LITERATURE REVIEW

INTRODUCTION

Our focus in this chapter is to critically examine relevant literature that would assist in explaining the research problem and furthermore recognize the efforts of scholars who had previously contributed immensely to similar research. The chapter intends to deepen the understanding of the study and close the perceived gaps.

Precisely, the chapter will be considered in two sub-headings:

Conceptual Framework

Chapter Summary

2.1 CONCEPTUAL FRAMEWORK

MONKEY POX

Monkeypox is a viral infection generated by monkey pox Virus. It is identical to smallpox which belongs to the genus Orthopox virus, family Poxviridae, and sub-family Chordopoxvirinae1 .The illness is distinctly developed in the distant areas of Central and West Africa.Initially it was identified in 1958 in animals like macaque monkeys and was first reported in Humans in 1970 in a 9-month Old boy developed illness, which was ultimately approved as human monkey pox by the World Health Organization from Zaire2 .

Monkey pox is a rodent virus which can mostly disseminate among certain rodents in Africa3 . The viruses are oval brick in appearance and have a lipoprotein layer that envelope the viral DNA. The recognition of monkey pox virus is based on biological feature and endonuclease sequence of viral DNA4 .Monkey pox has a clinical presentation equivalent to smallpox like fever, malaise, back pain, Headache, muscle pains but only the dissimilarity is presenting lymphadenopathy5 . Besides monkeys, reservoirs for the virus are developed in Gambian pouched rats, dormice and squirrels.Currently, there is no validate, secure treatment for monkeypox6.

Monkeypox is a zoonotic viral disease, endemic in western and central Africa, which circulates in wild animal hosts and emerges periodically to affect humans, captive or wild nonhuman primates, and other species, particularly rodents. Congo Basin monkeypox viruses are particularly virulent, with human case fatality rates in parts of Africa estimated to be around 10%. West African viruses tend to cause milder disease; however, deaths are seen occasionally in young children, individuals with secondary bacterial sepsis or rare complications such as encephalitis, and people who are immunosuppressed. Monkeypox outbreaks have been reported sporadically in nonhuman primate facilities around the world, especially in the past. Human cases are almost always seen in Africa, but a large outbreak in Nigeria in 2017-2018 resulted in a few imported cases among travelers to Europe and Asia, with one case resulting in person-to-person transmission to a hospital worker. One outbreak occurred in the United States in 2003, associated with virus transmission between exotic pets and from pets in humans. A prompt diagnosis of imported monkeypox can help prevent this disease from becoming established outside Africa in potential animal reservoirs, such as prairie dogs or released exotic pets.

History Of Monkeypox

Monkeypox virus was first reported in 1959 as an outbreak of a pox-like disease in monkeys kept at a research institute in Copenhagen, Denmark [8]. The first human MPXV case in medical history was recognized when, on 1 September 1970, a nine-month-old child was admitted to the Basankusu Hospital in the Democratic republic of Congo (at that time, known as the Republic of the Congo). The boy had a smallpox-like disease from which MPXV-like virus was isolated [8,9,10,11]. Six cases of human MPXV were described in Liberia, Nigeria, and Sierra Leone between October 1970 and May 1971. The first index MPXV case in Nigeria was recorded in 1971, and 10 MPXV cases were reported between 1971 and 1978 [12]. Since then, several thousand human cases of monkeypox have been confirmed in 15 different countries, with 11 of them in African countries. Monkeypox was imported to the United Kingdom, the USA, Israel, and Singapore [13].

Epidemiology

Monkeypox is an illness in humans was first integrated in the Democratic Republic of the Congo, in the town of Basankusu, in 19709 . A second sudden appearance of human illness was distinguished in DRC/Zaire in 1996–1997. In 2003, a small explosion of human monkeypox in the United States appeared among holders of pet prairie dogs10. In 2005, a Monkeypox outburst happened in Unity, Sudan and sporadic Cases have been reported. In 2009, an Outreach campaign among refugees from the Democratic Republic of Congo into the Republic of Congo recognized and confirmed two cases of Monkeypox. A monkeypox outbreak in the Central African Republic was carried with 26 cases and two Deaths between August and October 2016. Normally, the prediction involves the proportion of exposure to the virus, host immune response, comorbidities, vaccination status, and extremity of complications. Poxvirus infections have no ethnic preference and the prevalence is uniform in males and females. Roughly one third of the infections were evaluated to be Sub-clinical. The increase in instances was imputed to the effect of the civil war which had led to increased hunting for forest animals that carry monkey pox, especially Squirrels. Improvement in lifestyle due to increasing urbanization, and intensified Agricultural activities replacing hunting and trapping, the chances of reducing monkey pox, either from the primary reservoir or intermediate hosts, thenit will become a disappearing disease11.

