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Diagnostic notes
Non refereed
Update on classical swine fever (hog cholera)
Douglas Gregg DVM, PhD
Foreign Animal Disease Diagnostic Laboratory, NVSL, APHIS,
USDA.
Gregg D. Update on classical swine fever (hog cholera). J
Swine Health Prod. 2002;10(1):33-37. Available
as a PDF
Summary
Classical swine fever (CSF), commonly known in the United States
as hog cholera, is a highly contagious viral disease of swine
caused by a Pestivirus related to bovine virus diarrhea
(BVD) and border disease virus (BDV) of sheep. Virulence varies
from mild to severe. Most current outbreaks are associated with
moderately virulent strains.1 The classic virulent
disease is now rather uncommon. Classic highly virulent disease
characteristically presents with high fever, extreme lethargy,
hemorrhages in numerous organs, neurological signs, leukocytopenia,
and high mortality. Moderately virulent disease causes high fever,
mild lethargy, mild hemorrhages in lymphoid organs, transient
leukocytopenia (or none), and low mortality.2 Recovered
pigs may have a chronic disease with intermittent fever and poor
reproductive performance. Pigs born of infected sows may be persistently
infected and carry the virus for life, but with no immune response.
The virus can also be transmitted in semen to sows. An outbreak
of moderately virulent CSF may go undiagnosed for months due to
its mild nature and few lesions.
Etiology
Classical swine fever virus (CSFV) is a lipid-enveloped virus
in the family Flaviviridae, genus Pestivirus. The virus
has one serotype, but many strains have antigenic similarity to
BVD and BDV. Pestiviruses comprise a spectrum of strains that
are difficult to distinguish serologically. Virus neutralization
tests or monoclonal antibodies can differentiate CSFV from these
related viruses, but multiple tests may be required. Both BVD
and BDV have been isolated from swine in Europe. Bovine viral
diarrhea occasionally causes a syndrome in pigs similar to that
caused by CSF.3 Classical swine fever virus infects
all swine including wild boar and peccaries, but is not known
to infect cattle or sheep.
Geographic distribution
According to the 1996 Office International des Epizooties Manual,
classical swine fever has a nearly worldwide distribution involving
44 swine-producing countries on all continents except North America
and Australia.4 In Europe, CSF is endemic in wild boar
in Italy, Germany, and parts of France and Switzerland. Countries
of the European Economic Community no longer vaccinate for CSF
but experience periodic outbreaks, often originating from wild
boar. Reports from Asia are incomplete, but the disease is believed
to be present in swine-producing areas and controlled by vaccination.
Many countries of South America and Asia vaccinate for CSF. The
most recent outbreaks in the Netherlands and England were both
of Asian origin.
CSF: A disease on the move
Historically, CSF has moved with the transport of infected
pork products. Since the earliest reports of hog cholera in Tennessee,
this disease has been spread widely in cured hams and sausage.
The recent outbreak in England in 2000 was suspected to have been
introduced in ham that may have come from southeast Asia. Despite
strict animal importation regulations, CSF-infected swine products
are likely to be introduced into the United States by air, sea,
or ground transportation in garbage or the baggage of travelers
from endemic areas. Specialty ethnic pork products are highly
valued and are regularly confiscated from international travelers
at US airports. Smuggled pork products confiscated at the borders
amount to hundreds of tons per year. The CSF virus can survive
in fresh meat for 45 days at 4°C and for years at -20°C,
and is quite resistant to inactivation by salting or curing. Virus
survives for 85 days in cured smoked hams, and up to 180 days
in salted and dried Sorrono hams, loins, or sausages.5 The
virus is quite resistant to pH changes between 3 and 11, and can
survive in the environment for months in contaminated soil of
barnyards, particularly in temperate climates.6 Scraps
of CSFV-infected fresh, cured, or insufficiently cooked meat fed
to pigs can transmit the virus. Some international airlines and
ships serve meals containing specialty pork products from their
country of origin, and the protein-rich scraps may be fed to pigs
at the destination. This common but risky practice of feeding
to pigs garbage from air and sea ports should be prohibited, or
at least carefully monitored cooking should be required.
