Classical Swine Fever

Classical swine fever is caused by a small, enveloped RNA virus in the genus Pestivirus of the family Flaviviridae. Classical swine fever virus (CSFV) is antigenically related to the other pestiviruses, mainly to bovine viral diarrhea virus Bovine Viral Diarrhea and Mucosal Disease Complex Bovine viral diarrhea/mucosal disease is a pestivirus infection of cattle and other ruminants. Infection leads to immunosuppression and can cause signs in multiple body systems in addition to... read more (BVDV) of cattle and to border disease virus Border Disease Border disease is observed in young ruminants exposed to border disease virus during gestation. Surviving lambs demonstrate failure to thrive, a long hair coat, and tremors, giving rise to the... read more (BDV) of sheep. These viruses are highly prevalent in bovine and ovine populations and can infect pigs. Although infections of pigs with ruminant pestiviruses in most cases do not lead to clinical disease and are rapidly cleared, infections with both BVDV and BVD induce an antibody response in swine. Therefore, antibody discrimination tests must be applied to differentiate CSF infections from infections caused by ruminant pestiviruses. Transmission of ruminant pestiviruses to pigs usually requires direct contact with cattle, sheep, or goats. CSFV naturally infects members of the Suidae family, ie, domestic and wild pigs.

In the laboratory, CSFV is cultured in cells of porcine origin, notably in the PK-15 cell line (porcine kidney), but does not generally cause a visible cytopathic effect. The virus has only one serotype, although some minor antigenic variability between strains is seen. Strains can be typed for epidemiologic mapping purposes by sequencing the entire viral genome or specific regions of the viral genome (ie, 5′UTR, E2, and NS5B regions) combined with phylogenetic analysis.

CSFV is moderately fragile and does not persist in the environment or spread long distances by the airborne route. However, it can survive for prolonged periods in a moist, protein-rich environment such as pork tissues or body fluids, particularly if kept cold or frozen. Virus survival times up to several years have been observed in frozen pork meat. CSFV may also survive months in chilled or cured cuts.

CSF is distributed worldwide. It is considered endemic in certain countries of Central and South America, in the Caribbean basin, and in many pork-producing countries in Asia. Australia, New Zealand, Canada, USA, and countries in Europe are considered free of the disease. The main source of CSFV infection is the pig, either via infected live animals or via uncooked pork products. In areas where CSF is endemic, the major concern is the spread of disease via movement of infected animals. Wild boars and species within the Suidae family are susceptible to CSFV infection. In Europe, CSFV is endemic in wild boar populations, and infected wild boars tend to be the source for CSF outbreaks reported among domestic pigs.

Another major risk for CSF outbreaks is the accidental introduction of CSFV into herds through illegally imported pork meat or pork products that often find their way into the porcine food chain via swill feeding. However, CSFV is readily inactivated by heat (ie, cooking), which emphasizes the importance of enforcing regulations for heat treatment of swill feed. In addition, many countries have completely banned swill feeding practices.

Mechanical transmission by vehicles and equipment, as well as by personnel (notably veterinarians) travelling between pig farms, are also significant means of spread of CSF within infected areas. The persistence of CSFV within herds for long periods has been observed. Infections of sows during pregnancy with low to moderately virulent strains of CSFV may lead to in utero infections of fetuses. These infections lead to litters born persistently infected with CSFV that are carriers of the virus and source for new infections.

Persistently infected carrier pigs usually do not show clinical signs but constantly shed CSFV into the environment. Therefore, it is particularly important to consider CSFV infections while investigating herds presenting with unexplained reproductive failures that include clinical manifestations in piglets such as congenital tremor or congenital abnormalities.

Presumably, the widespread use of CSFV vaccines in China has led to the emergence of CSFV escape variants that are not fully neutralized by antibodies elicited against the C strain. CSFV isolates from genotype 2.1 are neutralized to a lesser extent by sera from pigs immunized with LAV C strain than isolates of the genotypes 2.2 and 2.3. The significance of these findings in relationship with potential vaccine failures is yet to be determined.

