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A novel, noncytopathogenic, picornavirus-like contaminant in the porcine kidney cell line PK-15 (ATCC-CCL33) was described in 1974. This agent was later shown to be a small nonenveloped virus containing a single-stranded, circular DNA genome; it was named porcine circovirus (PCV). PCV antibodies in swine were found to be widespread and experimental infections with this virus in pigs did not result in clinical disease, suggesting that PCV was nonpathogenic.
A new disease was described in Western Canada during the early and mid 1990s. The etiology was unknown and the condition was named postweaning multisystemic wasting syndrome (PMWS). Affected pigs, mainly nursery pigs, showed primarily poor growth rate, ill thrift, and/or wasting, and they were histopathologically characterized by systemic inflammatory lesions. In the late 1990s, an apparently novel PCV-like virus was isolated from PMWS-affected pigs. The new virus was antigenically and genetically distinct from the PCV contaminant of PK-15 cell cultures. Subsequently, PCV isolates from diseased pigs were designated as porcine circovirus type 2 viruses (PCV2) and the original PCV from PK-15 cell cultures as porcine circovirus type 1.
PCV2 has been further associated with a number of disease syndromes in pigs. Therefore, the terminology porcine circovirus diseases (PCVD) was proposed to collectively name PMWS (also known as PCV-associated diseases [PCVAD] in North America), PCV2-associated reproductive failure, porcine dermatitis and nephropathy syndrome, and proliferative and necrotizing pneumonia. Congenital tremor type AII was also considered as a potential PCVD, but most available data do not support this conclusion. Only PMWS is considered to severely impact swine production worldwide, but the introduction of efficacious vaccines to the market has largely ameliorated these effects.
PMWS is considered a multifactorial disease in which PCV2 is the essential infectious agent. PCV2 should also be considered in the differential diagnostic list of agents that cause reproductive problems. Although porcine dermatitis and nephropathy syndrome is considered a PCVD, confirmation of PCV2 as the antigen related to this immune complex disease is lacking. Porcine respiratory disease complex and proliferative and necrotizing pneumonia are also multifactorial clinical and pathologic conditions, respectively, and their occurrence may be concomitant with PCV2 infection and/or PMWS.
Etiology and Pathogenesis
Circoviruses are small (17–22 nm in diameter), nonenveloped viruses that contain a single strand of circular DNA. There are 2 types of porcine circovirus, although only PCV2 is considered pathogenic. Phylogenetic studies have recently shown that at least 3 genotypes of PCV2 exist (PCV2 a, b, and c). Recent studies suggested a genotype shift (from a to b; PCV2c has been retrospectively detected in Denmark during the 1980s) coincidental with major outbreaks of PMWS in North America, Japan, and some European countries. It is not clear whether differences in pathogenicity exist among or within PCV2 genotypes.
Serologic surveys show that PCV2 is widespread in swine, independent of the PMWS status of the farm. Results from retrospective serologic studies indicate that PCV2 has been infecting pigs for more than 5 decades.
Initially, PMWS was identified in high health herds that were free of most common swine pathogens. However, under field conditions, swine that show signs of PMWS usually are infected with multiple agents, including porcine parvovirus, porcine reproductive and respiratory syndrome virus, Actinobacillus pleuropneumoniae, Pasteurella multocida, Haemophilus parasuis, Staphylococcus spp, and Streptococcus spp.
Multiple attempts to experimentally reproduce PMWS have been published. Some early trials (using tissue homogenates from PMWS-affected pigs or a PCV2 isolate) reproduced PMWS-like histologic lesions, but not the wasting condition. However, occasional studies subsequently reproduced clinical disease and lesions consistent with PMWS using only PCV2, presumably, as inoculum. Consequently, it was suggested that PCV2 infection, linked to other cofactors, was necessary for the consistent development of full clinical disease. It now appears that a number of factors such as age and source of pigs, environmental conditions, genetics, the nature of the PCV2 inoculum used, and the immunologic status of the pig at PCV2 infection play a significant role in the consistent experimental reproducibility of the disease. In fact, the more consistent and repeatable PMWS disease models have been obtained using infectious and noninfectious cofactors as triggers. The mechanisms by which other viruses or immunostimulation may trigger the development of wasting in PCV2-infected pigs is still unknown. High loads of PCV2 in blood, lymphoid, and other tissues and in potential excretion routes are associated with the expression of disease.
When multisystemic disease and wasting is apparent, damage to the immune system is the main feature suggesting that affected pigs have an acquired immunodeficiency. Lymphocyte depletion of lymphoid tissues, changes in peripheral blood mononuclear cell subpopulations and altered cytokine expression patterns have all been demonstrated in naturally and experimentally PMWS-affected pigs.