Once introduced, CSFV usually spreads through livestock production
systems either by direct movement of pigs or by fomites, farm
workers, veterinarians, farm equipment, and vehicles.7
Infected pigs shed virus in all excretions including feces, urine,
saliva, semen, and blood. Chronically or persistently infected
sows may infect piglets in utero, and boars may shed virus
in semen.1 Transmission is usually through ingestion,
but also through skin abrasions, bites (fighting), and contaminated
needles and instruments. Airborne, rodent, or insect transmission
is possible over short distances but is not likely to cause distant
spread. There is no evidence that CSFV replicates in insect vectors.
Introduction of CSF into a breeding herd is particularly devastating
for several reasons. Once introduced, moderately virulent CSFV
may cause only mild disease in mature sows and result in reproductive
problems that may be overlooked or attributed to other causes.
Sows may remain chronically infected for months and may farrow
persistently infected litters.8,9 Some of these offspring
are immunologically tolerant to CSFV and may carry high titers
of virus for life. If CSFV enters a large agribusiness operation,
persistently infected pigs would likely be moved hundreds and
even thousands of miles between farrowing and finishing, spreading
the disease widely before it is discovered.
The increasing popularity of wild boar meat has resulted in
commercial trade in wild and feral swine carcasses. It is suspected
that a number of European outbreaks have been caused by wild boar
hunting, particularly in Germany, or importation of Asian wild
boar meat.
CSF: Many faces of the same disease
The incubation period of CSF varies with the virulence of the
virus, and ranges from 3 to 15 days. Under experimental conditions,
4 to 7 days is the average time from exposure to the onset of
fever.
Clinical features of CSF vary widely, not only with virus virulence,
but also with the age, breed, and condition of the host. Younger
pigs are generally more susceptible than market weight hogs. Immunocom-promised
pigs experience more severe disease. Pregnant sows are more susceptible
than boars of the same age. Sows may have stillbirths or abortions
or farrow persistently infected piglets. Pigs prone to porcine
stress syndrome are paradoxically more resistant to CSFV.10
Since the late 1960's, moderate-virulence and low-virulence
strains have become more predominant in Europe and Central America.
In Central America, this may be the result of intermittent vaccination
used as a sole control measure to eliminate the more obvious virulent
CSF.
The classic disease is severe, acute, and nearly always fatal.
This form of CSF has received the most attention in veterinary
textbooks but is now relatively uncommon. The initial signs are
high fever and lethargy, trembling, and huddling or piling of
pigs. They rapidly lose appetite and may vomit. Fever may reach
42.2°C for several days. Pigs have constipation initially
and yellowish diarrhea in the last days. They continue to drink
but only when aroused. Conjunctivitis may be marked and eyes may
be heavily crusted with exudates (Figure 1). Pigs are reluctant
to rise, stand with arched backs, and move with a swaying or staggering
gait. Terminally, there may be purple discoloration of the skin
of the abdomen, thighs, and ears. Convulsions may be seen at any
time after onset of fever, and are often initiated by handling.
The initial clinical signs of moderately virulent CSF are similar
but milder than those of highly virulent CSF. There is a longer
incubation period (6 to 7 days) followed by a slight fever and
mild lethargy. Fever rises slowly for several days and usually
peaks at 40.5 to 41.1°C. Pigs prefer to huddle together but
will rise, drink, and eat when disturbed. Appetite is reduced.
Pigs appear weak upon rising, but there is little staggering and
no convulsions. There may be mild constipation. Fever persists
for 2 to 3 weeks with only trembling noted clinically. A few pigs
develop moderate diarrhea. Remarkably, most pigs do not die, and
the fever decreases or fluctuates through the fourth week. There
may be conjunctivitis and poor weight gain, but pigs are typically
not gaunt. There are few or no hemorrhages or areas of skin discoloration.
A few pigs may die suddenly with pneumonia due to enteric bacteremia.
Recovered pigs may appear normal and gain weight, but at a slower
rate. Some recovered pigs are chronically infected for months,
and following stress, have a sudden exacerbation of high fever
for 2 to 3 days and die.
There are even less virulent strains that only cause a mild
fever of 40 to 40.5°C for a week or two with no other signs.
These pigs usually recover but may become chronic carriers.
The Trojan horse: Congenital persistent infection
Congenital infections of fetuses are common in sows with CSF.
There may be a variety of sequelae, including abortion, stillbirth,
mummification, or birth of weak and dying piglets. Cerebellar
hypoplasia or hydrocephalus are rare congenital malformations.