Classical swine fever is characterized by fever, hemorrhages, ataxia, and purple discoloration of the skin; however, the clinical presentation varies, depending on host characteristics and the particular virus strain causing the infection. CSF occurs in several forms, including highly lethal, acute, chronic, or subclinical. Acute forms of CSF, associated with highly virulent CSFV strains, are characterized by an incubation period that is typically 3–7 days, with death occurring within 10 days after infection. Fever >41°C (105.8°F) is usually seen and persists until terminal stages of the disease when body temperature drops and becomes subnormal. Constipation followed by diarrhea and vomiting is common.

The principal lesion produced by CSFV infection is a generalized vasculitis, clinically manifested as hemorrhages and cyanosis of the skin, notably at the ears, lower abdomen, and extremities. There may also be a generalized erythema of the skin. Vasculitis in the CNS leads to incoordination (ie, staggering gait) or even convulsions. Histologically, nonsuppurative encephalitis with a characteristic vascular cuffing is common. At necropsy, the principal findings are widespread petechial and ecchymotic hemorrhages, especially in lymph nodes (eg, mandibular and retropharyngeal), tonsils, larynx, kidneys, spleen, urinary bladder, and ileum. Infarction may be seen, particularly in the periphery of the spleen.

Subacute and chronic forms of the disease are also characterized by high fever, staggering gait, cough, diarrhea, purple discoloration of the skin, and death. In the subacute form, death generally happens within 20–30 days after infection; in the chronic form, death may occur much later. Subacute and chronic forms of the disease are associated with CSFV strains of moderate to low virulence, respectively. Low virulence strains can be difficult to detect; the only clinical expression may be poor reproductive performance of sows and the birth of piglets with neurologic defects (eg, congenital tremor).

In chronic forms of CSF after an initial acute febrile phase, infected animals may show an apparent recovery but then relapse, with anorexia, depression, fever, and progressive loss of condition (ie, marked weight loss). Macroscopically, in addition to the lesions described above, “button” ulcers may develop in the intestine, particularly near the ileocecal junction. Histologically, atrophy of the thymus and depletion of lymphoid follicles in lymph nodes are seen.

Classical swine fever is first detected by veterinarians in the field. Because clinical signs manifested by CSFV-infected pigs are also seen with other diseases of swine, laboratory confirmation is always required.

Clinically, the differential diagnosis varies based on the course of CSF. African swine fever African Swine Fever is the main differential because this disease has a similar clinical presentation. Hemorrhagic lesions, systemic diseases of pigs, and reproductive failures caused by other infectious and noninfectious agents should also be considered.

Virologic tests are essential to confirm the diagnosis of CSF. Advice on sample submission should be sought from the laboratory. Suitable tissues to detect the presence of the virus are tonsils, lymph nodes (mandibular, retropharyngeal, gastrohepatic, and mesenteric), spleen, kidney, and ileum. Whole blood collected with EDTA as anticoagulant can be used for virus isolation or virus detection, particularly during the viremic phase of the infection. Clotted blood samples (serum) are taken when serologic tests for detection of CSFV antibodies are pursued. Nasal swabs and/or tonsil scrapings are commonly collected clinical samples used to detect the virus (ie, viral RNA).

Significant amounts of CSFV are shed from infected animals into the environment via the oronasal route, particularly early during infection. Detection of CSFV antigen can be performed using direct immunofluorescence on frozen tissue sections, particularly in tonsil samples using specific antibodies. Antigen detection can also be done using ELISA; however, this assay has low sensitivity and is only useful for screening for the presence of CSFV at the herd level. More commonly, viral nucleic acid detection is done using reverse transcriptase (RT)-PCR. The assay is highly specific and can differentiate CSFV from bovine viral diarrhea virus and BDV. Standardized methods such as RT-PCR can be scaled up to screen large numbers of samples, giving rapid results while retaining high sensitivity. This is particularly useful to screen herds during an outbreak of CSF.

