Canine distemper

Canine distemper virus
Virus classification
Group:	Group V ((-)ssRNA)
Order:	Mononegavirales
Family:	Paramyxoviridae
Genus:	Morbillivirus
Species:	Canine Distemper Virus

Dog infected with canine distemper. Note the purulent nasal discharge and hyperkeratotic nose.

Canine distemper is a viral disease that affects animals in the families Canidae, Mustelidae, Mephitidae, Hyaenidae, Ailuridae, Procyonidae, Pinnipedia, some Viverridae and Felidae (though not domestic cats; feline distemper or panleukopenia is a different virus exclusive to cats). It is most commonly associated with domestic animals such as dogs and ferrets, although it can infect wild animals as well. It is a single-stranded RNA virus of the family paramyxovirus, and thus a close relative of measles and rinderpest.^[1][2][3] Despite extensive vaccination in many regions, it remains a major disease of dogs.^[4]

Etymology

The origin of the word distemper is from the Middle English distemperen, meaning to upset the balance of the humors, which is from the Old French destemprer, meaning to disturb, which is from the Vulgar Latin distemperare: Latin dis- and Latin temperare, meaning to not mix properly.

History

Although very similar to the measles virus, canine distemper virus (CDV) seems to have appeared more recently, with the first case described in 1905 by French veterinarian Henri Carré.^[5] It was first thought to be related to the plague and typhus, and was attributed to several species of bacteria.^[6] It now affects all populations of domestic dog and some populations of wildlife. A vaccine was developed in 1950, yet due to limited use, the virus remains prevalent in many populations.^[5] The domestic dog has largely been responsible for introducing canine distemper to previously unexposed wildlife, and now causes a serious conservation threat to many species of carnivores and some species of marsupials. The virus contributed to the near-extinction of the black-footed ferret. It also may have played a considerable role in the extinction of the Thylacine (Tasmanian tiger) and recurrently causes mortality among African wild dogs.^[3] In 1991, the lion population in Serengeti, Tanzania experienced a 20% decline as a result of the disease.^[7] The disease has also mutated to form phocid distemper virus, which affects seals.^[8]

Infection

A. Lung lesion in an African Wild Dog B. Viral inclusion bodies

Puppies from three to six months old are particularly susceptible.^[9] CDV spreads through aerosol droplets and through contact with infected bodily fluids including nasal and ocular secretions, feces, and urine 6–22 days after exposure. It can also be spread by food and water contaminated with these fluids.^[10][11] The time between infection and disease is 14 to 18 days, although there can be a fever from three to six days postinfection.^[12]

Canine distemper virus tends to orient its infection towards the lymphoid, epithelial, and nervous tissues. The virus initially replicates in the lymphatic tissue of the respiratory tract. The virus then enters the blood stream and infects the respiratory, gastrointestinal, urogenital epithelium, central nervous system, and optic nerve.^[1] Therefore, the typical pathologic features of canine distemper include lymphoid depletion (causing immunosuppression and leading to secondary infections), interstitial pneumonia, encephalitis with demyelination, and hyperkeratosis of foot pads.

The mortality rate of the virus largely depends on the immune status of the infected dogs. Puppies experience the highest mortality rate, where complications such as pneumonia and encephalitis are more common.^[11] In older dogs that develop distemper encephalomyelitis, vestibular disease may present.^[13] Around 15% of canine inflammatory central nervous system diseases are a result of CDV.^[4]

Disease progression

The virus first appears in bronchial lymph nodes and tonsils two days after exposure. The virus then enters the blood stream on the second or third day.^[11] A first round of acute fever tends to begin around 3 to 8 days after infection, which is often accompanied by a low white blood cell count, especially of lymphocytes, as well as low platelet count. These signs may or may not be accompanied by anorexia, a runny nose, and discharge from the eye. This first round of fever typically recedes rapidly within 96 hours, and then a second round of fever begins around the 11th or 12th day and lasts at least a week. Gastrointestinal and respiratory problems tend to follow, which may become complicated with secondary bacterial infections. Inflammation of the brain and spinal cord otherwise known as encephalomyelitis is either associated with this, subsequently follows, or comes completely independent of these problems. A thickening of the footpads sometimes develops, and vesicularpustular lesions on the abdomen usually develop. Neurological symptoms typically are found in the animals with thickened footpads from the virus.^[1][8] About half of sufferers experience meningoencephalitis.^[8]

