Allergen immunotherapy in people, dogs, cats and horses - differences, similarities and research needs.

In human patients with seasonal allergic rhinoconjunctivitis sensitized to grass pollen, the first successful allergen immunotherapy (AIT) was reported in 1911. Today, immunotherapy is an accepted treatment for allergic asthma, allergic rhinitis and hypersensitivities to insect venom. AIT is also used for atopic dermatitis and recently for food allergy. Subcutaneous, epicutaneous, intralymphatic, oral and sublingual protocols of AIT exist. In animals, most data are available in dogs where subcutaneous AIT is an accepted treatment for atopic dermatitis. Initiating a regulatory response and a production of "blocking" IgG antibodies with AIT are similar mechanisms in human beings and dogs with allergic diseases. Although subcutaneous immunotherapy is used for atopic dermatitis in cats, data for its efficacy are sparse. There is some evidence for successful treatment of feline asthma with AIT. In horses, most studies evaluate the effect of AIT on insect hypersensitivity with conflicting results although promising pilot studies have demonstrated the prophylaxis of insect hypersensitivity with recombinant antigens of biting midges (Culicoides spp.). Optimizing AIT using allergoids, peptide immunotherapy, recombinant allergens and new adjuvants with the different administration types of allergen extracts will further improve compliance and efficacy of this proven treatment modality.

Detection of complement-dependent lytic antibodies in sera from feline leukemia virus-infected cats by the chromium-51 release assay.

Sera from feline leukemia virus-infected cats lysed FL74 cells in the presence of an appropriate complement source; lysis was detected with the use of the 51 Cr release method. Serum complement from both rabbits and guinea pigs mediated lysis. Partial correlation of results was obtained from preliminary comparisons of lysis and immunofluorescence tests with the use of FL74 cells as targets.

Prospective study of bacterial overgrowth syndrome in eight dogs.

Eight dogs with cutaneous lesions, clinical signs and cytological findings compatible with bacterial overgrowth syndrome were compared with four healthy dogs. The affected dogs were treated for 28 days with 30 mg/kg/day cephalexin. The results showed that the syndrome was a superficial cutaneous disorder characterised by marked pruritus, greasy seborrhoea, offensive odour, erythema, lichenification, hyperpigmentation, excoriations and alopecia involving principally the ventral aspect of the body, but no papules, pustules, epidermal collarettes or crusts; it was caused by overgrowths of Staphylococcus intermedius all over the body surface. Histopathological findings included a superficial, perivascular, hyperplastic and spongiotic dermatitis with a mixed inflammatory infiltrate, but no lesions suggestive of a true pyoderma. In the affected dogs, anti-staphylococcal immunoglobulin G levels were high, but anti-staphylococcal immunoglobulin E levels were low, suggesting that staphylococcal hypersensitivity is not the underlying pathogenic process. The antibiotic treatment improved the condition of all the dogs, but five of the eight had an underlying allergic skin disease.

Characteristics and mortality outcomes of thrombolysis trial participants and nonparticipants: a population-based comparison.

OBJECTIVES: This study was done to compare characteristics and outcomes of patients with acute myocardial infarction participating in two thrombolysis trials with those of nontrial patients at study hospitals and external hospitals. BACKGROUND: Preferential recruitment of lower risk patients into randomized trials of thrombolysis has been suggested by earlier studies. However, to date there has not been a definitive population-based comparison of characteristics and outcomes for thrombolysis trial participants and nonparticipants. METHODS: Population-based data on hospital admissions and mortality from acute myocardial infarction for all hospitals in Ontario from 1989 to 1992 were linked to data on trial participants in two distinct thrombolysis studies (GUSTO I and LATE). Included were 1,304 patients entered into GUSTO, 12,657 nonparticipants at GUSTO hospitals, 249 patients entered into LATE, 5,997 nonparticipants at LATE hospitals and 12,299 patients at external hospitals. The main outcomes were differences in age, gender, comorbidity scores, coronary revascularization and survival to hospital discharge. RESULTS: Patients in both GUSTO and LATE were significantly more likely to be <70 years old (odds ratio [OR] 2.8 and 3.2, respectively), to be male (OR 2.0 and 2.1, respectively), to have low comorbidity scores (OR 2.0 and 2.3, respectively) and, for GUSTO alone, to undergo coronary revascularization (OR 2.4). Nontrial patients were similar between trial hospitals and external hospitals. In-hospital mortality rates for GUSTO and LATE patients were lower (6.9% and 6.6%, respectively) than for nonparticipants at study hospitals (16.8% and 19.7%, respectively; p<0.001 for both comparisons). Survival to hospital discharge remained higher among GUSTO (OR 1.9) and LATE patients (OR 2.0) than nonparticipants at study hospitals even after adjustment for age, gender, revascularization and comorbidity scores. CONCLUSIONS: Compared with nontrial patients, thrombolysis trial participants are younger, more often male, undergo more revascularization and have less comorbid disease. Even after adjustment for these factors, participants have a survival advantage over nonparticipants that is larger than expected from thrombolysis alone. These findings are not attributable to inferior care or skewed populations at hospitals that did not join these major trials. Further study of these selection biases may guide future trial design and deepen our understanding of why thrombolytics have been underused for high risk patients in routine practice.

