Sheeppox and goatpox

Sheeppox and goatpox

Sheeppox and goatpox

Previous author: R P KITCHING

Current authors:
S L BABIUK - Research Scientist, PhD, National Centre for Foreign Animal Disease, 1015 Arlington Street, Winnipeg, Manitoba, R3E 3MA, Canada
A DIALLO - Advisor to the Director of Israe/LNERV, DVM, PhD, Route du fond de terre, Dakar-Hann, BP 2057, Senegal
C E LAMIEN - Technical Officer, Joint FAO/IAEA Division of Nuclear Techniques in Food and Agriculture, PhD, IAEA Laboratories Seibersdorf, Friedenstrasse 1, Seibersdorf, Lower Austria, A-2444,  Austria
R P KITCHING - Director, BVetMed, PhD, MRCVS, National Centre for Foreign Animal Diseases, Canadian Food Inspection Agency, 1015 Arlington Street, Manitoba, R3E 3M4, Canada

Introduction

Sheep- and goatpox are malignant systemic pox diseases of sheep and goats characterized by fever, macules developing into papules and necrotic lesions in the skin and nodular lesions in internal organs, secondary infections and death in susceptible stock. The diseases in sheep and goats are caused by strains of capripoxvirus which are indistinguishable serologically, and although strains derived from sheep may show genomic differences from those derived from goats, there are isolates with characteristics of both sheep and goat isolates.9 Similarly, while most isolates cause disease in either sheep or goats, there are isolates equally pathogenic in both species.35 Therefore, the classification used so far, based on the animal species from which the capripox virus is isolated, i.e. goatpox and sheeppox for viruses isolated from goat and sheep respectively, is inappropriate. To be informative nomenclature needs to take other criteria such as molecular-based data that enable clear differentiation between these two viruses into consideration.43, 44, 45 Experimentally, all sheep isolates will replicate in goats, and goat isolates will replicate in sheep, providing effective cross-immunity. Because sheep- and goatpox are serious epidemic diseases that may cause important losses in affected herds and represent also a major constraint to international trade for affected countries, they are classified in the list of animal diseases to be notified to the World Organization for Animal Health, the OIE: outbreaks should be reported immediately to the OIE. A third disease caused by a capripoxvirus, lumpy skin disease of cattle, can also elicit protective immunity against sheep- and goatpox in sheep and goats, as illustrated by the Kenyan sheep- and goatpox vaccine which is derived from a lumpy skin disease virus that was isolated from sheep.55 The difference in the geographical distribution of lumpy skin disease from that of sheep- and goatpox, as well as the fact that no sheep- or goatpox viruses have been isolated from cattle, suggests that sheep- and goatpox viruses do not cross from small ruminants to cattle.12

Aetiology

Capripoxviruses are large brick-shaped, double stranded DNA viruses, morphologically indistinguishable from orthopoxviruses, measuring 295 by 265 nm.34 The virion is covered in short tubular elements which give it a different appearance from orf virus, which is more oval in shape and covered in a continuous filament. Poxviruses have a very stable genome which is demonstrated by DNA restriction patterns of isolates collected in 1959 appearing the same as 1986 isolates, indicating very little change in the genome over time.38  However, sheep-and goatpox viruses will have subtle genetic changes to their genomes over time which can be identified using genome sequencing. In addition, there is evidence for recombination events occurring between strains of capripoxvirus in the field, as has also been seen in vitro, and this could result in changes in host range or virulence.27

As with other poxviruses, sheep- and goatpox is susceptible to sunlight and detergents containing lipid solvents, but in dark environmental conditions, such as contaminated animal sheds, it can persist for many months.24, 56 The source of environmental contamination occurs from infected animals shedding the virus. In addition, scabs shed from recovered animals contain large amounts of virus in association with antibody, but it is not known whether these scabs could remain a source of infection; certainly, it is difficult to recover live virus on tissue culture from scab material, but the presence of the virus within type A inclusion protein could protect the virus in the environment although this has not yet been proven.