Gastrointestinal and respiratory symptoms

Commonly observed signs are a runny nose, vomiting and diarrhea, dehydration, excessive salivation, coughing and/or labored breathing, loss of appetite, and weight loss. When and if the neurological symptoms develop, incontinence may ensue.^{[8] [9][14]}

Neurological symptoms

The symptoms within the central nervous system include a localized involuntary twitching of muscles or groups of muscles, seizures often distinguished by salivation, and jaw movements commonly described as "chewing gum fits", or more appropriately as "distemper myoclonus". As the condition progresses, the seizures worsen and advance to grand mal convulsions, followed by death of the animal. The animal may also show signs of sensitivity to light, incoordination, circling, increased sensitivity to sensory stimuli such as pain or touch, and deterioration of motor capabilities. Less commonly, it may lead to blindness and paralysis. The length of the systemic disease may be as short as 10 days, or the start of neurological symptoms may not come until several weeks or months later. Those few that survive usually have a small tic or twitch of varying levels of severity. With time, this tic will usually diminish somewhat in its severity.^[1][8]

Diagnosis

The above symptoms, especially fever, respiratory signs, neurological signs, and thickened footpads found in unvaccinated dogs strongly indicate canine distemper. However, several febrile diseases match many of the symptoms of the disease and only recently has distinguishing between canine hepatitis, herpes virus, parainfluenza and leptospirosis been possible.^[8] Thus, finding the virus by various methods in the dog's conjunctival cells gives a definitive diagnosis. In older dogs that develop distemper encephalomyelitis, diagnosis may be more difficult since many of these dogs have an adequate vaccination history.^[13]

The most reliable test to confirm distemper is a brush border slide/smear of the bladder transitional epithelium of the inside lining from the bladder, stained with Dif-Quick. These infected cells have inclusions which stain a carmine red color, found in the paranuclear cytoplasmreadability. About 90% of the bladder cells will be positive for inclusions in the early stages of distemper. This is good for at least the first 21 days from onset of the disease. After this point, it gets harder to detect as the disease progresses further in the stages and the physical clinical signs will become quite obvious.^{[citation needed]}

Prevention

See also: DA2PPC Vaccine

There exist a number of vaccines against canine distemper for dogs (ATCvet code: QI07AD05 and combinations) and domestic ferrets (QI20DD01), which in many jurisdictions are mandatory for pets. The type of vaccine should be approved for the type of animal being inoculated, or else the animal could actually contract the disease from the vaccine. A dog who has eaten meat infected with rinderpest can also sometimes receive temporary immunity.^[15] Infected animals should be quarantined from other dogs for several months due to the length of time the animal may shed the virus.^[1] The virus is destroyed in the environment by routine cleaning with disinfectants, detergents, or drying. It does not survive in the environment for more than a few hours at room temperature (20–25 °C), but can survive for a few weeks in shady environments at temperatures slightly above freezing.^[16] It, along with other labile viruses, can also persist longer in serum and tissue debris.^[11]

Treatment

Until recently, canine distemper has been associated with a long history of pessimism with respect to treatment of infected animals and the disease was usually assumed to have a poor prognosis. Most care offered was only palliative, geared toward easing the suffering. Several factors had an important role in maintaining the status quo.

Misdiagnosis, miseducation, a lack of treatment, inadequate, or inappropriate treatment has historically created barriers and slowed the development of effective solutions to the disease. Even today, the needs of affected animals often go unrecognized until the disease reaches the nervous phase, and the distressed behavior and/or impaired functional state of the animal is more obvious and less responsive to treatment.

Research and funding for the most part have focused on vaccination rather than on finding a cure for distemper.

Another factor is the outdated theory that the injuries that occurred were the result of a strictly autoimmune reaction, the thought being that initially the canine distemper virus was introduced, but then subsequently eliminated. However, the cytokines continued to attack and damage healthy tissue in the absence of a current pathogen. Based on that faulty assumption, anti-inflammatory and immunosuppressive drugs have been prescribed by some veterinarians in an attempt to bring the effects of the condition under control.

