Drug hypersensitivity reactions targeting the skin in dogs and cats

Adverse drug reactions (ADRs) can be dose dependent or idiosyncratic. Most idiosyncratic reactions are believed to be immune-mediated; such drug hypersensitivities and allergies are unpredictable. Cutaneous reactions are the most common presentation of drug allergies. In veterinary medicine it can be difficult to assess the true prevalence of adverse drug reactions, although reports available suggest that they occur quite commonly. There are multiple theories that attempt to explain how drug allergies occur, because the pathogenesis is not yet well understood. These include the (pro)-hapten hypothesis, the Danger Theory, the pi concept, and the viral reactivation theory. Cutaneous drug allergies in veterinary medicine can have a variety of clinical manifestations, ranging from pruritus to often fatal toxic epidermal necrolysis. Diagnosis can be challenging, as the reactions are highly pleomorphic and may be mistaken for other dermatologic diseases. One must rely heavily on history and physical examination to rule out other possibilities. Dechallenge of the drug, histopathology, and other diagnostic tests can help to confirm the diagnosis. New diagnostic tools are beginning to be used, such as antibody or cellular testing, and may be used more in the future. There is much yet to learn about drug allergies, which makes future research vitally important. Treatment of drug allergies involves supportive care, and additional treatments, such as immunosuppressive medications, depend on the manifestation of the disease. Of utmost importance is to avoid the use of the incriminating drug in future treatment of the patient, as subsequent reactions can be worse, and ultimately can prove fatal.     

Veterinary pharmacovigilance. Part 6. Predictability of adverse reactions in animals from laboratory toxicology studies

Toxicological studies are conducted on constituents of veterinary medicinal products for a number of reasons. Aside from being a requirement of legislation, they are carried out for predictive purposes in the assessment of user safety or for the determination of consumer safety, for example, in the elaboration of maximum residue limits or tolerances. Alternatively, the results of toxicology studies may be available as they have been generated for registration of the drug for human medicinal purposes. This paper examines if the results of such studies have any predictive value for adverse reactions, which might occur during clinical use in animals. A number of adverse reactions, notably the Type A (toxicology or pharmacology dependent) should be predictable from these laboratory studies. However, as with human pharmaceutical products, they have less utility in predicting Type-B reactions (idiosyncratic in nature).     

Veterinary pharmacovigilance. Part 4. Adverse reactions in humans to veterinary medicinal products

Although seemingly rare, adverse reactions to veterinary products do occur. These may arise from inadvertent exposure during use or as a result of occupational accidents. They are often mild in nature and include adverse effects such as minor skin reactions. However, more serious reactions may occur, and they are not restricted to the effects of the veterinary medicines themselves. For example, high-pressure injection injuries may occur as a result of accidents occurring during animal vaccination operations. This paper reviews some of these events, mentions where appropriate the regulatory actions taken, and describes some of the measures used to minimise such effects in the future, and serves to bring the issues discussed here to the attention of pharmacologists, pharmacoepidemiologists and others who train those who use veterinary medicinal products.     

Hymenoptera stings

The medically important groups of Hymenoptera are the Apoidea (bees), Vespoidea (wasps, hornets, and yellow jackets), and Formicidae (ants). These insects deliver their venom by stinging their victims. Bees lose their barbed stinger after stinging and die. Wasps, hornets, and yellow jackets can sting multiple times. Most deaths related to Hymenoptera stings are the result of immediate hypersensitivity reactions, causing anaphylaxis. Massive envenomations can cause death in nonallergic individuals. The estimated lethal dose is approximately 20 stings/kg in most mammals. Anaphylactic reactions to Hymenoptera stings are not dose dependent or related to the number of stings. Bee and wasp venoms are made up primarily of protein. Conversely, fire ant venoms are 95% alkaloids. Four possible reactions are seen after insect stings: local reactions, regional reactions, systemic anaphylactic responses, and less commonly, delayed-type hypersensitivity. Clinical signs of bee and wasp stings include erythema, edema, and pain at the sting site. Occasionally, animals develop regional reactions. Onset of life-threatening, anaphylactic signs typically occur within 10 minutes of the sting. Diagnosis of bee and wasp stings stem from a history of potential contact matched with onset of appropriate clinical signs. Treatment of uncomplicated envenomations (stings) consists of conservative therapy (antihistamines, ice or cool compresses, topical lidocaine, or corticosteroid lotions). Prompt recognition and initiation of treatment is critical in successful management of anaphylactic reactions to hymenopteran stings. Imported fire ants both bite and sting, and envenomation only occurs through the sting. Anaphylaxis after imported fire ant stings is treated similarly to anaphylactic reactions after honeybee and vespid stings. The majority of Hymenopteran stings are self-limiting events, which resolve in a few hours without treatment. Because life-threatening anaphylactic reactions can progress rapidly, all animals stung should be closely monitored and observed. In the following review article, we will examine the sources and incidence, toxicokinetics, pathological lesions, clinical signs, diagnosis, treatment, and prognosis for dogs and cats suffering Hymenoptera stings.     

