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Veterinary Pathology

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Research article

First published online July 11, 2016

Senecavirus A: An Emerging Pathogen Causing Vesicular Disease and Mortality in Pigs?

J. Segalés [email protected], D. Barcellos, A. Alfieri, E. Burrough, and D. MarthalerView all authors and affiliations

https://doi.org/10.1177/0300985816653990

Abstract

Senecavirus A (SVA) is the only member of the genus Senecavirus within the family Picornaviridae. This virus was discovered as a serendipitous finding in 2002 (and named Seneca Valley virus 001 [SVV-001]) while cultivating viral vectors in cell culture and has been proposed for use as an oncolytic virus to treat different types of human neoplasia. SVA was found in lesions in pigs affected by porcine idiopathic vesicular disease in Canada and the USA in 2008 and 2012, respectively. In 2014 and 2015, SVA infection was associated with outbreaks of vesicular disease in sows as well as neonatal pig mortality in Brazil and the USA. Phylogenetic analysis of the SVA VP1 indicates the existence of 3 clades of the virus. Clade I contains the historical strain SVV-001, clade II contains USA SVA strains identified between 1988 and 1997, and clade III contains global SVA strains from Brazil, Canada, China, and the USA identified between 2001 and 2015. The aim of this review is to draw the attention of veterinarians and researchers to a recently described infectious clinical-pathologic condition caused by a previously known agent (SVA). Apart from the intrinsic interest in a novel virus infecting pigs and causing economic losses, the major current concern is the similarity of the clinical picture to that of other swine diseases, because one of them—foot and mouth disease—is a World Organization for Animal Health–listed disease. Because the potential association of SVA with disease is rather new, there are still many questions to be resolved.

Senecavirus A (SVA) is the only member of the genus Senecavirus within the family Picornaviridae (International Committee on Taxonomy of Viruses, http://www.ictvonline.com). This virus was discovered as a serendipitous finding in 2002 while cultivating adenovirus-5-based vectors in the cell line PER.C6, and it was named Seneca Valley virus 001 (SVV-001).¹⁶ This name is derived from Seneca Creek State Park (Maryland, USA), near the laboratories that discovered the virus (Neotropix, Inc., Malvern, PA, USA) (P. L. Hallenbeck, personal communication). It was speculated that this agent could have been introduced into cell cultures by fetal bovine serum or porcine trypsin. The latter was considered more likely because a number of viruses serologically related to SVV-001 were isolated from pigs in the USA during the previous 20 years.¹⁶

The major research on SVV-001 was for its potential use as an oncolytic virus to treat different types of human cancer. Oncolytic viruses are replication-competent viruses that selectively cause cytotoxicity in cancer cells without significantly damaging normal tissues.¹⁰ SVV-001 has been used to infect tumors with neuroendocrine features, including small-cell lung cancer and pediatric neuroendocrine tumors, as well as others.^34,35 Initial data suggested that SVV-001 replicated specifically within tumor cells, but virus-neutralizing antibodies can be developed several weeks after exposure and may limit its applicability.^6,35 SVV-001 is known by the name NTX-010 within the medical field and is currently considered a “licensing opportunity, orphan product” in AvaRx (http://www.avarx.com), an online tool that expands on the Available Pharmaceutical Products List.

In the past 3 decades, the term porcine idiopathic vesicular disease (PIVD) has been used to designate infrequent cases in which swine display erosions and vesicles on the skin, snout, oral cavity, and coronary bands, with unknown cause.⁸ These cases have been described in several parts of the world, including the USA,^4,15 Australia,³⁰ New Zealand,²⁸ and Italy.³⁸ In all these cases, the involvement of well-known vesicular diseases such as foot and mouth disease (FMD), swine vesicular disease (SVD), vesicular stomatitis (VS), and vesicular exanthema (VE) was ruled out after proper laboratory investigations. In the Oceania cases, exposure to marine products, parsnips, or celery was suspected as potential causes of the vesicular problem.⁸ Subsequently, reports from Canada³² and from the USA³⁹ suggested that SVA could be associated with PIDV.

