Herpes Virus

From material provided by Dr Mats Abatzidis
 

Introduction
Experience has taught many breeders who had accepted neonatal pup death rates of 15 - 25% that simple management could greatly reduce mortality. Examination of bitches for general and reproductive health before and after whelping, supplemental or tube feeding of pups that fail to suckle and providing warmth, which is vital to pups during the first 2 weeks of life since temperature regulation is poor are important factors. Supplemental radiant heat to raise the environmental temperature to ~85ºF, and a relative humidity of ~60% during the first week of life, especially if pups are orphaned, has reduced mortality rates in several kennels from ~25% to <10%. More than 75% of pup deaths occur prior to the 3d week of life, the vast majority occurring during the first week due to physiologic, congenital/genetic, behavioural (bitch), environmental conditions or bacterial septicaemias. Unfortunately, there is a discouraging lack of knowledge of the true causes of most neonatal illnesses or death and little research is being done on this important subject.
Infectious diseases are believed to comprise only a very small portion of pup deaths up to the time of weaning; however, two viral infections have been described that affect pups during the first 2 - 5 weeks of life: Canine herpes virus is widely recognized; minute virus of canines (CPV-1) has only recently been recognized as a pathogen. Canine adenovirus-1, distemper and canine corona virus, as well as several bacterial infections, also may cause puppy deaths.
Canine Herpes virus
Etiology -
Canine herpes virus is a typical alpha-herpes virus. The virus is sensitive to lipid solvents and is readily inactivated at temperatures above 40ºC - the 1/2-life at 37ºC is <5 hours. It also is unstable at pH <~5 and >~8.0. CHV is stable at 40ºC and -70ºC, but is readily inactivated at -200ºC unless stabilizing solutions are added. It also is rapidly inactivated by common disinfectants. Only one serotype is recognized although differences in cytopathic effects of certain isolates have been reported. Weak antigenic relationships have been shown with several other herpes viruses, but the significance is unclear. The virus grows only in canine cells and growth is best in primary or secondary kidney or testicular cells, although growth also occurs in several canine cell lines. Growth is optimal at 34 - 35ºC, with diminished virus yields above 36ºC. In cell cultures, most isolates produce typical clusters of rounded cells that detach, leaving clear "plaques", especially under agarose, methyl-cellulose or antibody-containing overlay media. Certain isolates have been reported to form syncytia (giant cells). All produce type-A intranuclear inclusions in infected cells. Analysis of the genomic organization of CHV reveals a closer relationship between CHV and feline herpes virus, equine herpes virus-1, pseudorabies virus and varicella-zoster virus than with other herpes viruses.
Epidemiology
The virus appears to be present worldwide in domestic and wild dogs. The virus has been found only in canines. Serosurveys are limited, but seropositive rates of >30% are common in field dogs. Some kennels have antibody prevalence rates as high as 100% without the development of disease in pups (see below). Transmission is by direct contact with infectious body fluids, since CHV is unstable in the environment. As with other a-herpes viruses, CHV becomes latent after a primary infection and is shed periodically, primarily in nasal or, rarely, in genital secretions.
Clinical Signs and Pathogenesis
The disease is generally asymptomatic in dogs infected when older than 1 - 2 weeks of age at the time of exposure. Disease caused by CHV is generally fatal in neonatal pups who lack immunity derived from their dams. Neonatal pups may be infected during passage through an infected dam's birth canal or, more commonly, by contact with oronasal secretions of the dam or other dogs in a kennel. Infected littermates, or neighbouring dogs who are shedding virus, also serve as sources of infection. Deaths of 1 to 4week old pups are most common. Pups rarely die if they are 2 - 3 weeks old at the time of exposure. The duration of illness in newborn pups is 1 to 3 days. Signs consist of anorexia, dyspnea, pain upon abdominal palpation, in coordination and, often, soft, yellow-green faeces. There may be a serous, or hemorrhagic nasal discharge. Petechia are common on the mucous membranes. Rectal temperatures are not elevated. Thrombocytopenia has been reported in dying pups.