It was later considered that the action of macrophages on infected nerve cells indicated that the autoimmune reaction was likely a direct consequence of the presence of the virus.^[17] Often, owners seek expert help only when the disease is in its advanced stages (nervous phase) and prescription anti-inflammatory drugs (which are usually corticosteroids) undermine the immune system of the animal, allow the proliferation of the virus, and the autoimmune reaction increases as a means of containment of infected cells.

The most successful treatments for canine distemper are adaptations of established treatments used for other diseases caused by similar viruses, such as ribavirin and vitamin A, which are used to treat measles,^[18][19][20] which is in the same viral genus (Morbillivirus), and interferon alpha, also used for the treatment of measles ^[20] and a vaccine used to immunize birds against Newcastle disease,^{[21][not in citation given]} which is in the same viral family, but a different genus (Paramyxoviridae - AVULAVIRUS). However, there is absolutely no proof that this treatment works and most veterinary professionals believe it to be entirely invalid as a treatment protocol.cite

The first references to suggest effective treatments for similar viruses could be effective for canine distemper arose when studies found that canine distemper was a disease comparable to measles ^[17] and infected animals could be used to develop new technologies for treatment of measles. The question of whether the reciprocal would be true was resolved when studies assessed the efficacy of traditional treatments for measles, which were then successfully applied to animals with distemper.

Initially, induction of high levels of vitamin A, used to treat measles ^[18] (including being recommended by the World Health Organization ^[22]), produced a 100% cure in ferrets experimentally infected. The infected group given no vitamin A supplementation all died.^[23] Currently, it is known that the direct inhibitive effect of retinoids (vitamin A and subproducts) on the replication of the measles virus is what confirms their choice as a treatment for canine distemper.^[24]

The confirmation of the effectiveness of vitamin A in the treatment of canines, especially dogs, is its ability to convert the vitamin A into nontoxic esters.^[25] This characteristic of carnivores is well known; the risk of hypervitaminosis due to the maintenance of high doses is quite low. For dogs, there is a benchmark to measure the risk: a national research study found it takes a dose of 300,000 IU/kg daily for thirty days before the first signs of hypervitaminosis appear, and sixty days of ingestion at this dosage to kill the animal.^[26] This dosage, 300,000 IU / kg, is sixty times greater than the toxic limit established for humans.

The mechanisms of action that explain its effectiveness in the treatment of distemper (and measles) remain unexplained. Some evidence points to an indirect action, such as confirming there is a reduction in the amounts of vitamin A during infection,^[23] pointing to the hypothesis that it is raw material for some mechanism of resistance to infection. That the anti-infective characteristic^[27] is not specific to vitamin A is a mystery; however, there was no doubt about its effectiveness, action mechanisms elucidated or not.

The adoption of ribavirin as a treatment for canine distemper followed the same steps as vitamin A; it was the principle used in cases of subacute sclerosing panencephalitis under measles. The first verification of the effectiveness occurred "in vitro,"^[28] It was observed that the distemper virus is very susceptible to ribavirin, and 0.02 to 0.05 micromols are needed to induce its mechanism of error catastrophe and the inhibitory effect on virus replication by 50%.

The main concern in the use of ribavirin was the result of its interaction with the blood-brain barrier. As the brain is an immunologically privileged area, the concern was the capacity of ribavirin to overcome this barrier. In a study using mice with encephalitis due to measles, it was found that once the virus has become established in the nervous phase, the blood-brain barrier, fails in a way, reducing the restriction to the action of the ribavirin in these areas.^[29] The verification of all these results in vivo resulted in an effectiveness of 80% in animals that had already reached the nervous phase of viral infection.^[30] The application of ribavirin demands a close monitoring of the animal due the risk of leukopenia and the ingestion of long-chain tryglicerides (fats) are needed to better absorb the drug ^[31] and for preservation of gastric tissues, which are quite susceptible to it.^{[dubious – discuss]}

Canine distemper virus and Paget's disease

Paramyxoviruses, such as CDV, measles, respiratory syncytial virus, simian virus 5, and parainfluenza virus Type 3, have long been suspected as the causative agents of Paget's disease, a focal destructive disease of bone. Most studies, however, have pointed more directly at CDV and measles.^[32][33][34] A virus detection technique, in situ RT-PCR, has found CDV in 100% of Paget's disease samples, whereas other virus detection techniques have been less accurate.^[35]

