What we know and do not know about PMWS

Posted by Administrator on July 17 2009 15:09

Introduction

Postweaning multisystemic wasting syndrome (PMWS) is considered a multifactorial disease of pigs that involves infection with porcine circovirus type 2 (PCV2) and the influence of infectious and/or non-infectious risk factors (Segalés et al., 2005). PCV2 has also been associated to a number of diseases and conditions such as reproductive failure, porcine dermatitis and nephropathy syndrome (PDNS), porcine respiratory disease complex (PRDC) and proliferative necrotizing pneumonia (Segalés et al., 2004). Therefore, the acronyms PCVD (porcine circovirus disease) or PCVAD (porcine circovirus associated disease) have been used to group all these conditions. However, the true involvement of PCV2 in such pathologies has only been demonstrated in the case of PMWS and reproductive failure.

PMWS is, by far, the most economically significant PCVD. PMWS was first described in Canada in 1991 (Harding, 1996) and in many countries from all continents after that (Segalés et al., 2005). The disease is clinically characterized at farm level by increased postweaning pig mortality (mainly in the growing stage). Pigs show a variable degree of wasting, respiratory signs, diarrhea and enlarged inguinal lymph nodes (Clark, 1997; Rosell et al., 1999). PMWS was initially defined based on very characteristic microscopic lesions in lymphoid tissues. The lesions were characterized by moderate to severe lymphoid depletion and granulomatous inflammation, sometimes with multinucleate giant cell infiltration and/or presence of grape-like intracytoplasmic inclusion bodies in macrophage-like cells (Clark, 1997). Moreover, those lymphoid lesions were seen to contain moderate to high amounts of PCV2, mainly in macrophages and dendritic-like cells, and the inclusion bodies observed corresponded aggregates of this virus (Clark, 1997; Kiupel et al., 1998; Rosell et al., 1999).

Although much research has been done since 1997 to address many of the questions concerning PMWS, many aspects of the disease still remain unknown and, for many researchers and practitioners PMWS remains the true mystery disease.

The objective of this paper is to review what we know and what we do not know (and often what we think we know but we do not really know) on PMWS, with special emphasis to the points relevant to veterinarians and production personnel (etiology, transmission, epidemiology and control).

Etiology

Many experimental models have been tested since 1999 with an attempt to reproduce clinical PMWS (Allan et al., 2004). However, results have been quite variable. Most of the models using PCV2 only as inoculums have resulted in subclinical infections (Segalés et al., 2005). Fewer studies have succeeded in reproducing PMWS in a proportion of pigs using only PCV2 (Kennedy et al., 2000; Bolin et al., 2001; Harms et al., 2001; Albina et al., 2001; Okuda et al., 2003). More successfully, PMWS has been experimentally reproduced using a combination of PCV2 and other factors such as porcine parvovirus (PPV), porcine reproductive and respiratory syndrome virus (PRRSV), Mycoplasma hyopneumoniae and certain non-infectious stimulants of the immune system. Interestingly, those latter models have resulted in more repeatable outcomes with a higher percentage of animals presenting PMWS clinical signs and lesions.

Besides those experiments, it is without doubt that PMWS etiology remains the most controversial topic of this disease. PCV2 is a ubiquitous infectious agent and all farms with and without PMWS suffer from its infection. Moreover, the spatio-temporal spread of PMWS in certain countries (not all) suggests that another yet unidentified agent (the terminology of “agent X” has been used to name such a potential agent) should exist in association with PCV2 to cause the disease (Stone, 2004; Woodbine, 2005; Vigre et al., 2005).

Both epidemiological and experimental studies provide valuable information about PMWS and accurate interpretation is necessary. Surprisingly (or not), different opinions have evolved from the available data regarding PCV2 involvement in PMWS. Some researchers consider PCV2 as the sole agent responsible for PMWS, while others remain in the opposite extreme and defend the presence of a unique “agent X”, yet unidentified to date, as the cause of PMWS. However, the general consensus nowadays is that the disease is explained first or concomitantly by the presence of a triggering factor (known or unknown) followed by PCV2 infection. PCV2 is consistently detected in sick animals. Therefore, it should not come to a surprise that PMWS case definition includes the presence of PCV2 as one of the main criteria.