CHV also may cause occasional in utero infections that result in the death of foetuses or pups shortly after birth. The virus also has been isolated rarely from dogs with vaginitis, conjunctivitis and respiratory illness. Asymptomatically infected dogs, or dams who suffered in utero infections, remain latently infected and virus may be excreted for about 1 week in nasal secretions or in genital secretions, and, thereafter, at unpredictable intervals over periods of several months, or years. Latent virus may be provoked by stress (movement to new quarters, introduction of new dogs) or, experimentally, by immunosuppressive drugs (corticosteroids) or antilymphocyte serum. Latent virus, demonstrated by the polymerase chain reaction, persists in the trigeminal ganglia, but other sites such as lumbo-sacral ganglia, tonsils, and parotid salivary gland have been identified. Once the virus enters a kennel, it generally spreads and causes asymptomatic infections - except in pregnant dams or very young pups from susceptible bitches, where infections of the fetus or newborn may occur. Recrudescence of latent virus favours spread of the virus among dogs, as well as the development of immunity which is transferred to pups via the placenta and colostrum.
Initial viral replication occurs in the nasal mucosa, the pharynx and tonsils of pups infected when they are less than ~1 week of age. CHV spreads in the body via the blood (in macrophages) to liver, kidneys, lymphatic tissues, lungs and the central nervous system. The incubation period is about 6 - 10 days and most affected pups are 1 to 3 weeks old at the time of onset of illness. Deaths in affected litters usually occur over a period of a few days to a week. Litter mortality is commonly 100%. Pups exposed when they are older than 2 - 3 weeks of age, like adult dogs, usually have inapparent infections although central nervous signs, including blindness and deafness related to brain damage, have been observed.
Pregnant dogs infected at mid-gestation, or later, may abort weak or stillborn pups with no signs in the dam; foetal pups infected during late gestation may appear normal at parturition, but die within a few days of birth. In mature females, primary genital infections are characterized by enlargement of the submucosal lymphoid follicles with variable degrees of vaginal hyperemia and petechial or ecchymotic hemorrhages. Vesicular lesions also have been reported during proeustrus, but they regress during eustrus. Discomfort appears to be minimal. Similar lesions have been reported over the base of the penis, but reports are scanty. Only one case of a repeated episode of CHV abortion/infected pups in a bitch has been reported - in Japan. Normally, naturally infected bitches that have lost pups with CHV subsequently give birth to normal litters, probably as a consequence of low levels of maternal antibody that protect the pups from clinical disease during the first week of life when they are most susceptible.
Canine herpes virus is not considered a significant cause of respiratory illness; however, this virus has been isolated from the tracheas of dogs with respiratory disease; other agents (Bordetella bronchiseptica, canine distemper, canine parainfluenza virus) are considered the principal cause of respiratory illnesses.
Pathology Characteristic ("pathognomonic")
Pathological changes occur in the kidneys. They consist of petechial or ecchymotic haemorrhages and focal necrosis, giving the kidneys a "speckled" appearance - circumscribed areas of hemorrhage ("red spots") on a pale gray cortex (Fig. 1). Multifocal areas of necrosis and hemorrhage occurs in several organs, including the lung, liver, brain and intestine. Lymph nodes and spleens are enlarged. Meningoencephalitis also is common. Necrosis in the placenta is observed in infected pregnant females. Fetal lesions are similar to those seen in affected puppies. Intranuclear inclusions may be seen in necrotic areas, but they may be difficult to find.
Primary genital infections are characterized by lymph follicular lesions and vaginal hyperaemia; severely affected bitches may have ecchymotic submucosal haemorrhages. There appears to be no discomfort or unusual vaginal discharges. Vesicular lesions have been reported during proeustrus and they regress during anestrus. Males may have similar lesions over the base of the penis and the prepuce.

