CDV, a single-stranded RNA paramyxovirus of antimessage (negative) polarity, is a member of the Morbillivirus genus, which also includes measles, rinderpest, and the recently discovered seal plague (phocine) virus (1,14). These viruses are of great interest because they are highly contagious in their respective natural hosts (161); can be very neurotropic causing CNS inflammation or demyelination in many species, including humans (1,14,162,163); and can jump species (1,14,160, 164,165). A recent outbreak of a fatal disease in horses was thought to be caused by a new member of the Morbillivirus group. This virus was also apparently transmitted from horse to humans, causing a severe respiratory illness in two humans and death in one (166).
CDV infects dogs and other carnivores, including Japanese macaques. Susceptibility extends to a wide range of nondomestic animals and, more recently, CDV has been shown to produce disease in large cats, including lions, tigers, and leopards.
CDV can cause a subclinical disease in dogs but typically results in a febrile illness, with upper respiratory and gastrointestinal manifestations (161). Neurological sequelae are common either in close proximity to infection or after a variable latent period. Animals may develop optic neuritis, myelopathy, or encephalopathy. The neurological illness is commonly acute and monophasic but can be relapsing or progressive (1,14). In the former situation, the virus can be readily identified in brain tissue, whereas in the latter situation, viral identification can be problematic (167). Some strains of CDV can cause demyelination in up to 90% of dogs, which makes it far more neurotropic in its natural host than measles is in humans (1,14,163). Interestingly, vaccinating dogs with measles vaccine can prevent these neurologic complications. Pathologically, CDV can cause a panencephalitis or primary demyelination, occasionally with plaque-like lesions in periventricular white matter that are difficult to distin-guishfrom MS (1,14,167).
The CDV-MS hypothesis implies that MS should be more common in geographic areas where genetically susceptible individuals have the greatest exposure to dogs (i.e., in areas where dog-human contact is closest and where CDV is common in the canine population) (1,14). Conversely, risk for MS would be expected to be diminished in areas where dogs are uncommon, where dog-human contact is low because of cultural attitudes toward dogs or because dogs are kept outdoors, and in isolated regions where distemper is not endemic (1,14). In this regard, both MS and dog density (and the indoor dog location for pet dogs) are higher in North America and Europe than in India (168) and, probably, in China and Japan (1,14). Moreover, dogs are more likely to be kept indoors in colder climates, such as the northern United States, compared with the American South (169); dogs are more likely to have epidemics of overt CDV infection in cold, damp climates (DiGiacomo, personal communication); and CDV may survive longer at colder temperatures (170), conditions conducive to greater human-CDV-infected dog contact in regions of greatest MS prevalence (1,14). Examples of a geographic gradient for a dog-linked human infectious disease exist, with human hydatidosis being 10 times more common in colder regions of Kenya, where dogs are kept indoors, than in warmer regions of this country (1,14,171).
If MS is a zoonosis, spread by CDV from dog to human, one would expect MS patients to have more dog exposure before onset of the disease than matched controls. However, this might not be true for individual patients, because CDV, like measles, is an extremely contagious disease, typically spread by a respiratory route and even brief exposure to an infected dog could be sufficient to cause infection (1,14). The problem with epidemiological studies of dog exposure is the high background noise, as 60% to 80% of controls in some American and European studies own dogs, indicating the need for large numbers of MS patients and controls to properly study this relationship (1,14).
Although most studies of MS patients (involving relatively few individuals) have not shown more dog ownership, dog exposure before onset, or expected onset of MS, at least 11 studies have shown such a temporal (171-181) correlation. However, if CDV is the agent and the dog the vector, then the more important relation is the contact between humans and dogs with distemper and the subsequent development of MS. Three reports of increased exposure of MS patients to dogs with a CDV-like illness before onset of MS have been published (172,182,183), in one of which exposure to dogs with a neurological illness was greater in MS patients than controls in the five years before onset of MS (176). Other studies, although not statistically significant, have shown a trend in this direction (184-186). Of course, there is no documentation that these dogs truly had a CDV infection, and the possibility of recall bias cannot be excluded. Since the availability of distemper vaccine over the past 40 years, overt distemper is now less common than in the past. However, CDV infection still occurs as isolated cases, and occasionally as epidemics even in dogs previously vaccinated with distemper vaccine suggesting that protection from vaccine is not life long, and wild animal vectors as a possible source for CDV infection remain.
Until recently, it was difficult to determine by serological methods whether a human had been infected by CDV because of the similar peptide homologies and antigenic relation between measles virus and CDV (187,188). Several early studies searching for serum antibodies to CDV showed higher titers in MS patients than in controls using a tissue culture neutralization assay (1,14,189). In one such study, the highest antibody titers in MS patients were to virulent rather than vaccine strains of CDV, and no significant increase in antibody titer was found to six other dog viruses (190). Smaller studies or those utilizing different techniques found no difference in serum CDV titers between patients and controls (1). Unfortunately, these ser-ological studies were unable to distinguish definitively between CDV antibody and cross-reacting MV antibodies.
In 1995, following the publication of the entire nucleotide structure of CDV and measles, Rohowsky-Kochan et al. (191) were able to select peptide sequences present in the surface CDV hemagglutinin H protein, which had predicted antigenic determinants that differed structurally from corresponding measles peptides (1,14). They synthesized three such CDV H peptides, each 15 to 16 amino acids in length, which—in addition to being structurally different from measles virus—were also structurally different from each other (1,14,158). In studies of animals and humans vaccinated or infected with the measles virus and with high measles antibodies titers, the discriminatory capacity of the assay was demonstrated. None of the measles antibody-positive sera reacted with CDV in ELISA, whereas animals immunized with CDV reacted with all three CDV peptides (1,14,191). Subsequently, in a survey of large numbers of MS patients, age-sex-matched normal individuals and patients with other neurological and inflammatory diseases, a significant increase in serum CDV antibody titer to all three peptides was found only in the MS patients (1,14,191), with titers being significantly elevated over a wide age span (192). Some 70% of all high-titered CDV sera belonged to MS patients, indicating a relatively high degree of specificity, although not sensitivity, for this assay. A striking relationship was also observed between elevated CDV-H antibody levels and the diagnosis of MS (P < 0.0001, odds ratio = 5.0) (163). In contrast, no increase in viral antibody titer was found to varicella zoster or polio virus in these studies nor was there a relationship between CDV titer and serum IgG levels (1,14,191,192). These results suggest that humans can be infected by CDV, and are consistent with, but do not prove the hypothesis that MS may in some instances be triggered by this agent (1,14,191,192).
The criticisms of the CDV-MS hypothesis include the failure to date to find CDV protein or genome in MS brain (51,192,193), the high titers of CDV antibody that can occur in some individuals without MS, the low titers of CDV antibody in many patients with MS, lack of studies to show whether CSF OCBs bind to CDV, and the failure of MS to decline since the availability of distemper vaccine.
In summary, the possibility that MS is a zoonosis remains viable and canine distemper remains a leading candidate agent for triggering MS in some patients. However, more studies are needed to link CDV to MS.
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