Etiology

Monkeypox isoriginated by Monkeypox virus, which belongs to the genus orthopoxvirus, and is also generated by a class of viruses that include chicken pox and small pox belonging to the same genus12.The reservoir for monkeypox virus is unknown, but is thought to be squirrels or rodents in central Africa. In addition to African species, Studies have shown that there are multiple potential hosts for monkeypox virus encompasses primates, rabbits and rodents. Since Monkeypox virus has an animal reservoir, complete elimination of the disease is not feasible.

Species Affected

The monkeypox virus’s full host range is uncertain. Animals known to be susceptible to infection include diverse Old and New World monkeys and apes, and various rodents, shrews and other small mammals. Among nonhuman primates, clinical cases have been described in chimpanzees (Pan troglodytes) and an infant sooty mangabey (Cercocebus atys) in the wild, as well as captive gorillas (Gorilla gorilla), chimpanzees, Asian orangutans (Pongo pygmaeus), gibbons (Hylobates lar), marmosets (Hapale jacchus), and various monkeys in the genera Cercopithecus, Macaca and Siamiri. Antibodies have been found in other wild or captive nonhuman primates. During an outbreak in the U.S. associated with exotic pets, infected animals included Gambian giant pouched rats (Cricetomys spp.), North American black-tailed prairie dogs (Cynomys ludovicianus) rope squirrels (Funisciurus spp.), dormice (Graphiurus sp.), a groundhog/ woodchuck (Marmota monax), an African hedgehog (Atelerix sp.), a jerboa (Jaculus sp.) and two opossums (Didelphis marsupialis and Monodelphis domestica). Chinchillas (Chinchilla lanigera) and coatimundis (Nasua nasua) developed antibodies after exposure, but viral DNA or infectious virus was not found. Giant anteaters (Myrmecophaga tridactyla) were thought to have been involved in an outbreak among primates at the Rotterdam Zoo in the Netherlands in 1964. Limited early surveillance in sheep, goats and cats in Africa found no evidence of exposure, but antibodies were detected in one pig. A subsequent attempt to infect pigs by rubbing virus into the skin did not result in virus recovery except from the inoculation site. Experimental infections with clinical signs have also been reported in 13-lined ground squirrels (Spermophilus tridecemlineatus), the cotton rat (Sigmodon hispidus), forest giant squirrel (Protexerus strangeri), bobak marmot (Marmota bobak), and red squirrels (Sciurus vulgaris). Adult white rabbits (with the apparent exception of albino rabbits), guinea pigs, white rats (Rattus spp.) and wild type laboratory mice (Mus musculus) are refractory to experimental infection, though newborn rats and rabbits can be infected.

The reservoir host(s) for monkeypox viruses are uncertain, but are thought to be one or more African rodents or small mammals. It is possible that the Congo Basin and West African clades are maintained in different species. Two genera of African squirrels, Funisciurus spp. (rope squirrels) and Heliosciurus spp. (sun squirrels), are among the top candidates for reservoir hosts, but antibodies have also been found in many other species of African rodents, shrews and other small mammals including Gambian pouched rats. Attempts to detect the virus directly in wild small mammals or other free-living species have generally been unsuccessful, though it was recovered once from a wild rope squirrel with lesions.

Monkeypox Virus: Morphology, Genome Organization, and Morphogenesis

Having the same morphological characteristics as other orthopox viruses the morphology of MPXV reveals that virions are ovoid or brick-shaped particles which are enclosed by geometrically corrugated lipoprotein outer membrane. MPXV size ranges are known to be 200 by 250 nm [14,15]. Membrane bond as well as densely packed core containing enzymes, a double-stranded DNA genome, and transcription factors are protected by the outer membrane. Due to an electron microscopy fixation artifact, the core is being described as biconcave, and it has lateral body on each side [4,16,17].

The MPXV genome consists of a linear double-stranded DNA (197 kb) [18] covalently joined at its ends by palindromic hairpins, and the inverted terminal repeats (ITRs) are made up of hairpin loop, tandem repeats, and some open reading frames (ORF). Although MPXV is a DNA virus, its entire life cycle occurs in the cytoplasm of infected cells. All the proteins required for viral DNA replication, transcription, virion assembly, and egress are encoded by the MPXV genome. The genes encoding for housekeeping functions are highly conserved among OPVs and are present in the central region of the genome while those that encode for the virus–host interactions are less conserved and are located in the termini region [1,15,16,17,19,20,21,22,23]. In VACV (and most in likely MPXV) intracellular mature virus (IMV) and extracellular-enveloped virus (EEV) are two forms of infectious virions produced in poxvirus-infected cells. IMV is released on cell lysis, while EEV is released from cells via interaction with actin tails, and this is said to be the cause of rapid long distance spread of the virus within the infected host. Although the aforementioned features are for VACV, it is likely that these features are common to all OPVs [22]. However, cell-associated virions (CEVs) are formed following the microtubule-mediated transport of intracellular enveloped virus (IEV) to the cell periphery, in which the outer membrane of IEV fuses with the plasma membrane and remains attached to the cell surface. CEVs are mostly responsible for cell-to-cell spread [24]. IEV is formed when IMV is wrapped by a double membrane derived from early endosomal component [17] or the trans-Golgi network (TGN) [25]. However apart from IEV exocytosis, an alternative route for the formation of EEV is by the budding of IMV through the plasma membrane [26]. In the prototype VACV, virion morphogenesis can be defective resulting in non-infectious dense particles (DPs) [26,27], but this has not yet been reported for MPXV. In addition, unlike some strains of CPXV in which IMVs are occluded within A-type inclusions (ATI) [28,29], MPXV do not form ATIs or sequester IMVs into ATIs because of truncation in the ATIP gene [30].