Parkinsonism in Ontario: increased mortality compared with controls in a large cohort study.

BACKGROUND: PD was associated with increased mortality before levodopa therapy became available. There have been conflicting reports of PD mortality in the modern era. OBJECTIVE: To assess current mortality rates in a large unselected population receiving treatment for parkinsonism (PKM) followed for up to 6 years. METHODS: Cases were identified using linked administrative databases, including physician service and prescription drug claims, generated in Ontario's universal health insurance system. Control subjects were identified from the provincial registry of citizens and age and sex matched to cases. Comparative mortality was evaluated over the 6-year period of the study (1993/94 to 1998/99). The sensitivity of the findings was tested with differing case definitions. RESULTS: In 1993, 15,304 patients with PKM were identified and were age and sex matched to 30,608 control subjects (1:2 ratio). Over the study period, 50.8% (7,779) of the cases with PKM died compared with 29.1% (8,899) of the control subjects. The cases with PKM had an overall mortality odds ratio of 2.5 (95% CI: 2.4, 2.6) compared with the control group. Results were consistent whether cases were defined by physician diagnosis, use of anti-PD drugs, or both criteria. CONCLUSION: Despite modern drug therapy, PKM continues to confer a sharply increased mortality on unselected patients followed for several years.

Iron chelation in myocardial preservation after ischemia-reperfusion injury: the importance of pretreatment and toxicity.

Oxygen-derived free radicals have been implicated in myocardial ischemia-reperfusion injury. It has been proposed that deferoxamine, an iron chelator, improves myocardial preservation by reducing the iron-catalyzed production of the hydroxyl radical. The objectives of this study were to define the appropriate timing of iron chelation therapy and the dose-response properties of deferoxamine. Isolated working rat hearts were subjected to 25 minutes of normothermic global ischemia. Deferoxamine was given as pretreatment (n = 39; doses of 10 or 30 mg/kg), added to cardioplegic solution (n = 43; doses 0.46 to 1.90 mmol/L), or administered upon reperfusion (n = 52; doses 0.15 to 0.76 mmol/L) and compared with saline controls (n = 25). Deferoxamine pretreatment improved survival at each dose from a control value of 44% to 71% and 72% (p less than 0.05), respectively. A cardioplegia dose of 0.46 mmol/L improved survival from 48% to 75%. Higher doses reduced survival and implied a toxic effect. Reperfusion therapy did not alter survival. Regardless of time of administration, deferoxamine did not improve ventricular function or adenosine triphosphate levels. Deferoxamine given as pretreatment 1 hour before ischemia at doses of 30 mg/kg, and perhaps as low as 10 mg/kg, significantly improved survival. The addition of deferoxamine to cardioplegic solution was safe and may be protective at approximately 0.50 mmol/L; however, toxicity should be considered at concentrations greater than 0.76 mmol/L. These data support the postulate that iron catalysis is involved in the production of oxygen-derived free radicals during ischemia-reperfusion injury. We conclude that pretreatment before ischemia is an important component of iron chelation therapy in myocardial preservation.

Nicardipine: myocardial protection in isolated working hearts.