CSFV is isolated in cell cultures inoculated with tissue suspensions, WBCs, or oronasal fluids of CSF-suspected cases. CSFV can also be detected in infected cells or tissues (ie, tonsils) by immunofluorescence assay. RT-PCR or RT-qPCR are broadly used for rapid detection of CSFV RNA in tissues, blood, serum, or oronasal fluids. Antibodies against CSFV are detected later during the infection (2–3 weeks postinfection). ELISA and virus neutralization assays are commonly used to detect CSFV-specific antibodies. It is important to consider that BVDV Bovine Viral Diarrhea and Mucosal Disease Complex Bovine viral diarrhea/mucosal disease is a pestivirus infection of cattle and other ruminants. Infection leads to immunosuppression and can cause signs in multiple body systems in addition to... read more and BDV Border Disease Border disease is observed in young ruminants exposed to border disease virus during gestation. Surviving lambs demonstrate failure to thrive, a long hair coat, and tremors, giving rise to the... read more can infect pigs. The presence of antibodies against ruminant pestiviruses in pigs may hamper the serologic diagnosis of CSF. BVDV- or BDV-specific antibodies are sporadically detected in pig populations.

New generations of CSFV marker vaccines have been developed to make emergency vaccination compatible with control of CSF. The application of a marker vaccine is possible if tests such as ELISA can distinguish between antibodies produced in response to a natural infection and those produced by vaccination. This is the DIVA principle (differentiation of infected from vaccinated animals) that is based on detection of CSFV-specific antibodies that develop in the host only with CSFV infection but not on vaccination with a marker vaccine. These assays have been developed as necessary companion tests for CSF marker vaccines.

Classical swine fever is a notifiable disease. Control is usually strictly regulated by local laws that establish strict sanitary measures. No treatment is available. Outbreaks in countries free of CSF are controlled rapidly via culling of infected animals and preemptive slaughter of susceptible animals within determined distances from the focus. Restriction of movement within a well-defined radius from the outbreak is applied to contain spread of the infection. Eventually, emergency vaccination can be authorized to control the further spread of CSFV. Countries will regain their CSF-free status (no antibodies or virus detected) after establishing that CSFV is no longer present in the national pig herd.

Countries free of CSF forbid the use of prophylactic vaccination and exert strict control of movement of animals, including domestic pigs. In these countries, herds affected by an outbreak of CSF are quarantined and exposed animals eliminated. Pre-emptive slaughter of pigs is sometimes applied within established quarantine zones. Emergency ring vaccination around the outbreak can be done to prevent further spread of CSFV.

In countries where the virus is endemic, prophylactic vaccination is used. If systematically applied, vaccination may lead to the elimination of CSFV from swine herds.

CSF live-attenuated vaccines are safe and highly efficient, being able to induce protection shortly after vaccination (within 3 days). More recently, subunit CSFV vaccines containing only the major viral surface glycoprotein of the virus have been licensed. Although these vaccines allow differentiation of infected from vaccinated animals (DIVA capabilities), they lack the efficiency of live-attenuated vaccines. Oral vaccination of wild boars has been used successfully within the European Union using a live-attenuated vaccine delivered via baits. Oral vaccination has been a key strategy to control CSF, particularly where parenteral vaccine delivery is not feasible.

More recently, a live attenuated marker vaccine (LAV) was licensed by the European Medicines Agency. The vaccine is based on pestivirus chimera CP7_E2alf that carries the E2 glycoprotein from CSFV isolate Alfort/187 in a bovine viral diarrhea virus type-1 backbone (CP-7). Alongside, FT4Gv, an LAV marker vaccine candidate was developed on the CSFV Brescia isolate genetic backbone. Pigs vaccinated with these genetically modified viruses generate an antibody response that can be distinguished from the response elicited against CSFV isolates. The protective efficacy induced by these viruses is as effective as the immunity induced by first-generation LAV.