The ACVD task force on canine atopic dermatitis (VI): IgE-induced immediate and late-phase reactions, two inflammatory sequences at sites of intradermal allergen injections.

Intradermal testing is a common diagnostic procedure used in the evaluation of dogs with suspected atopic dermatitis (AD). To do this, most investigators assess the appearance of wheals that develop at the sites of intradermal allergen injections. However, wheals are rarely seen in dogs with naturally occurring AD. Furthermore, infiltration of inflammatory cells into the injection sites can occur 6-24h later, a phenomenon known as the late-phase reaction. The histological appearance of these late-phase reactions closely approximates that seen in the natural disease, suggesting that they might be more relevant than the immediate reactions. In this paper, we review the literature on immediate and late-phase reactions and re-assess the evidence for using current intradermal testing procedures as a diagnostic test in dogs.     

Food intolerance in dogs and cats

Food intolerance refers to any abnormal physiological response to a food or food additive believed not to be immunological in nature. Mechanisms include food toxicity, pharmacological reactions, metabolic reactions, dysmotility, dysbiosis, physical effects and non‐specific dietary sensitivity. Food intolerance reactions are variable, typically dose‐dependent, and can occur at any age. Signs may arise at any time, sometimes several hours or days after consumption of the offending food item, and can last for hours or days. Dietary indiscretion and non‐immunological food intolerance are probably more common in dogs than true dietary hypersensitivity. Hopefully, with a greater knowledge of the different pathophysiological mechanisms involved, we will become better at recognising, preventing and managing adverse food reactions.     

Future applications of biotechnology in poultry

The major biotechnological advances that can be applied in the poultry industry will include molecular genetics, molecular immunology, and solid-state reactions. The elucidation of the genetic code and the development of techniques to manipulate genes offer new opportunities for changing pathogenic agents and changing chickens to reduce the effect of disease and improve productivity. The monoclonal antibody technique and the discovery that cells of the immune response communicate with one another through peptide factors will permit improved diagnostic techniques and enhanced immune responses to vaccines. Immunologic and biochemical reactions that occur on a solid substrate can be used to simplify and accelerate diagnostic tests and to purify antigens and antibodies. These advances will lead to improvements in diagnosis, disease resistance, and productivity of poultry.     

Transfusion medicine in exotic pets

The decision to transfuse a patient should always be based on the packed cell volume and clinical status of the patient. This article discusses indications for transfusion and blood substitutes in exotic animal patients. The administration of blood products requires careful donor selection, knowledge of blood groups, cross-matching, and use of anticoagulants. Collection sites, volume, and administration techniques are given for different species of animals including birds, rabbits, and ferrets. Blood-transfusion therapy is not without risk. The frequency with which transfusion reactions occur in exotic pets is unknown. The most common transfusion reactions seen in small animals, along with suggested treatment, are discussed. The availability of blood products is limited in exotic pet medicine; therefore, the use of blood substitutes (Oxyglobin) has the advantage of long storage potential, no need for cross-matching, and no potential for disease transmission. General principles of blood substitutes and administration techniques will be discussed.     

Migration-inhibition response of peripheral leukocytes to tuberculin in cats sensitized with viable Mycobacterium bovis (BCG).

Delayed hypersensitivity reactions to antigens injected intradermally are reported as not occurring in the cat. Cats infected with viable Mycobacterium bovis (BCG) organisms developed a transient migration-inhibition response of their leukocytes to tuberculin. The migration-inhibition response subsided in 6 weeks in spite of the persistance of viable BCG. Significant intradermal reactions to tuberculin 60 days after BCG injection did not occur. The response of the cat differs from that of many mammalian species in which strong in vivo and in vitro delayed hypersensitivity type reactions persist with mycobacterial infections. Despite the lack of continued measurable delayed hypersensitivity, the cat appears to have adequate resistance to mycobacterial infections.     

Management of hard-to-heal wounds.

Some wounds do not heal normally and present the practitioner with a challenge. These can be thought of as hard-to-heal wounds. There are numerous causes of such wounds, and when they occur, the veterinarian should consider all factors associated with the wound. When diagnostic tests are indicated, they should be performed. Finally, appropriate measures should be taken to correct the underlying cause of the hard-to-heal wound.     