Some piglets exposed to CSFV in the first trimester may be
born healthy, but because they were exposed before the immune
system developed, become persistently infected with CSFV.8,9
These pigs are likely to have multiple secondary bacterial or
viral infections and will not be suspected of having CSF. They
may live for weeks or up to a year. Most will be chronic poor
doers and gain weight slowly. Clinical signs attributed to CSF
include depression, conjunctivitis, dermatitis, diarrhea, ataxia,
and death. Secondary infections with other viruses or bacteria
usually dominate the clinical picture. A common cause of death
is severe bacteremia and pneumonia resulting from bacterial invasion
through ulcers at the ilio-cecal junction (button ulcers) (Figure
2). Persistent CSFV infections are difficult to diagnose and may
spread to other herds by animal movement or artificial insemination.11
Poor reproductive performance may draw attention to such herds.
Pathology
Virulence of CSFV strains is closely linked to their tissue
tropism. Virulent CSFV is pantropic, infecting many tissues, particularly
endothelium, epithelium, lymphoid organs, and endocrine tissue.
Endothelial infection results in petechial hemorrhages in the
renal cortex, intestinal serosa, larynx, lungs, urinary bladder,
and skin. Epithelial infections may occur throughout the digestive
tract. Tonsillar epithelium is infected and there may be crypt
necrosis and abscesses. Changes in the small and large intestine
may include catarrhal exudate, hemorrhage, erosion, and ulceration.
Diarrhea results from epithelial erosion and atrophy. Ulceration
is more common in long-standing infections. Lymphoid lesions are
the most prominent and consistent, resulting in lymph node swelling,
necrosis, and variable hemorrhage in the submandibular, gastrohepatic,
renal, and mesenteric lymph nodes. The spleen may have raised,
dark, firm infarcts along its margin. Though splenic infarcts
are uncommon and are most often seen in the virulent form of the
disease, they should alert you to think of CSF.
Today, moderately virulent CSFV causes much milder gross lesions
that reflect a limited tissue tropism, primarily epithelial and
lymphoid infection. Without complications, most pigs recover.
Congestion and sometimes hemorrhages may be seen in the gastro-hepatic
and submandibular lymph nodes (Figure 3). A few pigs may die after
several weeks as a result of enteritis, with erosions or ulcers
developing in the cecal tonsil or spiral colon (button ulcers).
After several weeks of disease, chondrodysplasia may cause widening
of the costochondral junction (Figure 4). In some cases, fulminating
acute enteric bacteremia with diffuse pneumonia causes death.
There may also be focal liver necrosis and hemorrhages in various
organs, including mesenteric lymph nodes. Only careful examination
reveals cecal or colonic ulcers as the source of the bacteremia.
It is unlikely that CSF would be considered as a differential
in these mild cases.
Low-virulence CSFV causes no gross lesions in young piglets.
Sows may experience reproductive failure manifested as abortions,
stillbirths, or mummification. Congenital anomalies are rare.
Diagnosis
The palatine tonsil is the site of early infection and the
tissue most consistently positive for virus. It is the preferred
tissue for CSFV immunostaining and virus isolation. Both the direct
fluorescent antibody (DFA) test and immunohistochemistry demonstrate
CSFV antigen in the tonsillar crypt, surface epithelium, and germinal
centers. Other important tissues are the submandibular, gastrohepatic,
and mesenteric lymph nodes, thymus, spleen, kidney, lower ileum,
cecal tonsil, and brain. Histopathology is most useful as an adjunct
for CSF diagnosis if combined with immunohistochemical staining.
With relatively virulent CSF, pigs that die often have histopathological
lesions of marked lymphoid necrosis and atrophy of germinal centers
in lymph nodes and spleen. Hemorrhage may be present in many organs,
but is a nonspecific finding. Antigen may be demonstrated in vascular
endothelium in pigs with virulent CSF. There is often non-specific
mild encephalitis with perivascular cuffing of lymphocytes, and
microgliosis.
Differential diagnosis
The list of differential diagnoses for CSF must include any
highly contagious febrile disease of pigs. The most likely differential
in the United States is salmonellosis, but the list also includes
other important diseases like virulent porcine respiratory and
reproductive syndrome and swine erysipelas. Fibrinohemorrhagic
typhlocolitis may be present in CSF, salmonellosis, swine dysentery,
or Escherichia coli infection in weanling pigs.