SVA has been further associated with clinical disease in Brazil during the past 2 years and the USA in 2015.^11,24,42,47 Sows and finisher pigs infected with SVA developed cutaneous vesicular lesions mainly on the snout and coronary bands. In addition, neonatal mortality in the first week of life (referred to in some cases as epidemic transient neonatal loss) associated with high SVA load in tissues has also been described.¹¹

Therefore, taking into account the current disease presentation in Brazil and the USA thus far, the objective of this review is to summarize the current knowledge on SVA infection in pigs and its potentially related diseases. Because this virus is considered the cause of emerging clinical problems in different parts of the world, it is important that diagnosticians, including pathologists, virologists, and molecular biologists, be aware of these novel conditions and the establishment of proper diagnostic criteria as well as differential diagnoses.

Characteristics of SVA

SVA is the only species in the genus Senecavirus within the family Picornaviridae and has some features that are shared among all picornaviruses, such as a nonenveloped capsid that is about 25 to 30 nm in diameter with icosahedral symmetry and a linear single-stranded ribonucleic acid (RNA) genome of positive polarity and approximately 7.3 kb.⁴³ As for the other picornaviruses, the SVA genome encodes a large single open reading frame that is expressed as a polyprotein precursor. The 5′ portion of the polyprotein is flanked by an untranslated region (5′UTR) and a polyadenylated untranslated 3′ end (3′UTR).⁴⁴ The 5′UTR has a covalently linked protein named VPg (virio protein, genome linked) that probably acts in the replication process by binding initiation factors for the translation of the viral RNA.³³ A type IV internal ribosome entry site (IRES) that is structurally and functionally similar to those of classical swine fever virus and hepatitis C virus is present in the 5′UTR of SVA.⁴⁴ In fact, it has been suggested that this IRES similarity might possibly be due to genetic exchange in persistently coinfected pigs.⁴⁴

The SVA polyprotein follows the standard L-4-3-4 layout for picornavirus genomes and is processed to the mature virus proteins by virus-encoded proteinases.¹⁶ The virus genome consists of the leader (L) and 3 major protein regions, named polyproteins 1 to 3 (P1, P2, and P3).²⁰ The schematic organization of the SVA genome is depicted in Fig. 1.

Figure 1. Schematic organization of the SVA genome. At the top, the polyprotein precursor is flanked by the 5′UTR, which contains the genome-linked protein (VPg) sequence and the type IV IRES; the poly(A) tail is represented at the end of the 3′UTR. In the middle, sequences encoding the leader (L) and three major proteins P1, P2, and P3 are present, with the capsid and nonstructural coding sequences are indicated. At the bottom, each mature virus protein is shown after the polyprotein processing. Also present are the conserved picornavirus motif NPG/P at the end of the 2A protein, the VPg encoded by the 3B protein, the 3C proteinase, and the 3D polymerase, which is represented by the RNA-dependent RNA polymerase (RdRp).

Differently from the genera Cardiovirus, Aphthovirus, Erbovirus, Kobuvirus, Teschovirus, and Sapelovirus, which also contain the L protein, the L peptide of SVA likely has a distinct function, yet to be established.¹⁶ Regarding the major proteins, the P1 region is cleaved into the structural polypeptides VP0, VP3, and VP1, which constitute the virus capsid. A maturation site located within the VP0 generates the VP2 and the VP4 polypeptides.³³ The SVA VP1, VP2, and VP3 are 27, 36, and 31 kDa, respectively,¹⁶ and are expressed on the external surface of the virus capsid, while the VP4 lies in its inner surface.⁴³

The P2 and P3 genomic regions encode nonstructural polypeptides involved in protein processing (2Apro, 3Cpro, and 3CDpro) and are associated with viral replication (2B, 2C, 3AB, 3BVPg, 3CDpro, and 3Dpol).³³ The P2 region is divided into 2A, 2B, and 2C. The SVA 2A protein is a short peptide of 9 amino acids ending in an NPG/P conserved motif with a predicted ribosome-skipping function. The primary sequence of the SVA 2B protein is different from all the other known picornaviruses; however, the secondary structures of 2B proteins of picornaviruses are similar to one another and likely play a role in enhancing membrane permeability, acting like a viroporin. The 2C protein is a helicase-like polypeptide involved in RNA synthesis.¹⁶

The P3 region possesses the 3A, 3B, 3C, and 3D polypeptides. The function of 3A is not known. The 3B region encodes a VPg protein that acts like a primer for viral RNA synthesis, 3C is a proteinase, and the 3D polypeptide is the major component of the RNA-dependent RNA polymerase. The 3C and 3D sequences of SVA have active-site residues and amino acid motifs conserved with the other known picornaviruses.¹⁶