External links

• Teeth changes due to distemper in a dog
• Hard Pad Disease in a mink

References

1. ^ ^{a b c d e} "Canine Distemper: Introduction". The Merck Veterinary Manual. Merck & Co., Inc.. 2006. http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/56700.htm. Retrieved 2008-03-15. 
2. ^ "Information Sheet Canine Distemper virus (CDV)". UC Davis Koret Shelter Medicine Program. 2004. http://www.sheltermedicine.com/portal/is_canine_distempervirus.shtml. Retrieved 2008-03-15. 
3. ^ ^{a b} McCarthy AJ, Shaw MA, Goodman SJ (December 2007). "Pathogen evolution and disease emergence in carnivores". Proc. Biol. Sci. 274 (1629): 3165–74. doi:10.1098/rspb.2007.0884. PMC 2293938. PMID 17956850. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2293938. 
4. ^ ^{a b} Elia G, Belloli C, Cirone F, et al. (February 2008). "In vitro efficacy of ribavirin against canine distemper virus". Antiviral Res. 77 (2): 108–13. doi:10.1016/j.antiviral.2007.09.004. PMID 17949825. 
5. ^ ^{a b} Pomeroy, L.W.; Bj{o}rnstad, O.N.; Holmes, E.C. (2008). "The Evolutionary and Epidemiological Dynamics of the Paramyxoviridae". Journal of Molecular Evolution 66 (2): 98–106. doi:10.1007/s00239-007-9040-x. PMID 18217182. http://www.springerlink.com/index/NN32M04267142429.pdf. Retrieved 2008-06-02. 
6. ^ Moore, V.A. (1902). The Pathology and Differential Diagnosis of Infectious Diseases of Animals. Taylor \& Carpenter, Ithaca, NY. 
7. ^ Assessment, M.E. (2005). Ecosystems and human well-being. World Resources Institute. 
8. ^ ^{a b c d e f} Jones, T.C.; Hunt, R.D.; King, N.W. (1997). Veterinary Pathology. Blackwell Publishing. 
9. ^ ^{a b} "Canine Distemper: Overview, Transmission, Symptoms". 2001. http://www.animalhealthchannel.com/distemper/index.shtml. 
10. ^ Carter, G.R.; Flores, E.F.; Wise, D.J. (2006). "Paramyxoviridae". A Concise Review of Veterinary Virology. http://www.ivis.org/advances/Carter/Part2Chap18/chapter.asp?LA=1. Retrieved 2006-06-24. 
11. ^ ^{a b c d} Hirsch, D.C.; Zee, C.; Others, (1999). Veterinary Microbiology. Blackwell Publishing. 
12. ^ Appel, M.J.G.; Summers, B.A. (1999). "Canine Distemper: Current Status". Recent Advances in Canine Infectious Diseases. http://www.ivis.org/advances/Infect_Dis_Carmichael/appel/chapter_frm.asp?LA=1. Retrieved 2006-06-24. 
13. ^ ^{a b} Dewey, C.W. (2003). A Practical Guide to Canine and Feline Neurology. Iowa State Pr. 
14. ^ Hirsh DC, Zee YC (1999). Veterinary Microbiology. Blackwell Publishing. ISBN 9780865425439. http://books.google.com/?id=ed5Up4JFl7MC&pg=PA403&dq=canine+distemper. 
15. ^ Spinage, C.A. (2003). Cattle Plague: A History. Plenum Pub Corp. 
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17. ^ ^{a b} WELTER, J. Canine distemper virus (CDV) infection of ferrets as a model for testing Morbillivirus vaccine strategies: NYVAC-and ALVAC-based CDV recombinants protect against symptomatic infection. Journal of Virology, 1997, 71:2, p. 1506-1513
18. ^ ^{a b} KLEIN, M. A randomized, controlled trial of vitamin A in children with severe measles. N. E. Journal of Medicine, 1990, 323:3, p. 160-164
19. ^ Otaka, M. Inhibition of measles virus and subacute sclerosing panencephalitis virus by RNA interference. Antiviral Research. 2006; 70:3. p. 105-11.
20. ^ ^{a b} Toshimitsu, T. et al. The cooperative effect of interferon-α and ribavirin on subacute sclerosing panencephalitis (SSPE) virus infections in vitro and in vivo. Antiviral Research, 1998, 37:1. p.29-35