The identification of cells that support PCV2 replication is still controversial. The large amount of PCV2 virus antigen found in the macrophages and dendritic cells of diseased pigs appears to be the result of accumulation of viral particles. However, epithelial and endothelial cells seem to be the main target for PCV2 replication, as well as a small proportion of macrophages and lymphocytes.
Much less is known regarding the pathogenesis of other clinical diseases associated with PCV2 infection. PCV2 is able to replicate in fetuses as well as in zona pellucida-free embryos. Moreover, an experiment with embryos exposed to PCV2 and then transferred to receptor sows suggested that infection can lead to embryonic death. Transplacental transmission of PCV2 has been demonstrated. However, experiments using pregnant sows inoculated intranasally have yielded variable results.
Porcine dermatitis and nephropathy syndrome is considered a type III hypersensitivity reaction, in which the antigen present in the immune complexes is unknown. It has been speculated that PCV2 could be the antigen, but there is no definitive proof that PCV2 causes porcine dermatitis and nephropathy syndrome lesions. Indirect evidence exists, such as significantly higher serum antibody titers to PCV2 in affected pigs compared to healthy or PMWS-affected pigs.
Epidemiology and Transmission
PCV2 is considered a ubiquitous virus in countries with and without porcine circovirus diseases (including PMWS). PCV2 infection and PMWS have also been described in wild boar. The disease has been reported worldwide.
Transmission may be by direct contact with infected pigs. PCV2 has been detected in almost all potential excretion routes such as nasal, ocular, and bronchial secretions; saliva; urine; and feces. The virus can be found in semen, but the practical importance of this is unknown. Artificial insemination of sows with PCV2-infected semen has shown contradictory results; some studies suggest the possibility of associated reproductive problems. Although not demonstrated, it is assumed that contact with contaminated fomites, exposure to contaminated feeds or biologic products, multiple use of hypodermic needles, or biting insects may play a role in transmission.
PCV2 may persist in swine for several months under either experimental or field conditions. Convalescent swine may carry virus for extended periods and be important in disease transmission. PCV2 is fairly resistant to commonly used disinfectants and to irradiation, probably allowing it to accumulate in the environment and be infective for new groups of susceptible pigs if rigorous sanitary measures are not followed. The decline of colostral antibody titer in pigs is associated with onset of PMWS in late nursery or finishing pigs. Transplacental infection with PCV2 has been documented, but it is not known whether in utero-infected pigs are able to transmit the infection or, alternatively, develop clinical PMWS subsequently.
Some reports have suggested that animals other than swine may be infected with PCV2 or PCV-like viruses. However, results of serologic studies for antibody against PCV in cattle and other livestock have been contradictory, and experimental induction of disease using PCV1 or PCV2 in species of livestock other than swine has not been successful.
Clinical Findings
Multisystemic disease with weight loss often occurs in the fattening units, in pigs 8–18 wk old, although the disease can be also seen in older or younger pigs. Morbidity is typically 5–20% among cohorts in the late nursery or finishing stages. Mortality in swine with signs of PMWS can occasionally be >50%. In addition to death loss, PMWS in finishing pigs may cause a substantial increase in the time to reach market weight, resulting in economic loss for the producer. Growth retardation, wasting, and dyspnea are the clinical signs seen most frequently in outbreaks. Pallor, anemia, jaundice, diarrhea, and palpable inguinal lymphadenopathy also are seen in some affected pigs. A low-grade fever (104–106°F [40–41°C]) of several days' duration may be seen as well. Overcrowding, poor air quality, insufficient air exchange, and commingled age groups seem to exacerbate the course of the disease. Usually, only a few pigs in a group show wasting. The onset of disease may be acute, leading to death within a few days in some pigs. Other pigs show a more chronic disease and fail to gain weight or thrive.
Reproductive failure characterized by late-term abortions and stillbirths in the absence or presence of other well-known reproductive pathogens seems to be the hallmark of clinical PCV2 infection in sows. Most of these descriptions come from North America and usually occur in start-up herds. Return to estrus due to embryonic death as a potential outcome of intrauterine PCV2 infection has been suggested based on experimental data. However, there are no field data regarding this effect.
Porcine dermatitis and nephropathy syndrome may affect nursery and growing pigs, and, sporadically, adult animals. The prevalence of the syndrome in affected herds is relatively low (<1%), although higher prevalences (>20%) have been described occasionally. Pigs with severe acute disease die within a few days after the onset of clinical signs, due to acute renal failure with a significant increase in serum levels of creatinine and urea. Surviving pigs tend to recover and gain weight 7–10 days after the beginning of the syndrome. Affected pigs have anorexia, depression, prostration, stiff gait and/or reluctance to move, and normal temperatures or mild fever. The most obvious sign in the acute phase is the presence of irregular, red-to-purple macules and papules on the skin of the hindlimbs and perineal area, although distribution may be generalized in severely affected animals. With time, the lesions become covered by dark crusts and fade gradually (usually in 2–3 wk), sometimes leaving scars.
