Adverse vaccination events: Separating fact from fiction (Proceedings)

Vaccines are such a routine part of everyday veterinary practice that we often forget about potential reactions and complications until they occur. Veterinarians tend to be familiar with vaccine reactions such as fever and lethargy. Other adverse events are less common and may be difficult to link to vaccination. The following discusses recognition and management of various types of reactions, and whether there is evidence that vaccines cause autoimmune illnesses or chronic diseases.

Local reactions

Pain or stinging at the time of injection is usually not due to the antigen. Inactivating ingredients or adjuvants are responsible, although temperature (cold from the fridge) may play a role. Hand-warming the syringe before injection may help, but do not leave vaccines at room temperature for extended periods of time.

Inflammation (swelling) at the vaccine site appears about one day later and may last up to one week. Unless infection or abscessation occurs, no treatment is needed but this should be documented and reported. Lumps that persist for over a month, or increase in size (greater than 2 cm), should be biopsied, especially in cats.

Vasculitis, most often from subcutaneous rabies vaccines, may lead to alopecia, scaling, and a permanent scar-like circular area. This is reported in toy and small breeds of dogs, and the cause is unknown. Potential medical therapy includes pentoxifylline and vitamin E, while surgical resection of the lesion is curative. Future vaccinations should be avoided or minimized, if possible, and a different brand of vaccine may help avoid the same problem.

Systemic reactions

Type I hypersensitivity (allergy, acute vaccine reaction, anaphylaxis) can result from the vaccine antigen or other proteins and material found in the product. Antibodies to bovine serum albumin and fibronectin have been detected in dogs, presumably due to residues of fetal calf serum used in vaccine production. These reactions happen within minutes up to 2-3 hours, although owners may not recognize signs until up to 8 hours later. Late-phase responses may persist for 48 hours.

In dogs, the clinical sign is most commonly urticaria and angioedema ("hives" or swelling) involving the face, head, and ears. Vomiting and diarrhea may be seen, and respiratory distress is rare but serious. Cats more often have GI signs (acute onset vomiting and diarrhea), and less commonly respiratory distress or urticaria.

Treatment for both dogs and cats is supportive. As soon as signs appear, injectable drugs such as corticosteroids, antihistamines, and/or epinephrine are given depending on severity. Other therapies such as IV fluids and oxygen are occasionally needed, and facilities for endotracheal intubation and ventilation should be available. A typical approach for mild cases is to give dexamethasone 0.2 mg/kg IV and diphenhydramine 2 mg/kg IM. To treat late-phase reactions, oral corticosteroids and antihistamines are dispensed for 2-3 days. For pets with a history of these kinds of vaccine reactions, at all future vaccine visits they are pretreated with a similar protocol and then monitored in the hospital for at least 8 hours. In cases of life-threatening reactions, future vaccination should be avoided if possible. If absolutely necessary, vaccines should be split into multiple visits (3 or more weeks apart) along with pretreating and careful monitoring.

Immune-mediated diseases have been associated with vaccines in dogs. However, the mechanisms have not been elucidated and cause-and-effect is not proven. A retrospective study published in 1996 concluded that a temporal relationship existed between vaccination and immune-mediated hemolytic anemia (IMHA). 15 of 58 dogs (26%) with idiopathic IMHA were found to have onset of clinical signs within 1 month of vaccination. The remaining cases were presented 2 months to 55 months after vaccination. Different brands of vaccine were used, and all dogs received DHLPP. Eight of the 15 IMHA cases also received rabies and a few dogs had other vaccines. Other studies were undertaken to confirm this association but did not find any evidence that IMHA occurred more frequently after vaccination. In the United Kingdom, a retrospective study of 41 cases of IMHA or immune-mediated thrombocytopenia (ITP) showed that 12% had been vaccinated within the past month.

A case series in a veterinary orthopedic journal described 27 dogs with immune-mediated arthritis, of which 4 (15%) were recently vaccinated (3-15 days, mean 11 days). Clinical signs included stiff gaits, a reluctance to move, and difficulty rising. All received diagnostic workups and were treated with doxycycline and carprofen. Signs resolved quickly (1-2 days after treatment). One dog was revaccinated and developed arthritic signs 12 days later, while another dog was revaccinated with no signs.

Hypothryoidism resulting from autoimmune thyroiditis has been identified in dogs, and antibodies (Ab) produced against canine thyroglobulin are diagnostic of this condition. A study in research Beagles and pet dogs attempted to discover if vaccination could cause this disorder. Results were mixed - Ab were found to canine and bovine thyroglobulin (probably because of bovine protein contaminants in the vaccines) but no cases of hypothyroidism were observed.

Are certain breeds predisposed to vaccine reactions? One author suggests that Old English Sheepdogs, Akitas, and Weimaraners have higher rates of vaccine-associated immune-mediated diseases than other breeds, but evidence is lacking. Hypertrophic osteodystrophy has been linked with modified-live distemper vaccines in Weimaraners, with average age of onset 13.5 weeks and 10.5 days post-vaccination. In a retrospective study of over one million dogs, the reaction rate (all types) was 38.2/10,000. Young adult dogs (1-3 years) and small-breed dogs were at higher risk. The top 5 breeds for reactions were Dachshund, Pug, Boston Terrier, Miniature Pinscher, and Chihuahua. Boxers were the only large breed with more reactions than average. Breed variations in response to rabies vaccination were recently reported. Genetic makeup most likely plays a major role in the risk of vaccine reaction.

Other reactions reported in cats include lethargy (with or without fever), vomiting, facial edema, and generalized pruritus. In one study, the reported rate of vaccine adverse events was 51.6 per 10,000 cats vaccinated.