With chronic CSF, bacteremia or acute bacterial pneumonia is a
common complication. Dermatitis-nephropathy syndrome causes petechial
hemorrhages in the renal cortex, hemorrhagic skin lesions, and
possibly splenic infarcts resembling those of virulent CSF. Salt
poisoning-water deprivation may cause acute death and encephalitic
signs that mimic CSF. Other important viral differentials include
African swine fever and pseu-dorabies.
Sample collection and submission
Field diagnosis
Any investigation of a septicemic disease of pigs causing prolonged
high fever should include CSF in the differential. A thorough
history, searching for evidence of contact with raw garbage, recent
addition of pigs of unknown origin, or contact with people who
have traveled internationally, is recommended. Examine and send
for laboratory diagnosis samples from sick, dying, and dead pigs.
Blood counts may be useful, but are sometimes abnormal only immediately
after the initial rise in body temperature. An initial lymphopenia
may persist for a few days, but the lymphocyte differential may
return to normal or be masked by neutrophilia in a total leukocyte
count. Because of the frequency of secondary diseases in a CSF
outbreak, a presumptive diagnosis should not be based on only
one necropsy. A definitive field diagnosis of CSF is not possible
with the current strains of virus. Since there are few pathognomonic
lesions of CSF (and sometimes few lesions at all), an investigation
of any disease of high morbidity with persistent fever in pigs
should include a laboratory examination of tissues for CSF.
Laboratory diagnosis
The diagnosis of CSF requires laboratory confirmation by a
reference laboratory. Heparinized blood should be collected for
virus isolation.1 Samples should be collected from
several pigs in various stages of disease, as well as from all
available dead pigs. All samples should be individually collected
in plastic bags and shipped on ice packs in leakproof containers.
Avoid freezing as it will create tissue section artifacts. Submit
a full set of tissues, including the entire brain, in 10% buffered
formalin. Fresh tonsils will be examined by DFA. The DFA test
uses a polyclonal antiserum, thus BVD or BDV viral antigens in
swine tonsils may cross-react in a small percentage of cases.7
Positives or suspects by the DFA test must be confirmed by additional
tests.12,13 Monoclonal antibody staining, virus isolation,
and differentiation by serum neutralization can distinguish these
related pestiviruses.3 Monoclonal antibody immunostaining
takes a few hours, but virus isolation and neutralization take
a week or more. The polymerase chain reaction (PCR) test is a
useful and relatively rapid method for detection and differentiation
of pestiviruses.8 In countries that have been free
of CSF, the initial case should be confirmed by pig inoculation
in a high-containment laboratory with re-isolation of virus.
Moderate-virulence and low-virulence strains of CSFV cause
such a mild disease that outbreaks may not be suspected or investigated,
particularly if death losses are low. Continuous, random serological
surveillance programs are important, and may be the only means
of detecting occurrence of these mild forms of CSF. Feral and
wild pigs often range widely and come into contact with domestic
swine. They should be included in this surveillance. There are
a number of serological tests used for this purpose, including
enzyme-linked immunosorbent assays (ELISAs), complex trapping
blocking ELISA, and indirect immunoperoxidase tests.14
It is important to note that antibody is detectable for only 2
to 3 weeks after onset of disease. Therefore, serology may not
be useful in detecting disease during most of the clinical course.4
Vaccination complicates the interpretation of all diagnostic
tests. Modified live virus vaccines replicate in the tonsil and
other lymphoid tissues, and antigen is detectable for up to 10
days after vaccination.4 The C-strain vaccine can be
distinguished from field viruses by direct immunoperoxidase staining
of tissue sections, but this requires an additional test using
monoclonal antibodies. Animals vaccinated with conventional vacccines
cannot be serologically distinguished from pigs recovered from
CSF.
Zoonotic potential: Public health implications
Human beings are not susceptible to infection with CSFV.
Control, eradication, and vaccination
Control and eradication are vital for economic reasons. Vaccination
is employed in many countries to control outbreaks and has been
used effectively in systematic and consistent programs to reduce
disease outbreaks to a point where eradication measures are feasible.11
Currently, nearly all vaccines on the market are modified live
virus vaccines rendered non pathogenic for pigs over 2 weeks of
age and are safe to use in pregnant sows. These include the lapinized
Chinese (C) strain, Japanese guinea pig cell-culture-adapted strain,
and French Triverval strain.7 Subunit vaccines based
on the sequence of the E2 region are currently available and have
proven effective in experimental trials.11 At the time
of this writing, they have not been used in the field. It is possible
to serologically distinguish pigs that have been vaccinated with
a subunit vaccine from pigs that have recovered from a field strain
of CSFV.