Lesions
PMWS is diagnosed by characteristic histopathologic findings in affected pigs. Grossly, lymph nodes may be substantially enlarged and pale on cut surface, the thymus atrophied, and the tonsils thinner than normal. Splenic infarcts also may be present in a low proportion of PMWS-affected pigs. Histopathologic lymphoid lesions are characteristic, showing lymphocytic depletion and granulomatous inflammation, sometimes with the presence of multinucleate giant cells and amphophilic botryoid intracytoplasmic inclusion bodies of different sizes caused by accumulation of PCV2 particles.
Lesions in the lung are common in affected pigs; their severity is influenced by duration of disease and presence of concurrent infections. Gross lung lesions may include failure to collapse, firmness, diffuse pulmonary edema, mottling, and consolidation. Microscopically, a variable degree of lymphohistiocytic interstitial pneumonia to granulomatous bronchoin-terstitial pneumonia with bronchiolitis and bronchiolar fibrosis can be seen.
Grossly, the liver may appear icteric and/or atrophic in a low proportion of affected pigs. Interlobular connective tissue may be prominent. Microscopic lesions range from single cell necrosis (apoptosis) with mild lymphocytic infiltration of portal zones to extensive lymphohistiocytic periportal hepatitis with diffuse necrosis of hepatocytes. The kidneys may be enlarged and show scattered to diffuse white foci on the cortical surface. Microscopic lesions include interstitial lymphohistiocytic infiltration. Other lesions seen in affected pigs include gastric ulceration (probably due in part to a prolonged fastening period in chronically affected pigs) and occasional multifocal lymphohistiocytic myocarditis. In severely affected pigs, lymphohistiocytic infiltrates can be seen in virtually all tissues.
The pathology of reproductive tissues caused by PCV2 infection has been poorly described. It has been reported that stillborn and nonviable neonatal piglets show chronic passive congestion of the liver and cardiac hypertrophy with multifocal areas of myocardial discoloration. The key histopathologic feature is fibrosing and/or necrotizing myocarditis in fetuses.
Porcine dermatitis and nephropathy syndrome is easy to detect from a clinical point of view due to red-to-dark macules and papules, which correspond microscopically to necrosis and hemorrhage secondary to necrotizing vasculitis of dermal and hypodermal capillaries and arterioles. Necrotizing vasculitis is a systemic feature, but it is more prominent in the skin, kidney pelvis, mesentery, and spleen (splenic infarcts may also be present as a result of necrotizing vasculitis of splenic arteries or arterioles). Apart from skin lesions, pigs that die acutely with porcine dermatitis and nephropathy syndrome have firm, bilaterally enlarged kidneys, with a fine granular cortical surface and edema of the renal pelvis. The renal cortex displays multiple small, reddish pinpoint lesions, similar to petechial hemorrhages, which microscopically correspond to enlarged and inflamed glomeruli (fibrinonecrotizing glomerulitis). Histologically, a moderate to severe nonpurulent interstitial nephritis with dilation of renal tubules is also seen. Usually, both skin and renal lesions are present, but in some cases, skin or renal lesions may occur alone. Lymph nodes may be enlarged and red due to blood drainage from affected zones with hemorrhages (mainly skin). Histopathologically, PMWS-like lesions such as lymphocyte depletion and histiocytic and/or multinucleate giant cell infiltration (although less severe) are usually found in lymphoid tissues of affected pigs.
Diagnosis
The PMWS case definition includes 3 main diagnostic criteria: 1) clinical signs of wasting or ill thrift, 2) presence of gross and microscopic (moderate and severe) lesions that are characteristic of the disease, and 3) presence of viral antigen or DNA (moderate to high amount) in the microscopic lymphoid lesions. Visualization of viral DNA or antigen in lesions is usually done using in situ hybridization or immunohistochemistry, respectively. Recently, a herd case definition has been proposed, which includes 2 main criteria: 1) significant increase of mortality and number of runt pigs or pigs failing to gain weight or thrive in comparison to previous value for the farm, and 2) the fulfillment of the 3 individual criteria listed above in at least 1 out of 5 examined pigs. Differential diagnoses include conditions causing increased mortality and growth retardation, such as porcine reproductive and respiratory syndrome, chronic respiratory disease, Glässer's disease, salmonellosis, and porcine intestinal adenomatosis.
