Dr. John M. Angles
BVSc, BSc(Vet), MACVSc, DACVIM (Small Animal Medicine), DECVIM-CA
The Animal Referral Hospital
444 Hume Highway
South Strathfield NSW 2136
AUSTRALIA

Overview

Compilation of data from the Weimaraner project initiated at UC-Davis has shown several significant disease syndromes in the breed (Table 1). Many of these disease syndromes are part of a broader hyper-inflammatory syndrome seen in the breed, with hypertrophic osteodystrophy, meningitis, vaccine reactions and antibody immunodeficiency seen within similar breed lines. A different age of onset, varying clinical signs and differing prognosis dictate the most appropriate treatment. There is likely to be a common underlying cause for these hyper-inflammatory diseases.

A major manifestation of the hyper-inflammatory syndrome is hypertrophic osteodystrophy (HOD), which causes pain and lameness associated with swelling of the growth plates in the long bones (e.g. femur, humerus). This is typically seen in pups soon after multi-valent vaccination. Other disease syndromes recognized include a post-vaccinal reaction with high fever and nodular skin disease; antibody immunodeficiency syndrome (well recorded in the veterinary literature, with recurrent infections involving the bowel, skin, and urinary tract) and septic meningitis.

Disease Prevalence
Hypertrophic Osteodystrophy 5.4%
Vaccine Reactions 1.3%
Chronic Diarrhea / IBD 1.2%
Steroid-responsive Meningitis 0.6%
Immunodeficiency (IgA, IgM, IgG) 0.5%

Table 1. The prevalence of immune-mediated disease in the Weimaraner dog. (Source: Weimaraner DNA-disease database at University College Dublin, July 2000)

Weimaraner breeder survey

To further clarify disease prevalence and breeder practices in the Weimaraner breed, a survey was conducted during 1999 (published in the January 2000 issue of “The Weimaraner Magazine”). Of the 1500 mailings to all active members of the WCA, there were 275 respondents (20%).

The survey was divided into Demographics, Diet, Vaccination practices and HOD disease. Pertinent findings were presented in an open forum at the WCA National Specialty in St Louis and included the following:

i) 51 of the 275 respondents (18%) had experienced HOD in at least one of their Weimaraners. Of these dogs, all had clinical signs consistent with the disease but only 82% had confirmatory radiographs. Most dogs were diagnosed within one week of onset of the clinical signs (72%) but of concern, 14% had not received a correct diagnosis for upwards of three weeks.

ii) One of the major controversies in the Weimaraner breed is the apparent association of HOD-disease with vaccination. Our survey showed that 37% of dogs diagnosed with HOD had received a vaccine 0-6 days prior to the onset of clinical signs, 33% within 7-13 days, 12% within 14-20 days and 18% over 20 days. These results suggest a vaccine-association for HOD in the Weimaraner.

iii) Multiple regression analyses were performed looking for associations between owner practices (diet, vaccination protocol) and the occurrence of HOD. Recent vaccination was the only risk factor for HOD disease in Weimaraner puppies. The WCA split vaccine protocol, dietary supplements (in particular calcium and vitamin C) and dietary type neither predisposed to nor protected against disease.

Hyper-inflammatory disease syndromes

1) Hypertrophic Osteodystrophy (HOD)
Diagnosis of HOD relies on the typical history, clinical signs, and the presence of characteristic radiographic findings showing changes at the growth plate of long bones. Appropriate clinical signs include swollen, painful metaphyses; fever; lameness and reduced appetite. Many dogs have self-limiting small bowel diarrhea prior to the onset of the fever and joint pain. Males and females are equally affected, and the age of onset is typically 8-16 weeks of age.

The cause of HOD remains unknown, with earlier speculations of vitamin C deficiency or over-nutrition discounted in more recent times. To date, we have not been able to identify a link between HOD and antibody immunodeficiency disease of the Weimaraner. Low levels of blood antibody IgA, IgM, or IgA are documented inconsistently in HOD affected dogs. A high heritability for HOD suggests a significant genetic effect, and a DNA marker analysis is in progress at the Veterinary Genetics Laboratory at UC-Davis to further our understanding of this syndrome.