Vaccination allowed the United States and most countries of
the European Union to successfully reduce CSF to the point that
sanitary measures could eradicate the disease. This requires a
strong veterinary infrastructure, diagnostic laboratory system,
and strong support from the government and swine industry. Indemnities
must be paid promptly and be generous enough to encourage reporting
of disease. To prevent new outbreaks, strict importation restrictions
must be applied to pigs and pork products originating from countries
where CSF is present. Garbage feeding must be stopped or carefully
regulated to ensure proper cooking. Care must be taken to destroy
all port garbage.
Laboratories must be well staffed and funded to keep pace with
an eradication program. Rapid completion of serological surveys
and case investigations reduce the need for field personnel to
maintain lengthy quarantines. Once eradication is near completion,
serological surveillance must be intensified to identify carrier
sows in breeding herds. Surveillance must then be continued indefinitely
in high risk areas near borders, ports, and garbage-feeding operations
to insure there is no re-introduction.
References -- refereed
2. Crauwels APP, Nielen M, Stegeman JA, Elbers ARW, Dijkhuizen
AA, Tielen MJM. The effectiveness of routine serological surveillance:
case study of the 1997 epidemic of classical swine fever in the
Netherlands. Rev sci tech off int epizoot. 1999;18:627-637.
3. Wensvoort G, Terpstra C, Kluijver EP, Kragten C, Warnaar
JC. Antigenic differentiation of pestivirus strains with monoclonal
antibodies against hog cholera virus. Vet Microbiol. 1989;21:9-20.
4. Office International des Epizooties. Manual of Standards
for Diagnostic Tests and Vaccines. Lists A and B diseases
of mammals, birds, and bees. 3rd ed. 1996:145-154.
5. Mebus CA, Arias M, Pineda JM, Tapiador J, Housse C, Sanchez-Vizcaino
JM. Survival of several porcine viruses in Spanish dry-cured meat
products. Food Chem. 1997;59:555-559.
6. Horzinek MC. Non-Arthropod Borne Togaviruses. New
York: Academic Press; 1981.
7. Biront P, Leunen J. Vaccines. In Liess B, ed. Classical
Swine Fever and Related Viral Infections. Boston, Massachusetts:
Nijhoff; 1988:181-197.
8. Dahle J, Liess B. A review on classical swine fever infections
in pigs: epizootiology, clinical disease and pathology. Comp
Immun Microbiol Infect Dis. 1992;15:3:203-211.
9. Van Oirschot JT. Experimental production of congenital persistent
swine fever infections I. Clinical, pathological and virological
observations. Vet Microbiol. 1979;4:117-132.
10. Depner KR, Hinrichs U, Bickhardt K, Greiser-Wilke I, Pohlenz
J, Moenning V, Liess B. Influence of breed-related factors on
the course of classical swine fever virus infection. Vet Rec.
1997;140:506-507.
11. Bouma A, De Smit A J, De Jong MC, De Kluijver EP, Moormann
RJ. Determination of the onset of the herd-immunity induced by
the E2 subunit vaccine against classical swine fever virus. Vaccine.
2000;18:1374-1381.
12. De Smit AJ, Bouma A, Terpstra C, van Oirschot JT. Transmission
of classical swine fever virus by artificial insemination. Vet
Microbiol. 1999;67:239-249.
13. Ressang AA, den Boer JL. A comparison between the cell
culture, frozen tissue section, impression and mucosal smear techniques
for fluorescent antibody in the diagnosis of hog cholera. Neth
J Vet Sci. 1968;1:72.
14. Elbers ARW, Stegeman JA, Moser H, Ekker HM, Smak JA, de
Leeuw PW. The classical swine fever epidemic 1997-1998 in the
Netherlands: Descriptive epidemiology. Prev Vet Med. 1999;42:157-184.
References -- non refereed
1. De Smit AJ, Terpstra C, Wensvoort G. Comparison of virus
isolation methods from whole blood or blood components for early
diagnosis of CSF. Report on Meeting of the EU National Swine
Fever Laboratories, Brussels, Nov 24-25, 1994. 1994:22-24.
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