SVA is closely related to the Cardiovirus genus with respect to their P1 capsid proteins and the nonstructural 2C, 3Cpro, and 3Dpol proteins.¹⁶ However, the significant differences from the other genomic regions of Cardiovirus and other picornaviruses led to classifying the virus as a new species within a new genus of the Picornaviridae family.⁴⁴

SVA adapts to growth in cell culture, and the virus can be isolated in different cell lineages such as swine testis (ST), swine kidney (SK-RST and PK-15; Figs. 2–5), and human lung cancer cells (NCI-H1299).^24,46 In a comparative study with 3 of these cell lines (ST, SK-RST, and NCI-H1299), NCI-H1299 was the most permissible to SVA infection and produced a high virus titer (10⁹ PFU/mL) at 24 hours after infection.⁴⁶ Nonetheless, the first report of in vitro propagation of SVA was relatively recent, and the number of specific biologic studies of this virus in cell culture is limited. Therefore, specific biological features of the virus are unknown, including the pH stability, cellular macromolecules acting as receptors and coreceptors, and the replication cycle.

**Figures 2–5.** PK-15 porcine kidney cell monolayers. **Figure 2.** Negative control cell monolayer without cytopathic effect, low magnification. **Figure 3.** Cell monolayer 48 hours after inoculation with SVA showing cytopathic effects, including lumping, cells lysis, and partial destruction of the cell monolayer, low magnification. **Figure 4.** Higher magnification of negative control cell monolayer from Fig. 2. **Figure 5.** Higher magnification of the cell monolayer from Fig. 3.

Molecular Epidemiology of SVA

Understanding of the molecular epidemiology of SVA is limited because of the lack of global and temporal diversity of the available whole-genome sequences. Until recently, whole-genome sequences were limited to strains from the USA (n = 2) and Canada (n = 1). However, multiple global strains were generated in 2015 from Brazil (n = 3), China (n = 1), and the USA (n = 3), bringing the total to 9.^42,47 The whole genome of SVA has the highest nucleotide percentage identity (∼70%) to a bat picornavirus identified in 2013.¹⁹ The 9 SVA whole genomes have >93.78% nucleotide identity and 97.71% amino acid identity, with the lowest identities occurring between the prototype strain SVV-001 and the USA SVA strains from 2015 on both the nucleotide and amino acid levels (Table 1). The whole-genome phylogenetic tree indicates divergence from SVV-001 to the current 2015 SVA strains (Fig. 6).

Table 1. Nucleotide and Amino Acid Percent Identities of Senecavirus A.

	SVV_001 (2002)	US Strains (2015)	Brazilian (2015)	Canadian (2011)	Chinese (2015)
SVV_001 (2002)	NA^a	93.78–93.93^a	94.22–94.32^a	95.11^a	94.39^a
SVV_001 (2002)	NA^b	93.78–93.93^a	94.22–94.32^a	95.11^a	94.39^a
US strains (2015)	97.71–97.94^b	98.91–99.33^a	97.68–97.85^a	95.93–96.08^a	96.71–96.81^a
US strains (2015)	97.71–97.94^b	99.77–99.91^b	97.68–97.85^a	95.93–96.08^a	96.71–96.81^a
Brazilian (2015)	97.76^b	99.27–99.31^b	99.5–100^a	96.51–96.55^a	97.1–97.14^a
Brazilian (2015)	97.76^b	99.27–99.31^b	99.59–100^b	96.51–96.55^a	97.1–97.14^a
Canadian (2011)	98.54^b	98.67–98.91^b	98.63–98.99^b	NA^a	96.7^a
Canadian (2011)	98.54^b	98.67–98.91^b	98.63–98.99^b	NA^b	96.7^a
Chinese (2015)	98.4^b	98.99–99.04^b	98.9–98.99^b	99.13^b	NA^a
Chinese (2015)	98.4^b	98.99–99.04^b	98.9–98.99^b	99.13^b	NA^b

Abbreviations: NA, not applicable.

^aNucleotide.

^bAmino acid.

Figure 6. Phylogenetic trees of the whole genome of SVA. Strains are indicated according to country of origin: Brazil (BRA), Canada (CAN), China (CH), and the USA.