Because PCV2 is ubiquitous and the virus replicates in individual pigs for weeks to months, isolation of virus, detection of PCV2 DNA in serum or tissues, or detection of PCV2 antibodies in serum is not sufficient to establish a diagnosis of PMWS. Antibodies against PCV2 may be detected by ELISA, indirect fluorescent antibody, or immuno-peroxidase staining of infected cell cultures. Viral isolation can be done on several porcine cell lines (mainly porcine kidney cells) using serum, bronchiolar lavage fluid, or tissue homogenates. Viral DNA can be detected using PCR in most tissues or in serum from affected pigs. Several tissue samples from multiple pigs may be required for detection of virus in cases of chronic disease.Virus quantification in serum by real time quantitative PCR has been suggested as a potential diagnostic method in live pigs. However, PCV2 infection is extremely common in clinically normal pigs and interpretation of positive PCR results is not straightforward.
The diagnosis of reproductive problems associated with PCV2 infection should include the following criteria: 1) late-term abortions and stillbirths, sometimes with hypertrophy of the fetal heart, 2) extensive fibrosing and/or necrotizing myocarditis, and 3) high concentrations of PCV2 in the myocardial lesions and other fetal tissues. Differential diagnosis for PCV2-associated reproductive failure include porcine reproductive and respiratory syndrome, porcine parvovirus, pseudorabies (Aujeszky's disease), leptospirosis, and other diseases causing late abortions, stillbirths, and weak piglets.
The case definition for porcine dermatitis and nephropathy syndrome is relatively simple and includes 2 main criteria: 1) presence of hemorrhagic and necrotizing skin lesions, mainly located on the hindlimbs and perineal area, and/or swollen and pale kidneys with generalized cortical petechiae, and 2) presence of systemic necrotizing vasculitis, and necrotizing and fibrinous glomerulonephritis. From a diagnostic point of view, detection of PCV2 is not included in the diagnostic criteria.
Differential diagnosis of porcine dermatitis and nephropathy syndrome depends on the most significant pathologic outcome. Cutaneous manifestations may be confused with classical and African swine fever, swine erysipelas, septicemic salmonellosis, infection with Actinobacillus suis, porcine stress syndrome, transit erythema (urine-soaked floors, chemical burns, etc), and other bacterial septicemias. Differential diagnoses for kidney lesions include classical and African swine fever, swine erysipelas, and septicemic salmonellosis. Serum biochemical analyses may help differentiate porcine dermatitis and nephropathy syndrome from other diseases; urea and creatinine are markedly increased.
Treatment and Control
Because PMWS is a multifactorial disease, effective control measures before the advent of PCV2 vaccines were focused on the control or eradication of these triggers. The most widely used control measures were the use of antibiotics to prevent concurrent bacterial infections, improvement of biosecurity and sanitary measures such as isolation of affected pigs and disinfection of pens after their use, decreasing stressors (eg, high stocking density, inadequate ventilation, inadequate temperature control), and control of concomitant viral infections, especially porcine reproductive and respiratory syndrome. Other prevention and control measures that were used on young pigs prior to the anticipated time of onset include injection of vitamins, IP injection of serum harvested from finishing pigs, and vaccination against common pathogens.
Currently, control of PMWS is based on the use of PCV2 vaccines. There are 4 commercial vaccines worldwide; availability depends on licensing in different countries. The first commercial vaccine was based on an inactivated PCV2 isolate and was licensed for use in sows and gilts. Subsequently, 3 more vaccines have been developed, all to be used in piglets around 2–3 wk of age or later. Two of these are subunit vaccines (PCV2 capsid protein produced in a baculovirus system) and the third is an inactivated virus constructed by replacing the capsid gene of the nonpathogenic PCV1 with that of PCV2. In addition to significantly reducing mortality and runting percentages, these vaccines seem to improve batch uniformity, slaughter weight uniformity, feed conversion rate, and average daily gain as well.
All of the commercial PCV2 vaccines are based on PCV2a isolates, but cross-protection has been demonstrated against PCV2b. All PCV2 vaccines are able to generate both cellular and humoral immune responses, which are believed to be the key features to control the subsequent PCV2 infection that occurs under field conditions.
No treatment has proved successful for porcine dermatitis and nephropathy syndrome. Rapid hospitalization and supportive care may enable a few affected pigs to survive. Only those epizootic cases with moderate to high morbidity and mortality rates may be important in terms of economic losses. Treatment using a wide range of antimicrobial agents has been unsuccessful. Because the antigen responsible for triggering porcine dermatitis and nephropathy syndrome is not known, no preventive recommendations are indicated.
Last full review/revision March 2012 by Joaquim Segalés, DVM, PhD, DECVP, DECPHM
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