Monkeypox Virus Infection Biology, Diagnosis And Treatment

Animal Models

In choosing an ideal animal model for a study of human disease, there are characteristics that the animals must possess in order to get a desirable result. The animal models must have similar mode(s) of transmission as in human cases, similar disease course, morbidity, and mortality as that of human cases, utilization of infection route identical to the natural transmission of the pathogen, and potentiality of obtaining disease with the same infectious rate as that of causing disease in humans [31].

Experimental infection of Guinea pigs and Golden Hamsters (being challenged with MPXV via intracardial, intranasal, oral, and route inoculation) showed that these animals were resistant to MPXV with the former (Guinea pigs) having no observable symptoms of the disease except edema at the inoculation site (foot pad), and the later (Golden Hamsters), in spite of large dosages of virus, showed no apparent signs of disease. Adult rabbits have no observable signs of the disease following oral inoculation with the same strain of MPXV, but acute illness, as well as, generalized rash was observed when the route of infection was intravenous [31,32].

When adult ground squirrels (Spermophilus tridecemlineatus) were challenged with 105.1 pfu (plaque-forming unit) of the West African MPXV via intranasal or intraperitoneal inoculation, anorexia and lethargy (as symptoms) were shown within four to five days of infection, and no other noticeable symptoms. However, when challenged with the Congo Basin MPXV, the animals were found to have more rapid and uniform severe respiratory distress from the onset, and the animals died earlier than the West African MPXV challenged animals. A hundred percent and sixty percent mortality were recorded when Prairie dogs were exposed to 105.1 pfu of West African MPXV via intranasal or intraperitoneal route of infection, respectively. According to Huston et al., generalized rash was observed in asymptomatic black-tailed prairie dogs (Cynomys ludovicianus) after 9–12 days of exposition to 104.5 pfu of both Congo Basin or West African MPXV via an intranasal and scarification routes. The notable symptoms observed in the animals included lethargy, inappetence, nasal discharge, respiratory distress, morbidity, and mortality. Lesser morbidity and mortality rate were observed for the West African MPXV, and LD50 (median lethal dose) was found to be hundred-times higher for the West African clade compared to Congo Basin clade (1.29 × 105 and 5.9 × 103, respectively) in the prairie dog MPXV model via intranasal route [31,33,34].

Hatch et al. tested the efficacy of the smallpox vaccines Imvamune (a.k.a JYNNEOSTM) and ACAM2000TM against 105 pfu aerosolized monkeypox virus in Cynomolgus macaques (Macaca fascularis) via intranasal route. Besides the red patches on all MPXV challenged animals at the vaccination site, declination of body weight was also observed in most animals especially in those mock vaccinated with TBS (Tris-buffered saline) with 10–18% loss in weight, and there was a consistent increment in body weight of all surviving animals in the vaccination groups from day 14 post-challenged [35].

African dormice (Graphiurus kelleni), previously treated with Dryvax vaccine, were protected from mortality following challenge with 2 × 104 PFU of MPXV-ZAI-79, and the unvaccinated group of dormice experienced uniform mortality [36]. The efficacy of the nucleotide analogue Cidofovir, via intranasal route, was tested in some African dormice, which were challenged with Congo Basin clade virus MPXV-ZAI-79. Nineteen percent mortality rate was observed in animals treated with Cidofovir while vehicle or placebo treated animals were susceptible to the disease. The antiviral drug Tecovirimat (ST246) was administered to prairie dogs, via the oral route of infection, after they had been exposed to 65 × LD50 of Congo Basin clade virus ROC-2003-358, and generalized rash coupled with 10–24% decrease of animals’ body weight was observed. There was deterioration of the symptoms of the disease, as well as an increase in viral titers, in untreated groups of animals. However, all animals (at rash onset) in the treatment group survived. Thus, ST246 was established to provide potent antiviral activity against MPXV infection [31].

Out of the 38 inbreed strains of mice (32 classical inbreed strains and six wild-derived strains) screened for susceptibility to MPXV, only three (CAST/EiJ, PERA/EiJ, and MOLF/EiJ) of the wild derived strains were highly susceptible to MPXV, and all the classical inbreed strains were highly resistant to intranasal MPXV infection. CAST/EiJ (abbreviated as CAST) is the most sensitive (of the three susceptible mouse strains) to MPXV with LD50 of 680 and 14 infectious units via intranasal and intraperitoneal infections [37,38,39,40]. CAST was also used as a model for testing efficacy of smallpox vaccines and antivirals (Dryvax and Cidofovir) against MPXV. Although both therapeutics gave protection to MPXV-infected CAST mice, Dryvax was more effective than Cidofovir [39].