Epidemiology

Sheep- and goatpox occur in Africa north of the equator, Turkey, the Middle East, many parts of Asia, including Pakistan, Afghanistan, Kazakhstan, Kyrgyzstan, India, Nepaland parts of China and Russia. In Morocco, sheeppox only occurs. New introductions of disease into a country are generally only identified in one of the two host species, i.e. depending on the isolate introduced. For example, goatpox was introduced into Bangladesh from India in 1984, and sheeppox has caused occasional outbreaks in Italy (1983), Greece (1988, 1995, 1996, 1997, 1998, 2000, 2006, 2007, 2013-2017) and Bulgaria (1995, 1996, 2013), having spread from Turkey, probably in illegally imported animals. In 2005 and 2008 outbreaks of goatpox occurred in Vietnam, likely originating from China.1 In Mongolia, there was an outbreak of sheeppox in 2006-2007 and then goatpox in 20086 and sheep pox and goat pox outbreaks were still occurring between 2013 and 2017. In Russia there have been outbreaks in 2008, 2010, 2011, and 2012 along the regions bordering China.46 A goatpox outbreak occurred in Chinese Taipai in 2008 and 2010 likely spread from China. These outbreaks demonstrate that sheep- and goatpox can spread to neighbouring regions from bordering countries.  It is not clear why sheep- and goatpox have not spread widely in central and southern Africa because the risk of introduction is similar to regions of Asia where sheep- and goat pox are expanding their geographic distribution. However, this may be because intra-African (i.e. regional) trade is a fraction of what it is in Asia.

Transmission of sheep- and goatpox occurs following contact between an infected and a susceptible animal. The mechanisms of transmission have not been fully investigated; however aerosol transmission is likely the predominant route of transmission with transmission by contact likely playing a minor role as this route requires damage to the buccal or nasal mucosa for transmission.  Experimental infections in sheep and goats can be produced using either intradermal inoculation10 or intranasal inoculation.5 Mechanical transmission of virus by biting flies has been shown experimentally, but there is no evidence that this mode of transmission is important in the field.33 Transmission occurs predominantly after the clinical appearance of papules (around six days post infection) (see below) because shedding of virus occurs in oral and nasal secretions when papules appear and reach the highest levels between ten to fourteen days following infection before the development of circulating antibody (around ten to fourteen days post infection) and the transition of the papules to scabs.1, 10, 11 However, the persistence of virus in the environment in the scab material cannot be excluded. When sheep of some breeds, such as the Soay, become infected with particularly virulent strains of capripoxvirus, they may die before the appearance of clinical signs, and they fail to transmit the disease, since the level of viral shedding is not high enough to cause transmission. Similarly, animals that develop only mild lesions frequently fail to transmit infection. It is the animals that develop severe clinical disease, with multiple lesions which eventually resolve without causing death, that are the most potent sources of virus.37 This is because the level of virus replication of sheep- and goatpox is correlated to the severity of the clinical signs of disease with viral shedding from oral and nasal secretions being the highest with severe clinical disease.1

Sheep and goats that recover from disease or infection are immune for life, and there is no virus carrier state. The virus can only survive by constant transmission from infected to susceptible animals, and therefore requires a susceptible population exceeding a critical size. The critical population size depends on the capripoxvirus isolate, the susceptibility of the host population and, ultimately, on the Ro (the basic reproductive number), i.e. the average number of animals infected by diseased animals in a fully susceptible population. There are clear breed differences in susceptibility, European and Australian breeds being particularly susceptible to infection and disease, while many African breeds of sheep and goats have some resistance, at least to the fatal form of the disease. There are differences in virulence of capripoxvirus isolates, and in their preference for adaption to sheep or goats. Other factors may also affect the rate of spread, such as the type of forage and the presence of other infectious diseases, for example peste des petits ruminants, foot-and-mouth disease and orf, in the flock or herd; any damage to the buccal or nasal mucosa can enhance entry of virus.