21. ^ MARCUS, PI et al. Interferon Action on Avian Viruses. I. Oral Administration of Chicken Interferon-alpha ameliorates Newcastle Disease. Journal of Interferon and Cytokine Research, 1999. 19:881-885
22. ^ World Health Organization, WHO. United Nations Children's Fund. Measles mortality reduction and regional elimination strategic plan 2001-2005. Geneva: World Health Organization, 2001
23. ^ ^{a b} RODENEFFER C. et al.. "Disease Manifestations of Canine Distemper Virus Infection in Ferrets Are Modulated by Vitamin A Status". Journal of Nutrition 2007 (137): 1916–1922. 
24. ^ TROTTIER C. et al.. "Retinoids inhibit measles virus in vitro via nuclear retinoid receptor signaling pathways". Antiviral Research 2008 (80): 45–53. 
25. ^ RAIL J et al.. "Retinol and Retinyl Ester Responses in the Blood Plasma and Urine of Dogs after a Single Oral Dose of Vitamin A". The Journal of Nutrition 2002 (132): 6. 
26. ^ MADDOCK CH, et al. Hypervitaminosis A in the dog. The Journal of Nutrition. Reprint 1949
27. ^ GREEN, HN Vitamin A as an anti-infective agent. The British Medical Journal, 1928.2. p. 691-696
28. ^ BELLOLI C. et al.. "In vitro efficacy of ribavirin against canine distemper virus". Antiviral Research 2008 (77): 108–113. 
29. ^ JEULIN, H. et al. Effective ribavirin concentration in mice brain using cyclodextrin as a drug carrier: Evaluation in a measles encephalitis model. Antiviral Research, 2009, 81:3, p. 261-266
30. ^ MANGIA, S. Tratamento experimental de cães naturalmente infectados com o vírus da cinomose na fase neurológica com o uso de ribavirina e dimetil-sufóxido (DMSO). Botucatu, 2008. Tese (Mestrado) – Faculdade de Medicina Veterinária e Zootecnia, Universidade Estadual Paulista Júlio de Mesquita Filho, 2008
31. ^ MARKS, IM et al. Administration of ribavirin with food results in higher and less variable plasma ribavirin concentrations. Journal of Hepatology, 2001. 34:1
32. ^ Gordon, M.T.; Anderson, D.C.; Sharpe, P.T. (1991). "Canine distemper virus localised in bone cells of patients with Paget's disease". Bone 12 (3): 195–201. doi:10.1016/8756-3282(91)90042-H. PMID 1910961. http://www.ncbi.nlm.nih.gov/pubmed/1910961. Retrieved 2008-05-05. 
33. ^ Friedrichs, W.E.; Reddy, S.V.; Bruder, J.; Cundy, T.I.M.; Cornish, J.; Singer, F.R.; Roodman, G.D. (2002). "Sequence Analysis of Measles Virus Nucleocapsid Transcripts in Patients with Paget's Disease". Journal of Bone and Mineral Research 17 (1): 145–151. doi:10.1359/jbmr.2002.17.1.145. PMID 11771661. 
34. ^ Basle, M.F.; Fournier, J.G.; Rozenblatt, S.; Rebel, A.; Bouteille, M. (1986). "Measles virus RNA detected in Paget's disease bone tissue by in situ hybridization". Journal of General Virology 67 (5): 907–913. doi:10.1099/0022-1317-67-5-907. PMID 3701300. http://vir.sgmjournals.org/cgi/content/abstract/67/5/907. Retrieved 2008-05-05. 
35. ^ Hoyland, J.A.; Dixon, J.A.; Berry, J.L.; Davies, M.; Selby, P.L.; Mee, A.P. (2003). "A comparison of in situ hybridisation, reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ-RT-PCR for the detection of canine distemper virus RNA in Paget's disease". Journal of Virological Methods 109 (2): 253–259. doi:10.1016/S0166-0934(03)00079-X. PMID 12711070. http://linkinghub.elsevier.com/retrieve/pii/S016609340300079X. Retrieved 2008-05-05.