Transmission

The two possible means of MPXV transmission are animals–human transmission and human–human transmission. Respiratory droplets and contact with body fluids, contaminated patient’s environment or items, skin lesion of an infected person have been found to be associated with inter-human transmission. Congo Basin clade (Central Africa clade) is reported to be more virulent than West Africa clade and thereby contributes more to inter-human transmission [41,42,43,44,45,46]. Animal-to-human transmission, which is also known as zoonotic transmission, occurs via direct contact with any of the aforementioned natural viral hosts or consumption of these hosts. In addition, zoonotic transmission could occur by direct contact with the blood, body fluids, and inoculation from mucocutaneous lesions of an infected animal [41,47,48,49,50]. Nosocomial transmission has been reported for CB and WA clades of MPXV [51,52,53] while sexual transmission has been speculated for infected individuals with groin and genital lesions [54]. At present human-to-animal transmission has not been reported. Human-to-human transmission, secondary attack rates (SARS), and serial transmission events is much higher with the CB clade compared to the WA clade [55]. The reproduction number R0 for the CB clade is estimated to be in the range of 0.6–1.0 [56,57]. The R0 has not be estimated for the WA clade of MPXVs, but it is presumed to be lower than that of the CB clade. The upper limit R0 of 1.0 in the CB clade indicates that the viruses will not only sustain human-to-human transmission but may persist in human population. Presumably, if as expected the R0 of the WA clade is much lower than what was estimated for the CB clade, then sustained human–human transmission and persistence in human population are highly unlikely and outbreaks will be largely due to spillover events from zoonotic hosts.

Disinfection

Disinfectants reported to be effective for orthopoxviruses include sodium hypochlorite, chloroxylenolbased household disinfectants, glutaraldehyde, formaldehyde and paraformaldehyde. During an outbreak in the U.S., the U.S. Centers for Disease Control and Prevention (CDC) recommended 0.5% sodium hypochlorite or other EPA– approved high–level disinfectants. Incineration or autoclaving is appropriate for some contaminated materials.

Infections In Animals

Incubation Period Reported incubation periods in experimentally infected animals range from 3 days to about 2 weeks in most cases. The incubation period was slightly longer (11 to 18 days) in prairie dogs infected by exposure to fomites than after direct exposure.

Clinical Signs

Nonhuman primates

The predominant syndrome in nonhuman primates is a self–limited rash, which begins as small cutaneous papules that develop into pustules, then crust over, and may leave small scars when the crusts drop off. A typical monkeypox lesion has a red, necrotic, depressed center, surrounded by epidermal hyperplasia. The number of lesions varies from a few individual pocks to extensive, coalescing lesions. They sometimes affect the entire body, but may be more common on the face, limbs, palms, soles and tail. Some animals have only skin lesions, which may be accompanied by a fever or lymphadenopathy, but do not appear to be otherwise ill. In more severe cases, there may also be respiratory signs (coughing, nasal discharge, dyspnea), ocular discharge, anorexia, facial edema or oral ulcers. Respiratory signs of varying severity, with minimal skin lesions (e.g., a single lesion on the lip), were observed in some wild chimpanzees during an outbreak caused by a West African virus. Other animals in this outbreak had more classical signs including a rash. Most naturally infected animals recover; however, fatalities are sometimes seen, particularly in infant monkeys. Asymptomatic infections are also possible.

Prairie Dogs And Other Rodents

In prairie dogs, the clinical signs may include fever, depression, anorexia, blepharoconjunctivitis (often the initial sign), respiratory signs (nasal discharge, sneezing and/or coughing, respiratory distress), diarrhea, skin lesions similar to those in nonhuman primates, and oral ulcers. Lymphadenopathy was seen in naturally infected prairie dogs, but did not occur in all experimentally infected animals. Elevated serum levels of liver enzymes have also been reported. Some cases are fatal, and experimentally infected prairie dogs sometimes died without developing lesions on the skin or mucous membranes. Similar clinical signs have been reported in other naturally or experimentally infected rodents; however, not all animals developed skin lesions. Intranasally inoculated dormice, which often died, had only nonspecific signs such as lethargy, an unkempt hair coat, a hunched posture, conjunctivitis and dehydration. Some naturally infected Gambian giant pouched rats had asymptomatic infections or mild illnesses, with no respiratory signs and limited skin lesions, but other animals died, and experimentally infected pouched rats sometimes became moderately to severely ill, with skin and oral lesions, ocular lesions and nonspecific signs of illness. Pox lesions were found in a wild Thomas’s rope squirrel (Funisciurus anerythrus) in Africa that was found infected with a Congo Basin strain. Some rope squirrels (Funisciurus anerythrus) inoculated with a Congo Basin strain developed skin and oral lesions, respiratory signs and, in one case, corneal lesions. However, African squirrels administered a high viral dose in an earlier study died with a generalized, nonspecific illness, and skin lesions occurred only in a few animals that received a lower, nonfatal dose.

