distemper

Canine distemper is a very serious 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, although ferrets are also vaccinated for it. 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.^[5]

History

Although very similar to the measles virus, CDV seems to have appeared more recently, with the first case described in 1905 by French veterinarian Henri Carré.^[6] It was first thought to be related to the Plague and Typhus and resulted from several species of bacteria.^[7] 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.^[6] 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 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.^[8] The disease has also mutated to form phocid distemper virus, which affects seals.^[9]

Infection

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

Puppies from three to six months old are particularly susceptible.^[10] Canine distemper virus (CDV) spreads through the 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.^[11][12] The time between infection and disease is 14 to 18 days, although there can be a fever from three to six days postinfection.^[13]

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 lymphatic tissue followed by respiratory, Gastrointestinal, urogenital epithelium, the Central Nervous System, and optic nerves^[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.^[12] In older dogs that do develop distemper encephalomyetilis, vestibular disease may present.^[14] 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.^[12] In older dogs that do develop distemper encephalomyetilis, vestibular disease may present.^[14] 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][9] About half of sufferers experience meningoencephalitis.^[9]

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, urination and defecation may become involuntary.^{[9] [10][15]}

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][9]

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 differing between canine hepatitis, herpes virus, parainfluenza and leptospirosis been possible.^[9] Thus, finding the virus by various methods in the dog's conjunctival cells gives a definitive diagnosis. In older dogs that develop distemper encephalomyetilis, diagnosis may be more difficult since many of these dogs have an adequate vaccination history.^[14]

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 cells will always have inclusions. Inclusions in these cells which will stain a carmine red color and be para nuclear in the cytoplasm of infected cells. 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.

Treatment

Until recently, canine distemper went back a long history of failures with respect to treatments affected animals. Two associated factors had an important role in maintaining this negative perspective.

The first may be considered cultural, affected animals do not receive adequate attention until the disease reaches the nervous stage. During non-neurological phase symptoms commonly seen are respiratory and intestinal disorders, apathy, and lack of appetite; this picture is often not enough to alarm the owners. Being sought medical assistance only when the disease reaches the nervous stage and disturbed state of the animal is more shocking.

The second factor is due to the old interpretation that had the mechanism of action of the virus in the nervous phase. It was assumed that the injuries that occurred were the result of a reaction strictly autoimmune, something like the canine distemper virus unleashed something, was eliminated, but the reaction initiated continue. It was therefore recommended an intervention by anti-inflammatory and immunosuppressive drugs, because they saw a need to eliminate this condition of self scourge.

It was considered that the action of macrophages on nerve cells is oriented on infected cells, indicating that the reaction autoimmune is a direct consequence of the presence of the virus.^[16] Once they have established that it is easy to understand the factors cited as contributing to the death of infected animals: Owners seek expert help only when the disease is in advanced stages (nervous phase) and prescription anti-inflammatory drugs (which are usually corticosteroids) undermine the immune system of the animal, besides allowing the proliferation of the virus, also the reaction autoimmune increases as a means of containment of infected cells.

The most successful treatments for canine distemper are appropriations of established treatments for other diseases caused by similar viruses, such as the Ribavirin and vitamin A, which are used to treat measles ^[17][18] ,^[19] the same family and gender (Paramyxoviridae - morbillivirus) and Interferon Alpha, used for the treatment of [[measles] ] ^[19] and when you want to preserve birds affected by the Newcastle disease,^[20] same family but different genera (Paramyxoviridae - AVULAVIRUS).

The first references that effective treatments for similar viruses could be effective for canine distemper arose when studies found that the canine was a disease comparable to measles^[16] and infected animals could be used to develop new technologies for treatment of measles. The question if the reciprocal would be true to each other was cleared when studies assessed the efficacy of traditional treatments for measles when they were applied to animals with distemper.

The first finding was when the induction of high levels of Vitamin A, which is a ostensibly treatment used to treat measles ^[17] (including being recommended by the World Health Organization ^[21]), produced an effect of 100% cure in animals experimentally infected. The group that received no supplementation all came to death. ^[22]. Currently, it is known that the direct inhibitor effect of retinoids (Vitamin A and subproducts) over the measles virus is what confirms the choice of Vitamin A as a treatment for canine distemper.^[23]

The confirmation of the effectiveness of Vitamin A in the treatment of canine found in carnivores, especially dogs, an ally of exception, which is its ability to convert the Vitamin A in non toxic esters.^[24] This characteristic of carnivores is well known, which removes the risk of hypervitaminosis possible due to the maintenance of high doses. For dogs there is a benchmark to measure the risk of hypervitaminosis, a national research found that it takes a dose of 300,000 IU / kg daily for thirty days so that the first signs of hypervitaminosis appear, and need sixty days of ingestion of this dosage to get the animal to death.^[25] Since this dosage, 300,000 IU / kg is sixty times greater than the limit established for humans.

The mechanisms of action that explain its effectiveness in the treatment of distemper remain unexplained, and this issue also exists for the case of measles. Some evidence points to an indirect action, such as checking that there is a reduction in the amounts of Vitamin A during infection,^[22] pointing to the hypothesis that [ [Vitamin A]] is raw material for some mechanism of resistance to infection. The very characteristic antiinfectiva ^[26] not specific Vitamin A is a mystery, however there was any doubt about its effectiveness, action mechanisms elucidated or not.

The adoption of Ribavirin as a treatment for canine followed the same steps of Vitamin A, it was the principle used in cases of subacute sclerosing panencephalitis under measles. The first verification of the effectiveness occurred in vitro.^[27] What observed that the distemper virus is very susceptible to Ribavirin and its mechanism of induction error catastrophe are needed from 0.02 to 0.05 micro mols to an 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. Being the brain a immunologically privileged area, the concerns was the capacity of Ribavirin to overcome this barrier. A study using mice with encephalitis due to measles it was found that once the virus has become established in phase nervosa, the blood-brain barrier in a way falls, reducing the restriction to the action of the Ribavirin in these areas.^[28] The verification of all these results in vivo results from a Brazilian study and was conducted using only animals that had already developed a nervous phase of the disease, the result was an efficiency of 80 %.^[29] Application of Ribavirin demands a close monitoring of animal due the risk of leukopenia and the ingestion of log-chain tryglicerides(in other words: fats) in order to better absorption of the drug ^[30] and for preservation of gastric region, which are quite susceptible to Ribavirin.

Canine distemper virus and Paget's disease

Paget's disease, a focal destructive disease of bone, has long suspected paramyxoviruses such as CDV, measles, respiratory syncytial virus, simian virus 5, and parainfluenza virus Type 3 as a culprit. Most studies, however, have pointed more directly at CDV and Measles.^[31][32][33] The virus detection technique in situ-RT-PCR has shown CDV in 100% of Pagetic samples whereas other virus detection techniques have been less accurate.^[34]

References