The following list summarizes most of what we know and do not know about PMWS etiology:
Known

• PMWS has been reproduced using homogenate tissues from PMWS positive pigs suggesting the presence of an infectious agent.
• PMWS has been reproduced using a number of PCV2 isolates as a solely inoculum. However, in these experiments only a limited number of animals showed clinical signs typical of the disease. PMWS characteristic lymphoid lesions were reproduced in a mild to moderate form in pigs without clinical signs (subclinical infection), and in a moderate to severe form in those pigs showing clinical signs.
• Same isolates, when used in an experimental mixed model (PCV2 + triggering factor), have been able to reproduce PMWS in a more consistent manner.
• PMWS was reproduced using PPV and a PCV2 isolate recovered from a healthy pig from a country that did not have PMWS at the time when the virus was isolated (Sweden, 1993).
• In all cases of PMWS, PCV2 is always associated to the microscopic lesions in moderate to large amounts. The characteristic lymphoid lesions of lymphocyte depletion with granulomatous inflammation (which defined the disease from the very beginning) (Clark, 1997) have never been found without PCV2.
• Different pathogenicity among PCV2 isolates is suspected. In one experiment, two different strains caused different degree of lesions in infected animals. However, none of them presented clinical disease.

Unknown

• It remains unclear whether PMWS can be reproduced without PCV2.
• Despite of the many efforts placed in the search for an infectious agent different than PCV2, it is still unknown whether an “agent X” solely responsible for the disease exists. Different groups have attempted the search but the results have been unsuccessful to date. Whether the samples, the challenge model, the age of the pigs, the cell culture types, the laboratorial procedures or whether other factors were not appropriate it is still unknown.
• If PCV2 is the main agent and certain triggering factors are needed, it is unclear yet what those triggering factors are. Different immune stimulants such as certain types of adjuvants, presence of viral and bacterial co-infections, pig genetics, and management factors have been considered as candidates for triggering PMWS. Since these “triggering factors” have been present all along in commercial farms these factors do not explain the outbreak-like appearance of PMWS infections in negative populations. Therefore, the aforementioned factors should be viewed as “worsening factors” instead of triggering factors, suggesting that still a primary triggering factor remains to be found. It is also unknown if just a single primary triggering factor does exist.
• Controversy also exists on whether different strains of PCV2 can produce the disease. Information on sequencing of PCV2 isolates recovered from both PMWS positive and negative pigs, does not support differences in pathogenicity of PCV2 isolates. However, it may be too early yet to rule out definitively whether differences in pathogenicity among PCV2 isolates exist.

Epidemiology and transmission

PCV2 is considered a ubiquitous virus in pigs, both in countries where PCVD has or has not been described (Allan and Ellis, 2000; Segalés et al., 2005). The oro-nasal route is considered the most likely and frequent route of PCV2 transmission. This is supported by experimental studies on PCV2 infection, which have mainly used the intranasal route of inoculation. Under field conditions, the majority of pigs seroconvert to PCV2 between 2 and 4 months of age, indicating that horizontal transmission of PCV2 between pigs is very efficient. Horizontal transmission of PCV2 to contact susceptible pigs commingled with already infected pigs has also been demonstrated under experimental conditions (Segalés et al., 2005). Moreover, transplacental transmission of PCV2 has recently been demonstrated following experimental intranasal infection of sows (Park et al., 2005), indicating that vertical transmission of PCV2 is also feasible. However, the real frequency of these reproductive alterations under farm conditions is really unknown and probably very rare, since it has been reported sporadically. However, data from Korea showed PCV2 infection in about 13% of aborted fetuses and stillborn piglets (Kim et al., 2004).

However, it is worthy to discriminate between PCV2 epidemiology and transmission, and PMWS epidemiology and transmission. The latter one is very poorly understood. Most of the countries worldwide have reported PMWS cases, and in some cases PMWS has appeared as a propagating epidemic despite the fact that PCV2 infection is enzootic worldwide. In addition, PMWS transmission to contact susceptible pigs has also been demonstrated in PCV2 seropositive pigs. Risk factors for PMWS transmission are poorly understood but age, semen, pigs and farm location have been suggested as relevant for the disease to spread. However, minimal scientific, contrasted data exist on these subjects.