Post Mortem Lesions

At necropsy, the skin may contain one or more papules, umbilicated pustules (“pocks”) with central necrosis, or crusts over healing lesions. Ulcers, erosions or lesions with necrotic centers may be found in the mouth of some animals. Peripheral lymphadenopathy is common but not always present. Conjunctivitis or blepharoconjunctivitis may also be noted. Pox lesions (white plaques or small, white, firm, deeply embedded foci with umbilicated necrotic centers) are sometimes detected on internal organs or in the stomach and small intestine. Some animals may have other internal lesions including lung involvement (e.g., pleuritis, consolidation of the lung, pulmonary edema, multifocal necrotizing pneumonitis or bronchoalveolar pneumonia), enlargement and/or mottling of the liver, orchitis, and multifocal necrotizing lesions in various organs and tissues including the spleen, liver, colon, thymus, brown fat, uterus or vagina. Hemorrhages were noted in the upper gastrointestinal tract, nasal cavity, gall bladder and brain of intranasally inoculated dormice, and in the lungs of experimentally infected ground squirrels, together with pulmonary edema.

Control

Disease reporting

Veterinarians who encounter or suspect monkeypox should follow their national and/or local guidelines for disease reporting. In the U.S., state or federal authorities must be notified immediately.

Prevention

As a result of a monkeypox outbreak in 2003 that was caused by imported exotic pets, the U.S. banned the importation of six types of African rodents – squirrels in the genera Heliosciurus and Funisciurus, dormice, Gambian giant pouched rats, brush-tailed porcupines (Atherurus sp.), and striped mice (Hybomys sp.). This ban applies to these animals whether they were born in Africa or on another continent. In addition, prairie dogs can no longer be captured from the wild for use as pets. Exceptions to these restrictions are allowed, by permit, for organizations such as zoos and scientific institutions. Similarly, some other countries and governing bodies such as the E.U. banned the importation of prairie dogs from the U.S. and some rodents from Africa. Good infection control measures, including the isolation of new animals, help prevent outbreaks in primate facilities and facilities that import exotic pets. Because infections have been reported in Asian monkeys mixed with primates from Africa, these species should not be housed in the same area. Care should be taken to avoid spreading the virus on fomites. Vaccination with vaccinia virus (smallpox vaccine) is protective in nonhuman primates. Research suggests this vaccine is also protective in some other species such as prairie dogs. Anyone who has been exposed to monkeypox should avoid contact with animals that might be susceptible to infection, particularly rodents and nonhuman primates.

Morbidity and Mortality

A few outbreaks have been reported among captive primates, but the only cases observed in wild species were in an infant sooty mangabey found dead with pox lesions and an outbreak in a group of monitored chimpanzees in 2017- 2018. Based on these reports, both published recently, and a study that found antibodies in 8% of nonhuman primates in Africa, it appears likely that some clinical cases in wild primates are missed. The morbidity rate in nonhuman primates is usually high and the mortality rate low, with most adult animals recovering. More severe illnesses may be seen in infants, which sometimes die, and primates of all ages infected experimentally via aerosols. There also seem to be species-related differences in susceptibility. Crab-eating macaques (Macaca fascicularis) appear to be more susceptible than rhesus macaques (M. mulatta), and 6 of 9 captive Asian orangutans (Pongo pygmaeus) died in an outbreak at the Rotterdam zoo while two gorillas and most chimpanzees survived despite becoming ill. As of 2020, only a single clinical case has been described in a wild rodent in Africa, a squirrel (Funisciurus anerythrus) with poxvirus lesions. However, antibodies are reported regularly in African squirrels of the genera Funisciurus and Heliosciurus, and high seroprevalence rates have sometimes been found in other species, such as Natal multimammate mice (Mastomys natalensis), tiny fat mice (Steatomys parvus) and shrews (Crocidura spp.) in Zambia. Prairie dogs seem to be very susceptible to monkeypox. Many of the prairie dogs exposed to monkeypox became infected during the outbreak in the U.S., and mortality rates as high as 60% have been reported after experimental inoculation. Another study reported 50-75% mortality in rope squirrels (Funisciurus anerythrus) inoculated with a Congo Basin strain. However, some species of rodents might be relatively resistant to clinical signs. During the outbreak in the U.S., monkeypox virus was found in one Gambian giant pouched rat that died soon after arrival, but another animal had a very mild illness, and orthopoxvirus antibodies were found in 12 of 18 healthy individuals after the outbreak. Limited experimental evidence also suggests that Gambian pouched rats are less susceptible than rope squirrels or prairie dogs. The Congo Basin clade seems to be more virulent than West African viruses for nonhuman primates and some rodents (e.g., prairie dogs, squirrels), although a West African virus was reported to be at least as virulent for Gambian pouched rat as the Congo Basin strain.