Treatment of HOD in other breeds has traditionally relied on rest, non-steroidal anti-inflammatory drugs (such as metacam and rimadyl), and opiate analgesics (such as butorphanol or fentanyl) as necessary. In most cases, the disease is self-limiting, and most dogs recover in several weeks. The disease in the Weimaraner is different. The Weimaraner breed is prone to a severe multi-organ inflammatory form of the disease, with progression in many dogs resulting in death without appropriate treatment. Our current recommendation is for practitioners to rule out infectious causes for the fever, and in the presence of radiographic changes in the growth plates consistent with HOD, to treat these dogs with corticosteroids. Prompt recognition of the disease, and appropriate treatment are the keys to a good outcome in this disease.

Antibody immunodeficiency
Immunodeficiency in the Weimaraner breed is well known, although the cause is poorly understood (See Couto, 1989; Hansen, 1995; Day, 1999; Foale, 2003). Low immunoglobulin levels are the consistent feature in all of these reports, and low IgA, IgG, or IgM have been associated with chronic, recurrent disease involving a variety of tissues including the bowel, skin, and central nervous system. This disease syndrome is present in the Weimaraner breed in the USA, and we suspect that many of the chronic diarrhea and inflammatory bowel disease animals may have low immunoglobulin levels (Table 1), but have not had these specifically measured to confirm the diagnosis.

Steroid-responsive (aseptic) meningitis
Another disease syndrome that has not been reported previously in the Weimaraner is breed-specific meningitis. We raised the possibility of this disease at the 1998 Weimaraner Nationals, and have now over 15 Weimaraners with this disease. All of these dogs were presented to veterinarians for fever and neck/back pain. The age of onset is older than for pups with HOD, typically between 16-30 weeks of life. Males are more frequently affected. The diagnosis can only be confirmed by spinal tap and cerebrospinal fluid (CSF) analysis, requiring anesthesia for sample collection. Many of these dogs have required long term treatment with corticosteroids and azathioprine to control the disease, with recurrence seen at lower doses.

Genetics of hypertrophic osteodystrophy
The mode of inheritance of HOD in the dog has not been reported, but there is an obvious breed predisposition suggesting that genetic factors play an important role. Our group has found a high heritability for HOD in the Weimaraner of 0.68 (95% confidence interval of 0.65 - 0.71), suggesting that HOD in the Weimaraner may have a significant genetic component. This is important both for genetic counselling and for potential development of a genetic marker test for susceptibility to HOD.

Our data support an autosomal mode of inheritance for HOD, with no exceptions to the mode of inheritance shown to date. Some of the characteristics of an autosomal recessive disease that we are seeing in the Weimaraner include: 1) skipping of generations, and 2) mating of known carriers results in expected proportions of 25% affected and 75% normal. It is not possible to detect carriers at present other than by test matings, as there are no biochemical or conformational traits to indicate their carrier status.

Weimaraners with HOD-susceptibility genes do not have any known conformation or blood test results that permit identification. The only way to detect these carriers has been by test matings. Detection of these carriers has been hampered by use of modified vaccination protocols that are designed to prevent expression of HOD during the susceptible growth period. While it is important to look after the health of our puppies, this factor must be borne in mind when a selection program against HOD is to be implemented in the absence of a sensitive genetic marker. One of the aims of our group has been to locate a genetic marker for susceptibility to HOD, allowing for sensitive detection of these carriers, and thereby, design of a suitable breeding program.

A genetic marker study for HOD is in progress at UC-Davis. This study offers the possibility of understanding a complex hyper-inflammatory syndrome by concentrating on one of the more common manifestations of the syndrome. This approach to genetic dissection of complex traits is novel but increasingly being used in human genetics.

Vaccination
An important finding of the study has been the association of the HOD disease with recent vaccination. Approximately 70% of the Weimaraners diagnosed with HOD have received a recent multi-valent vaccine within 1-2 weeks of the disease onset. Most of these would have been vaccinated within 2-3 days of disease onset. To date there has been no association with a particular brand or type of vaccine, with most brands implicated at some point. It is important to note that there have been Weimaraners with HOD not receiving vaccines within the previous 3 weeks. This indicates that vaccination is one trigger for the HOD disease on a susceptible genetic background.