The VP1 region (795 nucleotides or 265 residues) contains multiple neutralization domains, is the most immunodominant of the capsid proteins, and has been used to determine serotypes for numerous picornaviruses. Thus, additional VP1 sequences were available from the USA (n = 7) and Brazil (n = 2) (Fig. 7). While the USA SVA strains were generated in an epidemiologic study, the Brazilian strains were associated with clinical disease.^21,24 Phylogenetic analysis of the VP1 gene indicates 3 clades of SVA. Clade I contains the historical SVA strain SVV-001. Clade II contains USA SVA strains identified between 1988 and 1997, and clade III contains global SVA strains from Brazil, Canada, China, and the USA identified between 2001 and 2015. Although the Californian SVA strain from 2001 clusters in clade II, it is a distant ancestor to the strains from 2011 and 2015.

Figure 7. Phylogenetic trees of the VP1 region of SVA. Strains are indicated according to country of origin: Brazil (BRA), Canada (CAN), China (CH), and the USA.

On the basis of the available 18 VP1 sequences, 18 of the 265 predicted amino acid residues contain polymorphic sites, and residue shifts occur in 7 residues (E63 T, A93 V, G97D, F161A, A172 T, V221I, and I239 V) in strains before and after 2001 (Table 2). The strain California/131395 from 2001 contains 5 residues (63, 97, 161, 172, and 221) from historical and 2 residues (93 and 239) from current SVA strains. Because clinical disease was not reported with strain California/131395, 4 residues (63, 97, 161, and 239) could be connected to the putative increased pathogenicity in current SVA strains. Alternatively, these residue changes could be a natural evolution of the virus. Additional research comparing sequences with clinical findings is required to confirm this relationship.

Table 2. Amino Acid Changes in 18 Residues From the VP1 Region Compared With Strain SVV_001 (Reference Strain).^a

Clinical presentation	Strain Name	10	57	62	63	65	93	94	97	133	155	161	172	197	210	221	232	239	250
		Amino Acid Location in VP1
NA	USA/SVV_001/NC_011349	I	R	Q	E	A	A	N	G	D	D	F	A	G	A	V	V	I	S
Variety of clinical signs	USA/NorthCarolina/88_23626/1988/EU271759	V	H	L	.	V	.	.	.	.	.	.	.	.	V	.	A	.	N
	USA/Minnesota/88_36695/1988/EU271760	V	H	L	.	V	.	.	.	.	.	.	.	.	V	.	A	.	N
	USA/Iowa/89_47752/1989/EU271757	V	H	L	.	.	.	.	.	.	.	.	.	.	.	.	A	.	.
	USA/NewJersey/90_10324/1989_12/EU271761	V	H	L	.	.	.	.	.	.	.	.	.	.	.	.	A	.	.
	USA/Illinois/92_48963/1992_09/EU271762	V	H	L	.	.	.	.	.	.	.	.	.	.	.	.	A	.	.
	USA/Louisiana/1278/1997/EU271763	.	.	.	.	.	.	.	.	N	.	.	.	.	V	.	.	.	.
	USA/California/131395/2001/EU271758	.	.	K	.	.	V	.	.	.	G	.	.	.	.	.	.	V	.
NA	CHN/CH-01-2015/KT321458	.	.	A	T	T	V	S	D	.	.	Y	.	.	.	I	.	V	.
Porcine idiopathic vesicular disease	CAN/Manitoba/11_55910_3/2011/KC667560	.	.	E	T	.	V	.	D	.	.	Y	T	A	.	.	.	V	.
	USA/IA40380/2015/KT757280	.	.	A	T	.	V	.	D	.	.	Y	T	.	.	I	.	V	.
	USA/IA46008/2015/KT757282	.	.	A	T	.	V	.	D	.	.	Y	T	.	.	I	.	V	.
	USA/SD41901/2015/KT757281	.	.	A	T	.	V	.	D	.	.	Y	T	.	.	I	.	V	.
	BRA/UEL-SVV-B2/15/KR075678	.	.	A	T	.	V	.	D	.	.	Y	T	–	–	–	–	–	–
	BRA/UEL-SVV-A1/15/KR075677	.	.	A	T	.	V	.	D	.	.	Y	T	–	–	–	–	–	–
	BRA/GO3/2015/KR063109	.	.	A	T	.	V	.	D	.	.	Y	T	.	.	I	.	V	.
	BRA/MG1/2015/KR063107	.	.	A	T	.	V	.	D	.	.	Y	T	.	.	I	A	V	.
	BRA/MG2/2015/KR063108	.	.	A	T	.	V	.	D	.	.	Y	T	.	.	I	A	V	.