Infections in Humans

Incubation Period

Reported incubation periods in humans range from 7 to 24 days, with a mean of 12 days in Africa and 14.5 days during the outbreak in the U.S.

Clinical Signs

Human monkeypox resembles smallpox, with a rash and constitutional signs, but the symptoms are generally milder and, unlike smallpox, the lymph nodes are usually (though not always) enlarged. Most often, the illness begins with nonspecific, flu–like symptoms that may include malaise, fever, chills, headache, sore throat, myalgia, backache, fatigue, nausea, vomiting and a nonproductive cough. Lymphadenopathy can be regional or generalized, and most often affects the submandibular, postauricular, cervical and/or inguinal lymph nodes. Most patients develop a rash one to several days after they begin to feel ill, though there have been instances where patients noticed a few skin lesions (e.g., at the site of an animal bite or scratch, or in the groin) shortly before they felt unwell. Skin lesions are usually concentrated on the extremities (including the palms and soles), but they can also be seen on the head and torso, as well as the mucous membranes and genitalia. They vary in number from less than 25 to more than a hundred, and may become confluent in severe cases. As in animals, skin lesions usually begin as macules and papules, which develop into vesicles and pustules (“pocks”), umbilicate, form scabs and are eventually shed. During the outbreak in the U.S., some pustules had prominent erythematous flares. Such flares have not been noted in African cases, possibly because most affected people have darker skin. The skin lesions usually resolve within 14 to 21 days. Residual varioliform scarring, with hypopigmented and/or hyper-pigmented skin lesions, may be a sequela in some cases. Severe scarring, as seen in smallpox, is rare. Some patients also have ocular signs including conjunctivitis, or more rarely, keratitis or corneal ulceration. Respiratory complications including bronchopneumonia, coagulation disorders, and rare cases of encephalitis or multiorgan failure have also been reported. Secondary bacterial infections can occur, and may lead to sepsis. Pregnant women may abort or give birth to an infected fetus. One fetus infected in utero was stillborn, with cutaneous maculopapular skin lesions and severe hepatic involvement; another had skin lesions and was born prematurely but alive. At least one mildly affected pregnant woman gave birth to a full-term, healthy child. Most patients recover in 2-4 weeks, but deaths are possible, especially in people infected with the Congo Basin clade or immunosuppressed individuals infected with either clade. Subclinical and very mild cases have also been reported.

Treatment

Treatment of monkeypox is mainly supportive. Tecovirimat (chemical agent ST‐246), which is also known as Arestyvir, has been licensed for use in humans infected with orthopoxviruses, but its specific efficacy against monkeypox in people has not yet been evaluated. Other possible agents, including a derivative of cidofovir (CMX001/ Brincidofovir) are in clinical trials. Vaccinia immune globulin, which was used at one time to treat smallpox, might also be tried, especially in those who are immunocompromised.

Prevention

Smallpox (vaccinia) vaccination appears to provide some protection from monkeypox, and it has been recommended for some healthy people in occupations at high risk of exposure. Post–exposure vaccination also seems to be helpful, and may be offered to people who are exposed to a monkeypox-infected person or animal. This vaccine cannot be used in those who are immunocompromised. The general population is not currently vaccinated in endemic areas of Africa, due to the expense of the vaccine and the risk of serious side effects, particularly in areas where undiagnosed severe T cell immunodeficiencies (e.g., untreated HIV-1 infection) may be relatively common. A vaccine specifically for monkeypox is in clinical trials in Africa, as of 2020.

As a routine preventive measure, care should be taken to treat and cover breaks in the skin when working with nonhuman primates or other animals that may be hosts for monkeypox virus. Infection control procedures such as good hygiene, frequent hand washing, disinfection of surfaces and equipment, and the use of personal protective equipment (PPE) are important during contact with animals suspected to have monkeypox. Necropsies should be done in Biosafety Level 2 laboratories, using a certified Class II Biological Safety Cabinet. Anyone who has been in contact with a monkeypox suspect should contact a health care provider immediately. Health authorities (e.g., the local or state health department) must also be informed. Isolation of infected patients and good infection control measures are helpful in preventing person-to-person transmission. Ring vaccination might also be used in some outbreaks. Because the full host range of monkeypox virus is uncertain, infected individuals should also limit their contact with any pet, particularly species known to be susceptible to this virus.