Figure 1. Pathological changes in the kidneys: petechial or ecchymotic haemorrhages and focal necrosis, giving the kidneys a "speckled" appearance - circumscribed areas of hemorrhage ("red spots") on a pale gray cortex.

Factors that Influence the High Susceptibility of Neonatal Pups
The high susceptibility of neonatal pups to generalized infection has been associated with poor thermoregulation, low body temperatures, and incompletely developed immune systems during the initial 10 days of life. Experimentally infected newborn pups reared at elevated temperatures survived CHV infection; however, artificial temperature elevation of sick pups is not beneficial and cannot be recommended as a "treatment". Some pups who survived experimental infections at elevated temperatures became blind, deaf or suffered brain damage.
Immune Response
Neutralizing antibodies may be detected within 2 - 3 weeks of infection, and they persist for several years. Repeated viral shedding occurs sporadically, primarily in the nasal secretions. Shedding has been observed shortly after introduction of new dogs into a kennel ("threat stress") and, as noted above, immunosuppressive drugs given over a course of several days provoke episodes of recrudescence, where virus is shed for about 1 week. In such cases, there are concurrent increases in neutralizing antibodies. Such intermittent shedding assures the survival of CHV in the dog population and in breeding kennels.
Vaccines
An inactivated, subunit vaccine (Eurican Herpes 205, Merial Animal Health) has been available in Europe since 2003. The vaccine is specifically indicated for bitches during pregnancy. It consists of purified CHV glycoproteins in a mineral oil solvent. It has been shown to have few undesirable effects; nevertheless, transient oedema may occur at the injection sites. Reactions usually regress within 1 week. Eurican Herpes 205 was shown to provide good immunity to newborn pups after 2 injections had been administered to their dams. Vaccine should be given to dams during heat or early pregnancy and, again, 1 to 2 weeks before the expected date of whelping.
An experimental attenuated live viral vaccine consisting of a "cold adapted" CHV mutant (small-plaque, SP) also has been developed, but it is not available commercially. There is little information on other suggested prophylactic measures such as the use of avian poxvirus.
The role of canine herpes virus in neonatal mortality and reproductive failures has not been determined and many closed kennels with 100% seroprevalence have not had problems with CHV disease. However, when pregnant, susceptible (non-immune) bitches, within a month of whelping, are introduced into a kennel together with infected dogs, serious outbreaks may occur in their pups. Notwithstanding, at the present time the general value of CHV vaccines in reducing neonatal mortality cannot be estimated.
Treatment
Antiviral drugs have been generally unsuccessful, although some success has been reported with pups in exposed litters given vidarabine before the onset of symptoms. Antiviral treatment may spare life, but residual damage to the CNS and heart may occur. There has been success in preventing infection in neonatal puppies prior to exposure to CHV during kennel outbreaks by injecting 1 - 2 ml of immune sera from affected dams. Such treatment is effective only if virus has not generalized. Once illness develops in pups, serum treatment is ineffective. Immune serum is not available commercially.

‘Fading puppy’ syndrome an avoidable breeding outcome?

The highly infectious Canine herpes virus (CHV-1) threat seems to have been underplayed for many years, by vets and breeders alike. It has recently become evident, however, that CHV-1 can have serious effects on both puppies and adult dogs.

If the puppy is infected soon after birth, CHV may be instrumental in triggering ‘fading puppy’ syndrome, during which the pup fails to suckle, loses weight and fades away despite intensive care.

In adult male dogs, CHV may cause painful lesions on the genitals. While bitches don’t generally display external symptoms of CHV-1 infection, she either appears unfertile, or gives birth to undersized, weak litters. In all dogs, CHV is known to be one of the causes of kennel cough.

Diagnosis difficult … no cure in sight

Diagnosis is difficult as dogs that are negative today may in fact be infected, and will remain carriers of the virus for life, with flare-ups occurring during periods of stress. There is no cure for infection with CHV-1. Therapy with antiviral medicine does not appear to be effective, and is very costly.