BRA, Brazil; CAN, Canada; CHN, China; NA, not available; SVA, Senecavirus A.

^aThe upper half of the table includes historical SVA sequences, and the lower half includes recent strains of SVA.

Clinical and Pathologic Outcomes of SVA Infection

The well-known vesicular diseases of pigs—FMD, SVD, VS, and VE—are characterized by an acute febrile reaction and the formation of vesicles in and around the mouth and on the feet.¹ Clinical SVA infection in pigs, on the basis of the available data from naturally occurring disease in the USA and Brazil, presents similar characteristics, but clinical signs and lesions are relatively mild, albeit indistinguishable from other vesicular diseases.^24,42 Cutaneous lesions are found more frequently on the lips, snout (Fig. 8), and tongue, and on the feet affecting the coronary band, interdigital area, dewclaws, and hoof pads. These lesions appear initially as blanched swollen areas that evolve to vesicles. The vesicles quickly rupture (Figs. 9–11) to form ulcers that may be covered by a serofibrinous exudate. As in other vesicular diseases,² the ulcers begin to repair in 7 days, and regeneration of epithelium is usually complete within 2 weeks. Scarring degree is variable but particularly occurs after severe lesions. No other gross or microscopic lesions have been observed in affected animals.

**Figures 8–13.** Naturally occurring SVA infection. **Figure 8.** Snout, sow. A large vesicle typical of SVA infection is present on the dorsal aspect of the snout. **Figure 9.** Snout, sow. Ulcerated skin on the tip of snout after rupture of a vesicle. **Figures 10 and 11.** Hooves, sows. Multifocal ulceration of the coronary band at different locations, primarily affecting the weight-bearing areas (Fig. 10). **Figure 12.** Abdominal cavity, piglet affected by diarrhea. The intestines are distended with watery content, and there is moderate mesocolonic edema and hepatic lipidosis. **Figure 13.** Hooves, piglet. Ulceration and crusting of coronary bands on both hind limbs.

Vesicles and erosions associated with SVA infection are seen mainly in sows and fattening (finisher) pigs. Lesions may be preceded by a short period of anorexia and hyperthermia (40.3°C–40.8°C) and/or lameness. The course of the vesicular disease on the farm is usually short, lasting for 1 or 2 weeks.

Initial descriptions of the SVA-associated clinical problems in Brazil and the USA^11,24,42,47 referred to a vesicular disease compatible with PIVD. Subsequently, additional clinical signs were linked to SVA infection, including sudden death, as well as severe and sometimes fatal diarrhea, dehydration, and lethargy in neonatal piglets born from healthy, clinically ill, and recovered sows. Mortality of piglets varied widely between litters from different farms but was typically 5% to 60%, and mainly affected animals between 1 and 4 days of age. Approximately 4% to 60% of affected piglets had diarrhea of 1 to 5 days’ duration.

The relationship between the vesicular disease in adult sows and the condition of diarrhea and mortality in neonatal pigs was investigated in an unpublished observational case-control study (n = 33 cases, n = 19 controls) in Brazil in 2015. Farrowing houses from 52 large herds (each with 1180 to 4000 sows) were studied. Of the 52 farms, piglets remained healthy on 19 farms (35%), diarrhea and/or increased mortality in piglets was present without disease in sows in 23 herds (43%), vesicular lesions were present exclusively in sows on 2 farms (4%), and disease was present both in sows (vesicular lesions) and piglets (diarrhea, mortality, and/or vesicular lesions) on 8 farms (14%) (D. Barcellos, personal observation). The increased piglet mortality occurred in the farrowing phase, lasted about 2 to 3 weeks and was about 2 to 3 times higher than on unaffected farms. Piglet mortality returned to normality after 2 to 3 weeks (Fig. 14).

Figure 14. Mean and standard deviation of weekly mortality rate in litters of piglets affected with the acute form of SVA infection (weeks 1–3). Data were collected from 17 Brazilian herds, each with 1180 to 4000 sows, in 2015.