Morbidity and Mortality

In Africa, monkeypox is usually seen in rural populations, and is most common in children and young adults. Most cases occur among people who live in or near heavily forested areas, where the virus is thought to be endemic in animals, though outbreaks have been reported elsewhere. Clinical cases often occur after contact with wild small mammals, which are caught for food and other purposes, but person-to-person transmission and family clusters appear to be significant in some outbreaks. In the past, monkeypox was thought to be a rare disease; however, outbreaks and sporadic cases have increasingly been reported from Africa during the last few decades. Waning immunity from smallpox vaccinations may be a factor, as the disease predominantly affects young people born after vaccination campaigns ended. Other societal factors (e.g., changes resulting from poverty or war) that increase exposure to the reservoir hosts are also plausible, as are some impacts from increased awareness and reporting. Most outbreaks have occurred in central Africa and are caused by the Congo Basin clade, which is more virulent. Until recently, clinical cases caused by the West African clade were seen only rarely. The first significant outbreak in recent years occurred in 2003 in the U.S. and was linked to imported exotic pets, which disseminated the virus to pet prairie dogs and hence to humans. Seventy-two human infections were reported, including 37 that were laboratory confirmed. Most cases occurred after direct contact with pet prairie dogs. African rodents appeared less likely to transmit the disease to humans, possibly due to different types of behavioral interactions with these animals. In 2017-2018, a West African virus caused at least 132 confirmed and approximately 300 suspected cases in Nigeria. This event, the first significant outbreak in Nigeria since the 1970s, occurred after floods that may have increased human exposure to rodents. Many cases appeared to result from person-to-person propagation of the virus. Since then, increased surveillance has uncovered sporadic, ongoing human cases in Nigeria. Serological surveillance has also revealed antibodies to orthopoxviruses in some healthy young people in West Africa who report no previous illness suggestive of monkeypox. The highest risk of death from monkeypox is in infants, young children and immunocompromised individuals. Reported case fatality rates in outbreaks caused by Congo Basin (Central African) strains reach 10% or more, and are occasionally as high as 20-25% in some smaller clusters. However, many clinical cases caused by West African clade viruses seem to be milder. No deaths occurred during the outbreaks in the U.S., while 7 deaths were seen in the recent outbreak in Nigeria. Four fatalities occurred in immunocompromised individuals, two of whom had uncontrolled HIV-1 infections. One case of encephalitis and bronchopneumonia was fatal in a neonate, and two HIV negative adults died with bronchopneumonia and sepsis. Although secondary bacterial infections were relatively common in this outbreak, other serious complications such as encephalitis, keratitis or bronchopneumonia were rare in both this outbreak and the 2003 outbreak in the U.S. The availability of advanced health care facilities and good supportive care, as well as the absence of poor nutrition and concurrent diseases, may contribute to higher survival rates for monkeypox in some areas.

Signs and Symptoms

In individuals, the manifestations of monkeypox are identical to small pox but milder than the indications of smallpox. Monkeypox initiate with fever, headache, muscle aches, and fatigue.The principal dissimilarity between indications of smallpox and monkeypox is that monkeypox produces lymphadenopathy while smallpox does not. The incubation time for monkeypox is generally 7−14 days but can range from 5−21 days13.

The infection can be divided into two periods:

1) The invasion period (0-5 days)

2) The skin eruption period (within 1-3 days after appearance of fever) The invasion period: The illness starts with Fever, Headache, Muscle aches, Backache, Swollen lymph nodes, Chills, Exhaustion14.

The skin eruption period: Within 1 to 3 days after the arrival of fever, the patient appears a rash, often developing on the face then extending to other parts of the body15. The face and palms of the hands and soles of the feet are most affected. Three weeks might be necessary before the complete withdrawal of the crusts. Lesions progress through the following stages: 

Rash 

Macules 

Papules 

Vesicles 

Pustules 

Scabs

The illness usually lasts for 2−4 weeks. In Africa, monkeypox has been shown to cause death in as many as 1 in 10 persons who had the disease.

Pathophysiology

Exposure to the polluted animal by a bite or through extreme contact with skin lesions or body fluids shows to be the predominant mechanism of infection in the US monkeypox outburst. Circulation through touch with contaminated bedding or cages is feasible, however it not approved18 .InAfrican instances, person-to-person transmission through direct contact and respiratory droplets.Howeverthere is no confirmation of human-tohuman communication in the US. Airborne transference of the monkeypox virus is theoretically feasible, mainly in patients with cough19. In Africa, contamination may also occur by consumption of polluted animal for food. The duration of communicability, equivalent for both humans and animals, range from 1 day prior to the onset of the rash until 3 weeks, after rash onset all of the lesions have developed crusts.

Control Measures

Averting monkeypox augmentation through restrictions on animal trade or prohibiting the locomotion of small African mammals andmonkeys may be potent in lessening the enlargement of the virus in exterior Africa. Potentially polluted animals might be segregated from other animals and set into immediate quarantine. Evade connection with animals that could harbor the virus. Evade touch with any substances, such as bedding, that has been in contact with a sick animal. Segregate polluted patients from others who could be at danger for infection23 . Execute good hand hygiene after contact with contaminated animals or humans. For Example, cleaning your hands with soap and water or applying an alcohol-based hand Sanitizer.Use personal protective equipment when caring for patients.