Adverse reactions to veterinary drugs reported in Sweden during 1991–1995

The present article gives a summary of suspected adverse reactions reported by Swedish veterinarians during the period 1991–1995. The summary shows that severe adverse drug-reactions sometimes occur in Swedish veterinary practice. In horses, several cases of acute reactions in animals treated with procaine benzylpenicillin were reported and seven horses died within a few minutes after intramuscular injections of the drug. In cattle and swine most reports referred to the use of antimicrobial agents. In dogs reactions to vaccines were the most frequently reported adverse effects. The reactions were, however, usually rather mild. In dogs there were also several reports of severe reactions related to treatments with non-steroid anti-inflammatory drugs (NSAID) and α₂-receptor agonists. Amongst the reports six deaths were observed for each of these groups of drugs. In cats, as in dogs, adverse effects to vaccines were the most frequently reported reactions.     

How to respond to adverse drug reactions.

Adverse drug reactions (ADRs) are part of the risks, professional responsibilities, and liabilities inherent to veterinary medicine. The incidence of proven ADRs is not known, but veterinarians should anticipate, plan, and practice a response for patients that experience adverse reactions. The attending veterinarian should work closely with professional services personnel at pharmaceutical manufacturers to provide care for those patients, to investigate causes of ADRs, and to factually improve reports of ADRs that can be of considerable medicolegal benefit to the client and the profession.     

Principles of wound healing

Wound healing can be divided into immediate (zero to 1 hour), early (1 to 24 hours), intermediate (1 to 7 days), and late (greater than 7 days) stages. Many physical and physiologic events occur simultaneously and sequentially during these stages to produce the final wound scar. The processes of skin retraction, scab formation, would debridement, wound contraction, epithelial migration and proliferation, fibroplasia, and collagen maturation all must occur for healing to be successful. Many factors affect the size and shape of the resulting scar, including anatomic location and skin tension forces, systemic condition of the patient, blood supply to the wound, nutritional factors, environmental temperature, the presence of systemic drugs, wound infection, motion, wound oxygen gradient, wound moisture, and bandaging. Ideally, each of the factors would occur at a level compatible with optimal healing, but, in many clinical cases, one or more factors compromise normal, rapid healing. When we intervene with therapy, we probably adversely affect another factor in healing, while trying to correct the factor that is out of balance. In these decisions, the effects of our treatment on wound healing should be considered. The trade-off should be weighed and the treatment pursued only as long as necessary to allow healing to progress; then it should be discontinued or changed. With these considerations, it is hoped that we can attain healing at the most rapid physiologic rate.     

Corneal diseases of rabbits.

Corneal diseases are common in domestic rabbits. It is important to carefully evaluate the cornea and the entire eye when rabbit present with clinical signs such as squinting, tearing, or conjunctival hyperemia. Complete ophthalmic examination and general physical examination should be performed on all rabbits with corneal disease. Important diagnostic testing include culture and sensitivity, cytology, and fluorescein staining. Breed predispositions do not occur for most corneal problems, although some diseases are selected genetically in research rabbits. Corneal disease can be a primary condition or can occur secondary to other ocular or systemic disease.     

Anesthetic complications in the horse

The basis for management of all complications is early recognition, preparation, and a problem-solving approach. Some anesthetic complications, such as equipment malfunction and injuries from endotracheal intubation or misplaced drug injections, are common to all animals and can be prevented almost entirely by careful management. Other problems, such as pulmonary dysfunction and cardiovascular depression, seem to occur more often in healthy horses than in healthy members of other domestic species. Postoperative myopathy-neuropathy, sometimes a devastating complication, seems to be peculiar to the horse, and its incidence has been linked to hypotensive inhalant anesthesia. Careful positioning and padding, monitoring of anesthetic depth, and treating of cardiovascular depression may prevent most cases of postanesthetic myopathy. Idiosyncratic drug reactions, such as MH, are entirely unpredictable and can be rapidly fatal unless recognized early and treated vigorously and specifically.     

Lesions in sheep following administration of a vaccine of a Freund's complete adjuvant nature used in the control of ovine paratuberculosis

CASE HISTORIES: Occurrences of adverse reactions in seven sheep flocks in Australia following vaccination against paratuberculosis where veterinary attention was requested are reviewed. All cases occurred within the 3-year period following commencement of use of a vaccine of a Freund's complete adjuvant nature, at a time when approximately six million doses of vaccine had been administered.