Typically, in areas of the world where capripox is endemic, diseased animals may be found at any time of year in locations with high small ruminant density, usually in younger animals which are losing their maternal antibody; it is rare to find disease in animals over a year old as most by then they would have either died or be immune. However, in villages isolated by terrain or low rainfall, where there are insufficient numbers of animals to maintain the virus, the disease disappears until an infected animal is eventually introduced, either from a market or nomadic herd; it then spreads through the village affecting animals of all ages.41, 42 Some isolates of capripoxvirus spread between sheep and goats, therefore where mixed flocks occur such as in Asia and Africa, conditions for this to occur are ideal. It is not clear how important the dual host cycle is in the maintenance and spread of the virus. When the disease has spread into a new area, such as goatpox into Bangladesh in 1984, and sheeppox into Greece in the 1990s, the virus subsequently remained restricted to one host species. In endemic areas, outbreaks are frequently reported as affecting only one host species. However, there have been few investigations into the possible involvement of the other host species that are in-contact but apparently remain unaffected.

Pathogenesis

The pathogenesis depends on both the virus isolate and the host. In addition, virus replication is apparently correlated with the severity of clinical disease, i.e. the highest levels of virus replication occur in association with severe disease.1 Capripox viruses have a predilection for epithelial cells of the skin and lungs.10, 23

The understanding of the genes involved in virulence, as well as tropism for sheep- or goats is limited. Following experimental intradermal inoculation, the virus replicates in the cells of the dermis and glandular cells at the base of the hair follicles. Large single or multiple, eosinophilic, intracytoplasmic inclusion bodies may be detectable in infected mononuclear cells in stained histological sections of skin lesions. Virus spreads to the draining lymph node which becomes enlarged as inflammatory cells accumulate, eventually producing micro-abscesses. Infection spreads in macrophages around the body, and becomes localized in the skin and internal organs, such as the mucosa of the rumen and abomasum, kidneys, testes and lungs. In the skin initial focal epidermal hyperplasia precedes papule development, followed by coagulation necrosis as thrombi develop in the blood vessels supplying the papules. Eventually scabs forms at the sites of papules. Micro-vesicles may develop as affected cells disintegrate, but the large vesicles characteristic of orthopoxvirus infections and orf are not usual. Papules on mucous membranes quickly ulcerate, and provide the major source of virus shed in oral and nasal secretions, which enable aerosol transmission.1, 10 The lesions in the internal organs are usually grey and nodular and approximately 20 mm in diameter, while those in the lungs may also be haemorrhagic. The highest level of virus is found in the skin papules ranging between 106-7 TCID50/ml, reaching the highest level about six days after their first appearance prior to the development of scabs.37 When scabs appear it is difficult to isolate virus, despite the fact that there is high levels of viral genome present. Virus occurs primarily in pox lesions in affected tissues with the exception of skin where apparently normal skin may contain virus ranging between 103-4 TCID50/ml in severely infected animals between eight and fourteen days post infection.10

Viraemia occurs between six and fourteen days following infection and can be detected by real-time PCR but is difficult to isolate virus.1, 10 Virus is shed from oral, nasal and conjunctival secretions and can be detected by real-time PCR at four days post infection, two days prior to the appearance of papules and can be detected for an extended period of time up to fifty six days.10 Peak levels of virus shedding in oral, nasal and conjunctival secretions occur between ten to fourteen days post infection ranging from 102-105 TCID50/ml depending on the host and isolate.1, 10 Neutralizing antibodies are developed at ten to fourteen days post infection and the presence of these antibodies causes viremia to stop and decreases the level of virus shedding in mucosal secretions. Following sheep- and goatpox infection, both cellular and antibody mediated immunity is elicited; however the antibody responses are much greater in magnitude following infection causing clinical disease compared to animals vaccinated with live attenuated vaccines where antibody responses are lower/or cannot be detected.11 Immunohistochemistry revealed capripoxvirus antigen in keratinocytes, fibroblasts and interstitial macrophages in the skin. In the lung, capripoxvirus antigen was detected in spindle-shaped and histiocyte-like sheeppox cells as well as in pneumocytes, vascular smooth muscle cells and macrophages.23

Clinical signs and pathology

Sheep- and goatpox occurs in all ages of sheep and goats but it is most severe in lambs and kids with the mortality rate reaching 80 to 100 per cent. In endemic areas, however, the mortality is low, even in young animals.