The real question that still remains to be answered regarding PMWS epidemiology is the sudden appearance of PMWS cases despite the widespread of PCV2 infection. While PMWS has appeared as a worldwide epidemic, PCV2 has remained endemic all along.

Here we highlight most of what we know and do not know about PMWS epidemiology and transmission:
Known

• PCV2 infection is ubiquitous
• PCV2 nucleic acid (by PCR) has been demonstrated in serum from pigs up to 22 weeks of age under field conditions. However, it has not been assessed whether pigs were continuously or intermittently viremic. Pigs with persistent PCV2 infection can occur in both PMWS and non-PMWS affected herds.
• PMWS affects growing pigs with most of the cases affected in late nursery and early grower stages (6-14 wks of age). A later appearance of the disease has been detected in more recent years.
• Pig to pig transmission (both PCV2 and PMWS) has been documented from both experimental and field data.
• PMWS incubation period is estimated to be between 2 to 4 weeks based on experimental results and PCV2 monitoring in PMWS affected farms.
• PMWS transmission (by direct and indirect contact) has been documented despite the PCV2 serostatus of the farm of origin.
• PMWS has been transmitted to PCV2 seropositive pigs; however, the symptoms appeared at the age when maternal immunity is low or has disappeared.
• PCV2 is shed in feces, semen, urine and other secretions. The amount of PCV2 present in these excretions/secretions varies: PMWS affected pigs had higher viral load that non-PMWS affected animals.
• It has been reported that PCV2 infection, or low serological titers to PCV2 in sows at farrowing, had a significant effect on the overall mortality of its offspring due to PMWS. In other words, pigs coming from sows infected with PCV2 at farrowing or that received low amounts of PCV2 antibodies tend to develop PMWS at a higher degree than the opposite situation.
• Passive immunity against PCV2 plays a role in preventing the development of PMWS, but is not able to prevent the establishing of subclinical PCV2 infections.

Unknown

• It is not known whether the epizootic form of the disease is the result of the introduction of a new PCV2 strain, or specific genetic changes in existing PCV2 isolates or the introduction of a new, yet not identified, infectious agent (“agent X”) or even of an unknown non-infectious agent.
• Once the pigs succumb to PMWS, it is not know for how long the pigs remain infectious and can transmit PMWS to other pigs.
• Whether susceptibility is age related remains to be determined. Most cases are reported within an 8 week window (6-14 wks of age). Once the pigs have gone through the risk period, they do not seem to become affected again. The more likely explanation based on what is known to date is that pigs are protected because they are immune. Whether other factors such as the presence of specific receptors or other factors needs further evaluation.
• Whether older animals having recovered from the infection/disease, still shed PCV2 (or transmit PMWS) is difficult to assess and appropriate transmission models are required (sentinel pig models).
• The mechanism by which PCV2 persists in the pig is not known at present.
• Although PCV2 has been isolated from feces, semen, and other secretions, there is not a direct relationship between PCV2 exposure and PMWS transmission. This may indicate a host predisposition to disease development or the fact that the triggering factor is not consistently associated to PCV2 presence.
• The role of semen in PMWS transmission is unclear. There is not a clear relationship between use of semen from central AI centers and risk of infection in herds receiving semen.
• As in many diseases, the role of other possible sources of infection such as air, fomites, people and vectors still needs to be determined.

Control and prevention

As described above, PMWS is defined as a multifactorial disease which involves infection of pigs with PCV2 and the influence of infectious and non-infectious factors or triggers (Segalés et al., 2005). Consequently, effective control measures to date for PMWS have mainly focused on the understanding of the co-factors and triggers involved on individual farms and the control or eradication of these triggering or worsening factors (i.e. control of other co-infections). The most studied co-factors and triggers in relation to disease progression or protection are related with management, viral/bacterial co-infections and stimulation of the immune system. Although studied to a lesser or minimal degree, pig genetics, nutrition and PCV2 status of the sow should be considered among potential factors that can modify the final outcome of PMWS. Moreover, since PCV2 infection is ubiquitous, minimal efforts have been directed at controlling PCV2 infection until more recently. Nowadays, at least 3 vaccines (one of them to be applied on sows and the others to piglets) with PCV2 antigen are registered or with temporal licenses in some countries of Europe and North-America. Although promising results on their effects have been cited (sometimes as impressions or perceptions more than numeric data), the real efficacy of these vaccines in controlling PMWS under field conditions is still under evaluation. Even if those products have a real beneficial effect diminishing the losses attributed to PMWS (further confirming the etiological role of PCV2 infection in the disease), many questions on PMWS and PCV2 biology need to be answered and deserve proper research.