In the UK, a questionnaire was mailed to 9055 dog owners who had visited a veterinary clinic in the past year, and 4040 were returned. The main question was whether the dog had any signs of ill health after vaccination. The results were that 16.4% of dogs vaccinated within the past 3 months had an illness, while 18.8% of dogs vaccinated >3 months earlier had ill health.

Despite several studies that show no association between vaccination and immune-mediated diseases, it is reasonable that animals with a history of IMHA or ITP or other illnesses should not be vaccinated routinely in the future. Certainly it would be beneficial to customize individual protocols in such cases, and minimize the number and frequency of vaccinations.

Neoplastic reactions

Since the early 1990s, veterinarians have observed neoplasia, most often fibrosarcoma, in sites where cats commonly received vaccinations. Multiple studies have associated vaccination (or injections of other drugs or materials) with inflammation leading to neoplastic transformation. The exact cause is unknown, but a genetic predisposition is possible as the vast majority of cats never develop granulomas or tumors at vaccine sites. In one study, a deletion in the p53 genomic sequence was identified in 60% of cats with more aggressive tumors.

The incidence is unknown due to several factors - no central reporting database, incomplete medical records as to dates, types, and locations of vaccinations, controversy over whether tumors are vaccine-associated or spontaneous, etc. Many specialists believe that the incidence is between 1 in 1,000 to 1 in 10,000 but these numbers are estimates. Whether or not the number of cases is increasing, decreasing, or the same is also in dispute. An unscientific survey via e-mail in 2005 had these results: 108 veterinarians responded, 17 had never diagnosed a vaccine-associated tumor, greater than 400 tumors were diagnosed, and rabies was suspected to be the cause most of the time followed by FeLV and FVRCP. Less than 10 of these tumors were reported to the vaccine manufacturers. This informal survey demonstrates the difficulty of getting a handle on the extent of the problem.

While some believe that vaccines in and of themselves are not the primary cause of tumors, a recent retrospective case study of 392 cats demonstrated that prior to 1996 (when the Vaccine Associated Feline Sarcoma Task Force issued recommendations to separate vaccines and administer in specific sites), most sarcomas occurred in the interscapular area and thoracic areas. After 1996, the proportion of tumors in those areas decreased but increased in the right front limb, right rear limb, and left rear limb along with the lateral aspects of the abdomen. This is strong evidence that as many veterinarians changed their protocol around or after 1996 from vaccinating in the scruff of the neck to separate limbs, sarcomas continued to occur in cats but now were found in specific vaccine sites.

In dogs, vaccination is not believed to cause neoplasia. However, one retrospective study found 15 fibrosarcomas excised from presumed vaccine sites in dogs (from 1998-2001). A case report of a malignant fibrosarcoma in a dog at the site of a microchip implant was recently published.

Veterinarians use a variety of strategies to minimize the risk of vaccine-associated tumors. One recommendation is to avoid adjuvanted vaccine products whenever possible as adjuvants have been linked to tissue inflammation and potential tumor formation. Of the feline vaccine products currently on the market in the U.S., there is only one brand of nonadjuvanted rabies and leukemia (recombinant products) while there are many types of nonadjuvanted FVRCP vaccines. Another strategy is to minimize the number of feline vaccines given over a lifetimes. The American Association of Feline Practitioners advocates vaccinating no more often than every 3 years for core antigens (FVRCP and rabies, if state and local laws permit) and limiting FeLV vaccinations to cats at risk. Intranasal FVRCP vaccines are available that eliminate any risk of injection-related inflammation. If ongoing monitoring suggests that vaccine tumors occur in dogs, then similar strategies may be recommended.

Management of these suspected vaccine tumors should be done with consultation with the vaccine manufacturers. Often referral to specialists in oncology and surgery is recommended as radiation, chemotherapy, and surgery (or all three) may be needed. Some companies will help defray the costs of treatment, which is a good reason to keep accurate medical records detailing the exact vaccines given, dates, and locations. Keep in mind that there can be delay of months to years between vaccination and tumor detection. Therefore, it is not always the most recent vaccine that may be involved. A complete and accurate vaccination history dating back to the kitten series should be obtained, if possible.

Other adverse events

A lack of efficacy may not be considered an adverse reaction, but any suspected case should be documented and reported. Vaccine "breaks" were seen in the past, but today with improved products it is much less common to diagnose disease in appropriately vaccinated animals. Possible causes include vaccines that are weak, outdated, not stored properly, or given to immunosuppressed or non-responding animals. Ideally clinicians should avoid vaccinating any febrile or sick pet, even if there are only vague signs of illness. Therefore, a complete history and comprehensive physical exam is needed before considering vaccination. Delegating the task of vaccinating to technicians or other support staff is commonly recommended by practice-management consultants, but a responsible veterinarian should be involved in the history and physical exam.

On rare occasions, an irregular or contaminated batch of vaccine is released by manufacturers which leads to increased reactivity or even vaccine-induced disease (reversion to virulence). The only way to detect and evaluate these situations is to report any reaction directly to the manufacturer and to the USDA (the federal agency that regulates animal biologics). In some cases, a reaction rate that is higher than expected will lead to recall of that batch of vaccine. As newer products and brands are introduced, it is especially important for practitioners to be on the "front line" of monitoring for adverse events. It is much better to report all suspected reactions than to assume they are "normal" and not worth bothering anyone.

References

USDA Website with information on how to report vaccine-related adverse events:

http://www.aphis.usda.gov/animal_health/vet_biologics/vb_adverse_event.shtml

You may call the Center for Veterinary Biologics at 800-752-6255. Fax number is 515-337-6120.