The natural incubation period following aerosol infection until the onset of fever is approximately 12 days. It may be only six or seven days following insect transmission or experimental inoculation.10, 33 Macules, or red, hyperaemic areas on the skin, 20 to 30 mm in diameter, develop 24 hours after the start of fever, which may exceed 41 °C. These macules, which are difficult to see in pigmented skin, develop into papules over the following 24 hours, and may cover the whole body or be restricted to the more hairless or wool less parts of the skin, such as the face, axilla, groin and perineum (figure 1 and figure 2). Affected animals develop rhinitis and conjunctivitis. Papules also occur in the mucous membranes of the mouth, nose, eye, and vulva or prepuce, and cause a discharge which is at first serous, later mucopurulent. The papule stage is followed by the pustule formation and the formation of a thin crust. The skin lesions may coalesce (figure 3). The superficial (and internal) lymph nodes become enlarged, and pressure on the pharynx by the retropharyngeal nodes may interfere with breathing. A flat haemorrhagic form of the disease has been reported in white European goats, in which the papules coalesce over the body and the skin becomes discoloured by deep haemorrhages.37 This form is always fatal.

If the affected animal survives the acute stage of the disease, scabs replace the papules after five to ten days, as the humoral antibody response develops. The appetite usually remains unaffected throughout. Secondary bacterial infection in the skin and lungs can prolong the fever, and fly strike and corneal opacity can be additional complications. The scabs may persist for up to a month, and scars can often be seen on the faces of recovered animals.

Infection of endothelial cells causes vasculitis and thrombosis. Histological examination reveals hyperplasia of epidermal cells, local inflammation, oedema, cell degeneration and coagulative necrosis. Infected mononuclear cells contain single, or more rarely, multiple eosinophilic inclusion bodies observed in the cytoplasm. The nuclei may be vacuolated giving rise to the name ‘sheeppox cells’.49 The lung lesions are comprised of areas of proliferative alveolitis, bronchiolitis and necrosis.29 Animals may suffer respiratory distress due to the severity of the lung lesions.

Figure 1 Goatpox: papules and ulcers in the skin, particularly around the eyes and on the lips of a goat. (By courtesy of Dr Z. Schenkel, Jordon-Germany Veterinary Project)

Diagnosis and differential diagnosis

In areas previously free of sheep- and goatpox, a presumptive diagnosis can be made on clinical signs alone. Sheep- and goatpox need to be distinguished from orf. Dual infections with parapoxvirus and Dermatophilus congolensis may produce signs and lesions in sheep and goats similar to those of sheep- or goatpox.47 In addition, the diagnosis of sheep- and goatpox can also be confused with animals infected with both orf (which causes skin lesions) and peste des petits ruminants that causes fever and nasal discharge resembling sheep- and goatpox. Mange should also be considered.

The diagnostic tests for capripox are well described in the OIE Manual of Standards for Diagnostic Tests and Vaccines.51 To detect virus, viral antigen or viral genome, the most useful tissue samples are skin lesions since they contain the highest levels of virus. Other tissues including lung lesions and lymph nodes sampled at post-mortem can also be used.  Oral or nasal swabs and blood can also be used at the onset of fever and the development of skin lesions to detect viral genome.

The ideal diagnostic work flow for the index case in non-endemic countries would be to evaluate skin lesion homogenates by electron microscopy as well as detection of viral genome using a validated molecular real-time PCR assay such as the Bowden assay10, 54 or the Balinsky assay4 which is similar in performance to the Bowden assay.19 In addition, histology would be used on formalin fixed skin lesions to detect capripoxvirus A type inclusion bodies and immunohistochemistry using a capripoxvirus specific monoclonal antibody would be used to detect capripoxvirus antigen.23 Isolation of the virus using skin lesion homogenates on OA3.Ts cells would be performed to generate an isolate. Full genome sequencing of the isolated virus would be done to confirm the virus as either a sheeppox or goatpox virus. Capripoxvirus specific antibodies in sera would be detected by virus neutralization assays with OA3.Ts cells using two fold sera dilutions starting a 1:10 to evaluate neutralization of 100 TCID50 of capripoxvirus.