Local Canine herpes virus study findings a cause for concern

A study undertaken by the University of Pretoria in 2005 has drawn attention to the risk this disease poses to breeding dogs due to the substantial movement of dogs that occurs in South Africa, for the purpose of mating, distribution of puppies to new owners and the participation in dog shows across the country.

A total of 328 dogs from Gauteng were tested for prevalence of Canine herpes virus, using a serum neutralisation test and a specially developed ELISA test. The dogs were from 38 colonies and included 29 breeds. Twenty-two percent of dogs tested were positive. Within the colonies from which these dogs came, between 10 and 100 percent of dogs older than a year showed prevalence.

Gauteng contains approximately half of all breeding colonies in South Africa. This figure, along with the above statistics and the movement of breeding dogs, emphasises the need for effective Canine herpes virus vaccination.

Canine herpes virus vaccine now available

Merial South Africa (Pty) Ltd, an innovation-driven global animal health company, has recently launched a vaccine that induces immunity against Canine herpes virus in pregnant bitches, whether or not they are currently infected with the virus. Pups are passively immunised via the vaccinated dam’s colostrum.

Significant improvement was noted in the increased rate of pregnancy, the increased number of weaned pups and in an increase in puppy birth weights. Safety was established in large-scale trials, both in the laboratory and in the field, incorporating 20 breeds, 180 bitches and over 500 births.

This innovation will prove beneficial to breeders, kennel owners and most importantly, to dogs across South Africa, bringing greater peace of mind to those people who wish to see their dogs produce litters of healthy, thriving puppies. Please discuss vaccination options with your veterinarian. For additional information, contact Merial South Africa on 011 – 315 8001.

Eurican Herpes 205 is the new vaccine by Merial South Africa (Pty) Ltd.
This is the first vaccine to offer protection from canine herpes virus to both newborn puppies and adult bitches.

A fatal disease for newborn puppies: fading puppy syndrome, anorexia, abdominal pain with continued crying, neurological symptoms, soft faeces and diarrhoea, mortality within 1-2 days.

Serious consequences in adult dogs: infertility, embryonic deaths, abortions, premature births, stillbirths, genital ulceration.

Vaccinate the dam to protect the puppies!!!!!!

Protection was demonstrated by virulent challenge, and protection was confirmed under field conditions:
Results were as follows
– total decrease in neonatal mortality due to Herpes virus (from 62% in unvaccinated bitches to 0% in vaccinated bitches)
– increase in pregnancy rate (from 67.9% to 82%)
– decreased puppy mortality before weaning (from 27.7% to 11.4%)
– increase in the weaned puppy rate (from 58.3% to 78.3%)

The vaccination should be integrated in the pregnancy monitoring:
1st vaccination should be given between the 1st day of the heat period and the 10th day after mating.
2nd vaccination should be given 1-2 weeks before whelping.
The above schedule can be used safely for every pregnancy thereafter.

This is an inactivated vaccine, which means that only the immunogenic (immunity stimulating particles) glycoproteins obtained after several purification steps are present in the vaccine.

Demonstrated in large scale field studies involving 20 various breeds, >180 pregnant bitches and more than 500 births.

This vaccine can be used no matter what the serological status of the bitch: negative, infected or latent carrier.

www.canineherpes.com

http://www.canineherpes.com/

In: Recent Advances in Canine Infectious Diseases, Carmichael L. (Ed.)
International Veterinary Information Service, Ithaca NY (www.ivis.org), 2004; A0102.0899
Neonatal Viral Infections of Pups: Canine Herpes virus and Minute Virus of Canines (Canine Parvovirus-1) (Last Updated: 19-Aug-2004)
L. Carmichael
Baker Institute for Animal Health, Cornell University, Ithaca, New York, USA.
 

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Updated 23-06-06