 10 new cases of human EP and of EU; unfortunately, none of those cases would have been registered in any hospital or medical services. Consequently, after a decade it may be estimated that no less than 100 humans were infected and suffered mainly EP. Nonetheless, a review of scientific literature for that decade shows that fewer than 100 human cases of these Neotropical echinococcoses have been published in journals, studied, diagnosed, and received medical services [20, 49].

#### **4. Conclusions**

It is important to underscore that *E. oligarthra* unexpectedly showed ~90% identity and 76.3% coverage with *Echinococcus multilocularis*, a tapeworm located in Palearctic zones of the Northern hemisphere, and this conclusion of genetic identity similarity can lead to hypothesize that *E. oligarthra* could have arrived to the American Continent through the Bering icy bridge. Next, it moved down this continent in the guts of some feline predators, then it crossed the Panama land isthmus millions of years ago arriving to Norther seylvatic lands of South America (now

countries such as Colombia, Ecuador, and Venezuela), and nowadays, this *E. oligarthra* tapeworm appears to be still traveling down territories of the South Cone, perhaps heading toward Patagonia areas. The origin of the Neotropical echinococcosis showed that both tapeworms were brought to South America from North America. In the last year and for the first time, *E. oligarthra* was found, diagnosed, and its life cycle was completed in the Province of Misiones, north subtropical forest of Argentina. It may be hypothesized that both Neotropical *Echinococcus* still has a dynamic life cycle, which may be moving down toward some southern provinces of Argentina). Finally, a proposal would be to keep an epidemiological surveillance program in Southern provinces of Argentina as a public health action to figure out the presence or absence of these Neotropical echinococcoses in those Patagonic Regions.

#### **Acknowledgements**

Thanks to Consejo de Desarrollo Científico, Humanístico y Tecnológico (CDCHT) of Universidad Centroccidental Lisandro Alvarado (UCLA), Barquisimeto, Lara, Venezuela, for logistic and financial support upon this research.

#### **Author details**

Roy D. Meléndez Universidad Centroccidental Lisandro Alvarado (UCLA), Decanato de Ciencias Veterinarias (DCV), Unidad de Investigación en Parasitología Veterinaria (UNIPARVET), Barquisimeto, Lara, Venezuela

\*Address all correspondence to: empleomatic@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Gilberto Bastidas*

Zoonosis is a clear manifestation of a highly complex public health problem. This book discusses various aspects of zoonotic diseases, including their epidemiological behavior, transmission, pathogenesis, diagnosis, treatment, and prevention and control. The information contained herein will help in the development of effective health programs to control and protect against these pathologies.

Published in London, UK © 2022 IntechOpen © ozflash / iStock

Zoonosis of Public Health Interest

Zoonosis of Public Health

Interest

*Edited by Gilberto Bastidas*