Transmission electron microscopy can be used for laboratory confirmation by demonstrating capripox virions in skin lesions.34 Although capripox virions are indistinguishable from orthopox virions, no orthopoxvirus causes capripoxvirus-like disease in sheep and goats. Orf could potentially be confused with sheep- or goatpox, but parapox virions are morphologically different from those of capripox viruses.

The advent of PCR molecular assays has allowed laboratories without access to electron microscopy to be able to quickly diagnose sheep- and goatpox. A conventional polymerase chain reaction (PCR) has been developed where primers to the attachment gene of capripoxvirus are used.28 More recently, another conventional PCR has been developed to differentiate sheeppox and goatpox viruses.43 Real-time PCR assays have been developed for capripoxvirus.4, 10 However, these real-time PCR assays do not identify the specific capripoxvirus. The P32, the GPCR gene45 or the RPO30 gene43  which have been identified as genes that can be used to classify capripoxviruses into sheeppox, goatpox and lumpy skin disease allowing identification of the specific capripoxvirus using sequencing. Now several real-time PCR assays are available to differentiate sheep poxvirus from goat poxvirus and lumpy skin disease virus based on these genetic differences.25, 26, 44 The advantage of these assays is that they can be easily implemented in laboratories with moderate resources to identify the specific agent without the need for complete or partial genetic sequencing of the pathogen. Unfortunately molecular epidemiology for sheep- and goatpox is not fully described due to the lack of full genome sequences currently available.

A loop-mediated isothermal amplification (LAMP) has been developed targeting a conserved gene encoding the poly(A) polymerase small subunit,18 as well as the p32 gene.48 The benefit of LAMP is that it is a cost effective assay that can be run without expensive real-time PCR machines.

Real-time PCR assays were developed to support the differential diagnosis of pox like diseases in ruminants,26 and respiratory diseases of small ruminants53 including sheep- and goatpox. In capripox endemic areas, orf virus, sheeppox virus and goatpox virus infections in sheep and goats are characterized by generalized or localized skin lesions creating a challenge for the clinical diagnosis. The availability of a real- time PCR assay for differential diagnosis of pox like diseases in ruminants26 allows overcoming this problem. Likewise, sheep and goat pox can also induce respiratory distress similar to Peste des petits ruminants, Pasteurellosis and contagious caprine pleuropneumonia. The availability of a multiplex real-time PCR for capripoxvirus (CaPV), peste des petits ruminants virus (PPRV), Pasteurella multocida (PM) and Mycoplasma capricolum subspecies (ssp.) capripneumoniae (Mccp)53 is particularly essential in Africa and Asia where all these diseases can be present. Virus isolation of capripoxvirus can be performed on primary cell cultures of ovine, caprine or bovine origin; lamb testis cultures, with primary lamb kidney cells generally used. There are also several cell lines that can be used to propagate capripoxvirus including foetal bovine muscle-, Madin Darby bovine kidney- (MDBK) and ovine testes OA3.Ts cells.2, 8 The latter have been shown to be most sensitive. Development of cytopathic effects may be observed as early as 3 days after culture inoculation although field isolates may require up to 14 days to produce a cytopathic effect (CPE). For that reason blind passage of inoculated cell cultures may be necessary. When stained with haemotoxylin and eosin, large intra cytoplasmic inclusion bodies, surrounded by a halo, are confirmatory for the presence of poxvirus. Inclusion bodies can also be seen in histological sections of biopsy material, particularly if stained using specific inclusion body stains such as Gispen modified silver. For virus isolation it is important to collect material before the development of neutralizing antibodies and scab formation because although virus can still be seen under the electron microscope at later stages, its association with antibody in scabs makes isolation difficult.