CLINICAL FINDINGS: In the first case, 26/58 (45%) Merino sheep vaccinated as adults had palpable tissue reactions at or near the site of vaccination; enlarged prescapular lymph nodes were palpated in 17 (29%), and nine (16%) sheep had both palpable lesions at the site of vaccination and enlarged prescapular lymph nodes. The reactions included caseous nodules up to 5.5 cm in diameter. In the other cases, fistulating or granulomatous wounds were occasionally found at the recommended site of injection behind the ear, and myiasis was rare. Occurrences of inappropriate choice of injection site were recorded, including injection into the axilla of two Merino rams, and lesions in the tissues of the maxilla and nose of almost 50% of 350 Border Leicester lambs. Four outbreaks of progressive paralysis due to injection into cervical musculature were reported, described as ‘OJD staggers’ by producers.

DIAGNOSIS: Granulomatous cellulitis and lymphadenitis associated with oil droplets typical of ‘oil granulomata’. Injection of vaccine into the dorsal cervical area resulted in progressive paralysis due to myonecrosis and suspected granulomatous leptomeningitis.

CLINICAL RELEVANCE AND CONCLUSIONS: Although lesions at and near the site of injection are common, adverse reactions to vaccination were rare and included mortality from cervical spinal injection, production losses from injection in the maxilla or axilla or if myiasis resulted, and potential marketing losses if animals or carcasses are discounted as a result of the lesions. Risk factors for adverse reactions included inadequate restraint of sheep, breed of sheep, experience of the operator, poor injection technique, and inappropriate placement of vaccine. Increasing attention to the proper restraint of animals, restricting vaccination to the recommended site behind the ear, careful placement of the vaccine into subcutaneous tissue to avoid drainage of vaccine material into tissues such as the spinal cord, and post-vaccination supervision to address welfare concerns should adverse reactions occur are recommended.     

Lesions in sheep following administration of a vaccine of a Freund's complete adjuvant nature used in the control of ovine paratuberculosis

CASE HISTORIES: Occurrences of adverse reactions in seven sheep flocks in Australia following vaccination against paratuberculosis where veterinary attention was requested are reviewed. All cases occurred within the 3-year period following commencement of use of a vaccine of a Freund's complete adjuvant nature, at a time when approximately six million doses of vaccine had been administered. CLINICAL FINDINGS: In the first case, 26/58 (45%) Merino sheep vaccinated as adults had palpable tissue reactions at or near the site of vaccination; enlarged prescapular lymph nodes were palpated in 17 (29%), and nine (16%) sheep had both palpable lesions at the site of vaccination and enlarged prescapular lymph nodes. The reactions included caseous nodules up to 5.5 cm in diameter. In the other cases, fistulating or granulomatous wounds were occasionally found at the recommended site of injection behind the ear, and myiasis was rare. Occurrences of inappropriate choice of injection site were recorded, including injection into the axilla of two Merino rams, and lesions in the tissues of the maxilla and nose of almost 50% of 350 Border Leicester lambs. Four outbreaks of progressive paralysis due to injection into cervical musculature were reported, described as "OJD staggers" by producers. DIAGNOSIS: Granulomatous cellulitis and lymphadenitis associated with oil droplets typical of "oil granulomata". Injection of vaccine into the dorsal cervical area resulted in progressive paralysis due to myonecrosis and suspected granulomatous leptomeningitis. CLINICAL RELEVANCE AND CONCLUSIONS: Although lesions at and near the site of injection are common, adverse reactions to vaccination were rare and included mortality from cervical spinal injection, production losses from injection in the maxilla or axilla or if myiasis resulted, and potential marketing losses if animals or carcasses are discounted as a result of the lesions. Risk factors for adverse reactions included inadequate restraint of sheep, breed of sheep, experience of the operator, poor injection technique, and inappropriate placement of vaccine. Increasing attention to the proper restraint of animals, restricting vaccination to the recommended site behind the ear, careful placement of the vaccine into subcutaneous tissue to avoid drainage of vaccine material into tissues such as the spinal cord, and post-vaccination supervision to address welfare concerns should adverse reactions occur are recommended.     

Hog Cholera: III. Investigation of the Complement-Fixation Test for the Detection of the Virus in Swine Tissue

The complement-fixation test was investigated as a means of detecting hog cholera virus in spleen from experimentally infected swine. Various methods of extracting the tissue for production of antigen are described and emphasis is placed on the necessity of using the modified direct complement-fixation test to obtain reactions. The tissue should be obtained from animals showing advanced clinical manifestations of the disease. Preferably, the tissue should be maintained frozen or at least well refrigerated. The results indicate that tissue from dead animals or from breeding sows should be avoided. The 77 per cent positive reactions obtained suggest the test could be of diagnostic value provided two or three samples are obtained from the same herd.