In this study, at postmortem examination, a significant percentage (5%–27%) of piglets with diarrhea showed subcutaneous or mesenteric edema (Fig. 12), and most piglets had milk in the stomach. The contents of the small and large intestine were voluminous with a fluid consistency, without noticeable gross or microscopic lesions of the mucosa. Very few piglets (1%–10%) displayed vesicular lesions on the snout and feet (Fig. 13). Apart from vesicular lesions and mesocolonic edema, histopathologic examination of affected piglets was unremarkable.

In most affected herds, reproductive data remained normal. Some affected farms had a lower farrowing rate and high return to estrus after an acute outbreak (D. Barcellos, personal observation). Vesicular lesions were detected in 5% to 10% of the sows, particularly those in late gestation and in the weaning-to-estrus interval. In nurseries, the main problem was the transfer of weak piglets that survived diarrhea in the farrowing house and then experienced impaired growth and higher mortality associated with secondary bacterial infections, including Glässer’s disease and colibacillosis. In many cases, because of the short-lived vesicular lesions in sows, the main manifestation of outbreaks associated with SVA infection were acute losses of newborn piglets. In growing and finishing phases, clinical signs were of low prevalence (0.5%–3%) and limited to vesicular lesions on the snout and feet. To our knowledge, affected farms have not experienced subsequent outbreaks, but this may change with declining immunity or introduction of naive gilts in affected herds and would depend on the degree of persistence of the virus in the animal and in the environment.

Differential Diagnosis for Vesicular Lesions in Swine

In addition to SVA infection, FMD, SVD, VS, and VE all cause vesicular lesions of varying severity in susceptible swine (Table 3). Porcine parvovirus (PPV) has been associated with necrotic and vesicle-like lesions in swine, but experimental reproduction of the lesions has been difficult, and it was later concluded that PPV infection may predispose to other skin diseases.²³ Along with viral diseases, environmental factors such as caustic agents and inappropriately applied disinfectants should also be considered, particularly when lesions are limited to or concentrated on skin in contact with flooring surfaces (http://www.fao.org).

Table 3. Differentiating Features of the Viral Vesicular Diseases of Swine.

Disease	Virus	Virus Family	Genus	Reported Lesion Distribution (vesicles)	Species Commonly Affected
NA	Senecavirus A	Picornaviridae	Senecavirus	Snout Oral mucosa Coronary bands	Swine
FMD	FMD virus	Picornaviridae	Aphthovirus	Snout Oral mucosa Tongue Pharynx Coronary bands Interdigital Teats	Cloven-hoofed animals
SVD	SVD virus	Picornaviridae	Enterovirus	Snout Oral mucosa Tongue Coronary bands Hooves Heels	Swine
VS	VS virus	Rhabdoviridae	Vesiculovirus	Snout Oral mucosa Tongue Coronary bands Interdigital Heels Teats	Swine Cattle Horses
VE	VE virus San Miguel sea lion virus	Caliciviridae	Vesivirus	Snout Oral mucosa Coronary bands Interdigital Heels	Swine Pinnipeds

FMD, foot and mouth disease; NA, not available; SVD, swine vesicular disease; VE, vesicular exanthema; VS, vesicular stomatitis.

Of the diseases associated with vesicular lesions in swine, FMD is of primary concern given its highly infectious nature, broad host range, and importance to international trade.² FMD virus has been detected in many countries since its discovery more than 100 years ago and remains endemic in large areas of Africa, Asia, and South America.² FMD has been eradicated from many countries, and the potential threat of reintroduction has placed FMD on the World Organization for Animal Health (OIE) list of diseases. Accordingly, the detection of vesicular lesions in pigs is often the trigger for a foreign animal disease investigation in FMD-free countries, and herds should be considered affected with FMD until proved otherwise.²⁵ Exposure occurs via direct or indirect contact with infected animals, aerosols, and fomites. Initial infection typically occurs via the noncornified epithelia of the pharynx and soft palate, although direct infection of damaged cornified epithelium can also occur.² Viral infection proceeds to regional lymph nodes and then the systemic circulation with seeding of secondary sites and multiple cycles of amplification.³ Affected animals are generally febrile and often develop lameness and inappetence.² In the skin, viral RNA is readily detectable in the basal layers of lesional epithelium.¹² Vesicles are consistently observed in and around the mouth and feet; however, lesions may also occur on the snout, teats, and genital epithelium.¹ Coronary band lesions, if severe, may lead to shedding of the claws. Importantly, FMD can cause myocarditis in young animals,² which is not observed in the piglet mortality attributed to SVA infection.