There is no vaccination protocol that will prevent all cases of hyper-inflammatory disease in the Weimaraner. This does not mean that puppies should not be vaccinated, as the risk for acquiring infectious disease far outweighs the risks associated with vaccination in most Weimaraner puppies. In certain lines this may not be true, and alternative vaccination protocols have long been recommended for these puppies. The use of such protocols desperately requires scientific study and validation, as many are counter to veterinary and state regulations.

Weimaraner vaccine protocol pilot study
A pilot study was performed in 2001 to assess the efficacy of a single protocol involving vaccination at 8 and 12 weeks of age with parvovirus, distemper, infectious hepatitis and kennel cough. Rabies vaccination was performed as per state requirements, generally at 16 weeks of age. Vaccine titers for canine parvovirus and distemper were taken prior to each vaccination and at 6 months of age.

Four litters were enrolled, with three litters (19 puppies) completing the study. One litter was removed from the study after the first vaccination due to nodular skin reactions in several pups. HOD was seen in one of the pups completing the study after the second vaccination. 64% of puppies vaccinated using the study protocol showed “protective” antibody levels to distemper; 84% of puppies were “protected” against parvovirus. It is important to note that low antibody titers for these viruses does not equate to no protection against disease, as other components of the immune system can protect against clinical disease and are not easily measured.

This was the first study to look at the kinetics of vaccine response in the Weimaraner, and these results suggest that there is a spread of vaccine response within the breed. With only a single HOD-affected puppy, no conclusions are possible regarding vaccination and identifying puppies at risk for disease. Further studies documenting the efficacy of vaccination within the breed are long overdue, and will be needed for a more unified approach to vaccination and disease prevention.

Vaccination recommendations?
Without objective data on vaccine protocol efficacy and safety, few recommendations are possible at the moment. Our recommendation has remained the same for several years, based on more conventional vaccine protocols. No vaccine protocol will protect all puppies within the breed, and we have documented HOD-disease associated with most variants in use. The aim of vaccination still remains protection of our puppies from disease, and it is the role of the breeder and local veterinarian to assess risk-versus-benefit at all times. Vaccines should never be given in a sick puppy.

Core vaccine components including parvovirus (P), distemper (D), infectious hepatitis (A2) are recommended for all Weimaraner puppies. These diseases are rarely seen with vaccination, but outbreaks in non-vaccinated dogs have been seen in many locations worldwide. Canine parainfluenza (kennel cough) is not essential but generally given as it is part of the 4-in-1 vaccines (DA2PP). Killed rabies vaccination is recommended as per state requirements, usually at 16 weeks of age.

Non-core vaccines should remain at the discretion of the local veterinarian, e.g. vaccination for lyme disease or leptospirosis are indicated in endemic regions. These non-core vaccines are not essential and should be delayed in breed lines at high risk for vaccine reactions. Coronavirus and Giardia vaccination are not recommended as part of the puppy protocols.

Suggested further reading

1) Abeles V, Harrus S, Angles JM, Shalev G, Aizenberg I, Peres Y, Aroch I (1999) Hypertrophic osteodystrophy in six weimaraner puppies associated with systemic signs. Veterinary Record, 145(5):130-4.
2) Couto, CG, Krakowka, S, Johnson, G, Ciekot, P, Hill, R, Lafrado, L and Kociba, G (1989) In vitro immunologic features of Weimaraner dogs with neutrophil abnormalities and recurrent infections. Veterinary Immunology and Immunopathology, 23: 103-112
3) Day, MJ, Power, C, Oleshenko, J and Rose, M. (1997) Low serum immunoglobulin concentrations in related Weimaraner dogs. Journal Small Animal Practice, 38: 311-315
4) Foale RD, Herrtage ME, Day MJ. (2003) Retrospective study of 25 young weimaraners with low serum immunoglobulin concentrations and inflammatory disease. Veterinary Record, 153(18):553-8.
5) Hansen, P, Clercx, C, Henroteaux, M, Rutten, VPMG and Bernadina, WE (1995) Neutrophil phagocyte dysfunction in a Weimaraner with recurrent infections. Journal Small Animal Practice, 36: 128-131
6) Harrus S, Waner T, Aizenberg, Safra N, Mosenco A, Radoshitsky M, Bark H. (2002) Development of hypertrophic osteodystrophy and antibody response in a litter of vaccinated Weimaraner puppies. Journal Small Animal Practice, 43(1): 27-31

6/2004 Copyright John M. Angles