Figure 2 Sheeppox: reddish papules in the skin

Figure 3 Sheeppox: umbilicated pustules and ulcers in the skin

The virus neutralization test (VNT) is the most specific serological test, using either lamb testis cells or foetal bovine heart muscle cells, and the titre can be expressed as a neutralization index or the sera dilution which can neutralize virus. However, adaptive immunity to capripoxvirus is predominantly cell mediated, and an animal whose serum is negative on the VNT may still be immune, as occurs with some vaccinated animals.11 An immunofluorescence test and Western blot have also been described.20, 21  There have been several ELISA tests developed, however these tests have not been fully validated to be used as an alternative to the VNT.3, 11, 28 It is likely that it will be possible to have a validated ELISA for sheep- and goat pox in the near future.

Historically, the agar gel immunodiffusion (AGID) tests were formerly used as a diagnostic tool for both antigen detection and serology. For detection of capripoxvirus antigen, the tests were conducted using a suspension prepared from early lesion biopsy material (either papule or lymph node), against known positive capripox serum and for serology, the sera sample would be evaluated for reaction to capripoxvirus antigen. The precipitin line could be shown to be confluent with that produced using positive control antigen. However, capripoxvirus has a precipitating antigen in common with parapoxvirus resulting in potential confusion for both antigen as well as serological identification.39 An enzyme-linked immunosorbent assay (ELISA) has been developed to identify the virus. This assay traps capripoxvirus antigen using rabbit hyperimmune serum and guinea pig serum raised against a P32 capripox recombinant antigen as an indicator.14, 15 The advent of molecular PCR tests has made these tests obsolete.

Control

When sheeppox and/or goatpox occur in countries previously free of the disease, eradication is usually by slaughter of all infected and in-contact animals. Both diseases are on the OIE notifiable animal disease list, and as such are a serious constraint to international trade; countries free of the disease are usually economically obliged to eradicate outbreaks and resist the use of vaccination.

Live attenuated capripox vaccines provide almost lifelong immunity from a single dose, although, as immunity wanes, there can be local replication of virus at the site of challenge, but generalization is prevented. Immunity is predominantly cell mediated, but humoral antibody passed to lambs and kids in colostrum will protect them for at least the first three months of life, depending on the immune status of the dam. This colostral antibody will also interfere with the development of active immunity following vaccination, so that vaccination should be delayed until the lamb or kid is six months old, or be repeated in the following year as per vaccine manufacturer’s recommendations.

A number of vaccines, mostly live attenuated vaccines, are available. They contain virus strains that give some protection to both sheep and goats, although the majority of vaccines are recommended for only one species. The Kenyan 0240 strain, a LSD virus55 will effectively protect both sheep and goats, whereas SPPV derived vaccines based on the Romanian and RM-65 strains are recommended for sheep, and GTPV derived vaccines based on the Mysore and Gorgan strains for goats.13, 21, 36, 40 In India there are locally produced vaccines, Rumanian Fanar for sheep and Uttarkashi for goats.57 In China the CPV/AV41 vaccine is used.17 Recombinant vaccines which will protect against sheep- and goatpox and peste des petits ruminants have been developed although they have not been licensed yet.7, 17, 27, 52

Treatment of affected animals can only be supportive and it is aimed at reducing secondary bacterial infection and fly strike. Infected animals should be isolated, although not necessarily in insect-proof accommodation and, following full recovery, the premises should be thoroughly cleaned using detergent-based disinfectants.

Countries free of the disease should prevent the importation of live sheep and goats from endemic areas, and should follow OIE guidelines on importing other potentially infected material. The relatively long incubation period of sheep- and goatpox can ‘hide’ the disease in imported animals and make tracing the origin of an outbreak difficult.

As sheep- and goatpox is stable in the environment and similar to lumpy skin disease virus, the OIE recommendations for trade with lumpy skin disease virus would be applicable to sheep- and goatpox. Raw hides as well as untreated wool from endemic countries would not be considered safe commodities. Sheep and goat meat, pasteurized milk and cheeses would be considered safe commodities.

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