SVD virus has been reported in Europe and Asia and has a similar clinical appearance as FMD, thus making proper laboratory differentiation imperative.¹ Exposure occurs via direct contact, and infection occurs primarily through the skin or intestinal mucosa.⁷ The virus has strong tropism for epithelia but can also be detected in other tissues, including the myocardium and brain stem.⁹ Following experimental inoculation, vesicles first appear on the tongue and in the oral cavity, with lesions on the snout and coronary band occurring 24 to 48 hours later.⁹

VS virus causes lesions in cattle and pigs with similar appearance and distribution as FMD, making clinical differentiation difficult. One notable exception is the susceptibility of horses to VS. Thus, the observation of affected horses in an outbreak may help narrow the differential diagnosis. VS occurs in both endemic and epidemic forms and is currently limited to the Americas.⁴¹ Exposure occurs both through direct contact and mechanically via insect vectors.⁴¹ Infection is limited to the site of exposure and draining lymph nodes, and primary replication occurs within keratinocytes.³⁶ Excessive salivation is commonly observed and may be the only clinical sign.⁴¹ Foot lesions and lameness are more common in pigs with VS than in other susceptible species.

Clinical manifestation can vary from subclinical to severe, and factors such as virus strain and flooring composition are thought to influence severity.¹ Overall, the clinical appearance of SVD is milder than that of FMD, and fever and lameness are rarely observed.¹

VE virus, a calicivirus, induces an acute, febrile disease of swine clinically indistinguishable from other vesicular diseases. As with other vesicular diseases previously described, vesicles typically rupture within 24 to 48 hours of their appearance and form erosions.²² VE was first reported in California in the 1930s and then spread throughout the USA.²⁶ In 1959, the USA was declared free of VE, and the disease has not been reported in other parts of the world.²² However, in 1972, a similar but distinct calicivirus, named San Miguel sea lion virus (SMSV), was isolated from aborting California sea lions and was capable of inducing lesions of VE in swine.⁴⁰ Genetic investigations have revealed that these 2 viruses form a single genotype within the Caliciviridae.³¹ Many serotypes of SMSV have been detected and continue to persist in reservoirs in the Pacific Ocean, serving as a perpetual risk for reintroduction into swine populations.

Discussion

Emerging infectious diseases are those diseases occurring with increased incidence, because they are either caused by new pathogens or strains or existing diseases that emerge as a result of long-term changes in their underlying epidemiology.⁴⁵ This concept can also include infectious diseases that expand into an area in which they were not previously reported, or diseases that change significantly their clinicopathologic presentation.¹⁷ The number of emerging and reemerging infectious diseases in swine has increased importantly during the past 20 to 30 years.³⁷ Significant examples include the emergence of porcine reproductive and respiratory syndrome by the end of 1980s into the early 1990s, porcine circovirus type 2 systemic disease (PCV2-SD, also known as postweaning multisystemic wasting syndrome) by late 1990s and mid-2000s worldwide, and porcine epidemic diarrhea in North America and Europe in 2013 and 2014. Moreover, the list of novel emerging infectious diseases in swine is rather long if other diseases with less global impact are considered.²⁷ These numbers will probably increase in the near future because the temporal pattern of discovery of novel pathogens or variants is high (7.5 per year from 2001 to 2010).¹⁴ Although SVA was already known as an oncolytic virus of potential use in human therapies, its association with swine disease is novel.

The aim of this review is to draw the attention of veterinarians, including clinicians, pathologists, and researchers, to an apparently novel clinical-pathologic condition linked to a previously known pathogen, SVA. Apart from the intrinsic interest in a novel virus infecting pigs and causing economic losses, the major current concern is the similarity of the clinical picture with that of other swine diseases, because one of them, FMD, is an OIE-listed disease (http://www.oie.int). The regulatory impact associated with the notification of an OIE-listed disease can be extremely detrimental for the pig production of a given country or region, including the official investigation, banning of animal movements, restriction of human movement, culling of animals, and export restrictions on products of animal origin. In consequence, early warning of the clinical condition by the attending farm veterinarian is of considerable value, and immediate sampling and laboratory testing for FMD and other vesicular diseases of swine are compulsory.