Following statements include most of what we know and do not know about PMWS prevention and control strategies. In fact, the list on “unknowns” is much higher than the “knowns” since, besides PCV2 vaccine development, minimal scientific approaches have been performed for most of the methodologies used to prevent and control PMWS.

Known

• Most of the suggested control strategies are the result of field observations.
• Management improvement usually makes PMWS better. Madec’s “20-point-plan” clearly indicates it.
• Control of concurrent viral infections in the postweaning area usually decreases the incidence of PMWS.
• The induction of clinical disease following immunostimulation in PCV2-experimentally-infected pigs has also been supported by a number of on-farm studies, where PCV2 infection and the use of certain commercially available vaccines or immunomodulators have acted as apparent triggering factors for PMWS. To re-schedule the timing of vaccination as a potential plan to minimize the disease has been used successfully in some farms.
• Serum-therapy has been used to prevent PMWS with very variable results to date.
• It has been shown that conjugated linoleic acid (CLA) ameliorates PCV2 experimental infection induced lesions (neither control-infected nor treated-infected pigs developed clinical disease)
• All breeds and genetic lines are susceptible to PCV2 infection. However, not all breeds or genetic lines perform equally in PMWS positive environments. There are differences in mortality rates among genetic lines housed in the same PMWS positive environments.
• PCV2 vaccines have been shown to have a beneficial effect under experimental conditions and, very preliminarily, under field conditions.

Unknown

• Which precise management measures are those that result in improvement on the PMWS status are unknown.
• The precise mechanism by which some infectious and non-infectious agents are able to trigger or worsen PMWS is unknown.
• The mechanism of action of serum-therapy has not been elucidated yet. It is unlikely that PCV2 antibodies present in the serum play a role in protection since they represent “foreign proteins”, and the body usually remove (eliminate) them in two or three weeks. Whether other factors such as other antigens or other protective serum molecules are present in the serum needs further study.
• Although it is believed that nutrition (or certain nutritional factors) might favor a decrease in PMWS outcome, there is no scientific and contrasted information available to establish the real effect of nutrition. Even, if CLA has a real effect on PMWS outcome, it should be tested under field conditions
• A “litter effect” in PMWS has been suggested and partially characterized (effect of the sow PCV2 infectious and serological status on the offspring PMWS development). However, it is not known if other facts are related with this “litter effect” and its implications in treatment and prevention.
• Further work on pig genetics is needed. It is not known which gene or genes may be related with development or protection to the disease and whether the different genetic lines will perform consistently in PMWS positive environments. It is not known either the genetic by environmental interaction present in this disease.
• The real effect of commercial PCV2 vaccines on PMWS prevention still remains to be determined

It is logical to think that, if PMWS is a multifactorial disease, no proper methods for full prevention and control can be assessed unless all the associated factors are known.

Final remarks

It is worthy to remark that the most important “unknown feature” of PMWS is the fact that PCV2 has been circulating among pigs for several decades but PMWS has only been identified as a significant syndrome worldwide during the last 10 years. Why and how this has happened still remains in the shadow. In addition, when PCV2 circulates in a given group of pigs in a PMWS affected farm only a proportion of the pigs may result in the disease; why only “some” of them?, what happen with these pigs? Definitively, individual susceptibility and/or resistance should be considered as a key factor in PMWS.

However, this should not be seen as a unique feature of PMWS but rather as a common observation of how infectious diseases are presented in the field. In the case of PRRSV, for instance, not all sows will abort or not all pigs will perform and show clinical signs the same way when they become infected.

Definitively, the high number of still unknown features associated to PMWS and the continuous significance of the disease worldwide will make PMWS a major point of scientific and technical research on pig medicine for the next few years.