Most Recent Outbreak In Nigeria

The most recent outbreak started in September 2017 in the Yenagoa Local Government Area of Bayelsa State in the southern part of Nigeria,48 this being a riverine area, and home to the Edumanom Forest Reserve where chimpanzees were last seen in June 2008. The area is not in close proximity to the Democratic Republic of the Congo, which is the endemic zone of monkeypox, but proximate to Abia State where the first case was identified in Nigeria in 1971.29 The disease was first suspected in an 11‐year old boy who presented with fever, headache, malaise, sore throat and generalized well‐ circumscribed papulopustular rashes that eventually ulcerated, with crust and scab formation.48,49 Five of his siblings in the same household developed similar clinical signs and symptoms.53 Although the index case and two of the siblings had reported contact with a monkey in their neighborhood, it was very difficult to ascertain if that monkey was the source of infection,53 especially as it had no history of the illness. Thereafter, 262 suspected and 115 confirmed cases, with seven mortalities, were reported from 26 states and the FCT.34,43,48,49 The infected persons were mostly between the ages of 20 and 39 years (median age 30 years) with a male–to‐female ratio of 2.5 to 1, and of the seven patients who succumbed to the disease, four had immunosuppression.49 Laboratory investigations established a very close relationship with the two viral strains that were responsible for the previous outbreaks in the country. In addition, nine of the MPXV negative swab samples tested positive for varicella zoster virus.48 It was suggested that the index case of this outbreak was not imported, and that the cases were rather a spillover from the reservoir hosts.43 This may have occurred following civil conflict and displacements in the area, with the movement of individuals to more heavily forested areas exposing them to the interaction with wildlife, thereby allowing the movement of the virus, similar to the outbreaks in the Democratic Republic of the Congo and South Sudan.50-52 So far, this is the largest outbreak caused by the West African clade, and further investigation measures are in place to improve the existing knowledge to ensure effective prevention and control strategies.53

Therapy And Control

Initially, treatment of monkeypox infections was mainly syndromic, as there was no clinically approved and licensed antiviral agents for its specific treatment. While still at various stages of clinical trials, four compounds (NIOCH‐14, Cidofovir, CMX‐001, and ST‐246) may yield a good therapeutic effect.9,52 Recently, the US Food and Drug Administration (FDA) approved in 2018 the first anti-poxvirus drug intended to treat orthopox viruses, such as smallpox and monkeypox.60,61 This represents a long‐awaited addition to disease prevention strategies that have focused on selective antiviral chemotherapy. In addition, it is a move that could halt a lethal pandemic if the virus was to be released as a bioweapon or accidentally through a laboratory‐acquired infection. Tecovirimat or Arestyvir (previously ST‐246) was first reported in 2005 following screening of a chemically diverse library of more than 356 240 compounds,62-64 and was reported to be a selective and potent inhibitor of the replication of multiple orthopox viruses.63 The antiviral agent, tecovirimat, also known as Tpoxx, has never been tested in humans with smallpox, as the disease was declared eradicated in 1980,65 two years after the last known and reported case of smallpox in 1978. Tecovirimat, a virion egress inhibitor, was very effective at protecting nonhuman primates challenged with variola virus (the causative agent of smallpox)66 and MPXV67 as well as in two animal models deliberately infected with monkeypox and rabbitpox, in accordance with the US FDA Animal Efficacy Rule.68 It also caused no severe side effects when safety‐tested in a placebo‐controlled pharmacokinetic and safety trial involving 449 healthy adult human volunteers.68 Therefore, tecovirimat is the only currently available anti-poxvirus therapeutic agent, and it is stockpiled as part of the US Strategic National Stockpile for use as a defense to treat smallpox virus infections in the event of a possible bioterrorist attack.63,69 Nevertheless, the smallpox vaccine, although with limited use due to cost and safety concerns of a live vaccinia virus vaccine, is cross protective against many orthopox viruses, including MPXV.34 Despite continuous and unrelenting efforts to develop an effective therapy, other public health measures, such as case isolation, contact tracing, avoiding contact with animals or materials suspected of harboring the etiologic agent, use of personal protective equipment and good hand‐hygiene practices, remain the best measures for preventing and controlling human monkeypox.

2.2 THEORETICAL FRAMEWORK

The theory used for this study is the ecological models of health behavior, as it explains the relationship between two interactive variable. It is considered for this study since the study is based on the interaction/connection between man in the course of disease outbreak.

Ecological Models of Health Behavior (James F. Sallis Neville Owen and Edwin B. Fisher 2001)

An ecologic or population health model emphasizes the importance of the social and physical environments that strongly shape patterns of health risk behaviors. Ecological models of health behavior emphasize the environmental and policy contexts of behavior, while incorporating social and psychological influences (Gruenewald et al., 2014). It focuses on the linkages and relationships among multiple factors (or determinants) affecting health. The core concept of ecological model is that behavior has influences from multiple scales including individual, interpersonal, institutional, and community and is used to design and evaluate environmental interventions.

2.3 CHAPTER SUMMARY

In this review the researcher has sampled the opinions and views of several authors and scholars on the concept of monkey pox, its history, evolution in Nigeria etc. The works of scholars who conducted empirical studies have been reviewed also. The chapter has made clear the relevant literature.