Besides the vesicular form of the disease, it is also important to stress that new clinical and pathologic outcomes have been observed in the recent form of SVA infection in Brazil and the USA. Specifically, the pathogenesis of diarrhea and associated mortality in 1- to 4-day-old piglets must be clarified, as the absence of histologic lesions represents a diagnostic challenge.

The best samples to attempt a molecular diagnosis of a vesicular disease should include liquid from vesicles, swabs from erupted vesicles, skin scrapings at the margin of erosions or around blanched coronary bands, oral swabs, or oral fluids. In most cases, these samples can be taken from live animals in the acute phase of disease. In cases of neonatal death, a wide variety of tissues should be taken to establish a proper diagnostic investigation of the various causes of sudden death and diarrhea. Therefore, at a minimum, submission of any cutaneous lesions as well as lymph nodes, tonsil, spleen, liver, kidney, lungs, heart, large and small intestine, and brain is recommended.

Because the association of SVA with disease is rather new, there are still many questions to be resolved, including disease causality by this viral infection. To date, minimal data are available about the causative role of SVA in disease. An exploratory experimental infection performed at the National Animal Disease Center (Ames, IA, USA) has reproduced the vesicular disease in 9-week-old pigs.²⁹ However, other attempts at experimentally reproducing PIVD with SVA have failed in both North America^5,46 and Brazil (D. Barcellos, personal communication). Therefore, the association of SVA with disease is still speculative at this time, because SVA can be isolated from normal pigs, and other viruses were frequently detected in the samples from clinically affected pigs in which they demonstrated SVA.⁵ In fact, this scenario is rather typical of multifactorial diseases with infectious agents, like PCV2-SD.¹³ Therefore, it is very likely that SVA may cause disease under certain scenarios (eg, genetics, environment, coinfections, or others) that have not yet been elucidated.

Importantly, the establishment of proper diagnostic tools to detect the virus and antibodies against it are under way, but it is still too early for their global availability. The development of validated diagnostic tools will be necessary to identify the naive status of experimental animals, to determine infection status for epidemiologic studies, and for diagnostic purposes to identify SVA as a cause of natural disease occurrences. In fact, a recently published work aimed to develop a sensitive SYBR Green–based real time-quantitative polymerase chain reaction (PCR) assay suitable for the detection of SVA in swine diagnostic specimens.⁵ Interestingly, 88% of animals with vesicular lesions from the USA were positive for SVA by the newly developed PCR method, emphasizing the association between SVA and PIVD.

The possibility of SVA’s being a potentially endemic virus in some pig populations or causing subclinical infections cannot be ruled out at present. Moreover, SVA has also been detected in environmental samples as well as mice and houseflies present in affected and nonaffected pig farms,¹⁸ further emphasizing the likelihood of endemicity. Future epidemiologic research will be needed to investigate the association with disease and the current distribution of this viral infection worldwide.

SVA has demonstrated again that the risk for emerging infectious diseases in swine populations is high and that emerging diseases of swine have significant potential impact on the productivity and economics of the pork industry. Such events emphasize the importance of basic and applied research and the need for emergency preparedness to develop and implement methods for the early detection and containment of emerging infectious diseases. Pork production is a globalized industry, and swine veterinarians and researchers in conjunction with producers, consumers, and stakeholders should join efforts for more global, collaborative, and action-oriented approaches toward logical and practical solutions.³⁷

Acknowledgements

We thank Dr. Paul L. Hallenbeck for critical revision of the manuscript and Dr. Enric Vidal (IRTA-CReSA) for assistance with the iconography.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

1. Alexandersen S, Knowles NJ, Dekker A, Belsham GJ, Zhang Z, Koene F. Picornaviruses. In: Zimmerman JJ, Karriker LA, Ramirez A, et al., eds. Diseases of Swine. 10th ed. Ames, IA: Wiley-Blackwell; 2012:587–620.

Abstract

Characteristics of SVA

Molecular Epidemiology of SVA

Clinical and Pathologic Outcomes of SVA Infection

Differential Diagnosis for Vesicular Lesions in Swine

Discussion

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Declaration of Conflicting Interests

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