The effectiveness of the calcium antagonist nicardipine in protecting the ischemic myocardium was evaluated using the hemodynamic recovery of isolated working rat hearts subjected to hyperkalemic cardiac arrest followed by ischemia at 37.5 degrees C and 10 degrees C. Rat hearts (n = 51) received 20 mL of cardioplegia and were subjected to 27 minutes of ischemia at 37.5 degrees C. Group A (control) did not receive nicardipine. Groups B through F received nicardipine in the cardioplegia with total doses ranging from 2 micrograms to 6 micrograms. Group A had 46% survival of ischemia, whereas groups C (3 micrograms) and D (4 micrograms) had survival rates of 88% and 100%, respectively (p less than 0.05). The recovery of aortic flow after ischemia was 35% in group A, compared with 76% in group B (2 micrograms) and 81% in group D (p less than 0.05). Group A had 49% postischemic recovery of cardiac output, whereas groups B and D had 82% and 85% recovery (p less than 0.05). The postischemic recovery of stroke volume was 48% in group A compared with 84% in group B, 87% in group D, and 73% in group E (5 micrograms) (p less than 0.05). Additional rats were exposed to 210 minutes of ischemia (n = 41) or 240 minutes of ischemia (n = 56) at 10 degrees C. Control groups did not receive nicardipine, whereas treatment groups received nicardipine in the cardioplegia with total doses ranging from 1.4 micrograms to 6.4 micrograms. There were no significant differences in the survival of ischemia or the recovery of function after ischemia at 10 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Late results of aortic valvotomy for congenital valvar aortic stenosis.

Fifty-one patients, aged 1 to 18 years, having aortic valvotomy for congenital valvar aortic stenosis between 1956 and 1986 were followed up. The average age at operation was 11.5 years, with an operative mortality of 3.9%. The aortic valve gradient decreased from a mean preoperative value of 91 mm Hg to 27 mm Hg postoperatively. Current follow-up was 90% and averaged 16.8 years. Late cardiac mortality was 17.6%, with actuarial survival of 93.7% at 10 and 15 years, 81.8% at 20 and 25 years, and 70.9% at 28 years. Nineteen patients required reoperation (39%) at a mean of 17.7 years postoperatively, with a reoperation-free survival of 98% at 10 years. The reoperation rate accelerated in the following decade to 3.3% per year. Ten patients without reoperation were evaluated by continuous-wave Doppler echocardiography. The mean gradient was 21.6 mm Hg, and 90% had mild to moderate aortic insufficiency. This study confirms the efficacy of valvotomy in this age group and suggests that long-term survival and time to reoperation may be longer than previously reported.

Pulmonary venous aneurysm presenting as a middle mediastinal mass.

A large mediastinal mass in a 43-year-old man was proven at thoracotomy to comprise a right superior pulmonary vein aneurysm. Intraoperative transesophageal echocardiography was useful in defining the abnormality. Pulmonary venous aneurysm appears to represent an extremely rare but surgically correctable addition to the differential diagnosis of middle mediastinal masses.

Primary total hip arthroplasty with use of the modular S-ROM prosthesis. Four to seven-year clinical and radiographic results.

BACKGROUND: A multicenter retrospective study was conducted to determine the clinical and radiographic results of primary total hip arthroplasty with insertion of the S-ROM modular femoral stem without cement in a series of patients who had been followed for four to seven years. Four centers participated in the study, with one contributing surgeon at each center. METHODS: Two hundred and eight consecutive patients who had a total hip arthroplasty with implantation of the S-ROM femoral prosthesis at one of the four centers during the study period were identified. Twenty-nine patients were lost to follow-up or had incomplete radiographic data, and twenty patients died from causes unrelated to the index arthroplasty. The remaining 159 patients formed the basis of this study. Sixteen of these patients had a bilateral procedure, resulting in 175 hips with complete clinical and radiographic data. The average age of the patients at the time of the index operation was fifty-nine years (range, twenty-two to ninety-three years). The duration of clinical follow-up averaged 5.3 years (range, four to 7.8 years), and the duration of radiographic follow-up averaged 4.9 years (range, four to 7.3 years). RESULTS: One patient (0.6 percent) had a failed femoral component, which was evidenced by progressive subsidence and lack of bone ingrowth. In addition, two patients (1 percent) had a revision of the acetabular component. The average Harris hip score increased from 35 points (range, 10 to 76 points) preoperatively to 91 points (range, 52 to 100 points) at the most recent follow-up examination. The radiographic evaluation revealed that 172 hips (98 percent) had stable bone ingrowth, two hips (1 percent) had stable fibrous ingrowth, and one hip (0.6 percent) had unstable fibrous ingrowth. Periprosthetic osteolytic lesions were noted in twelve hips (7 percent). The lesions were observed in the femur in eight hips, in the acetabulum in two hips, and in both the femur and the acetabulum in two hips. All femoral osteolytic lesions were localized within the greater trochanter or the proximal-medial portion of the femoral neck. No osteolytic lesions were evident distal to the stem-sleeve junction. CONCLUSIONS: Use of the modular S-ROM femoral prosthesis yielded excellent intermediate-term outcomes with respect to standard radiographic and clinical criteria. The issue regarding the theoretical increase in the rate of osteolysis due to metal debris generated at the modular femoral stem-sleeve junction was specifically addressed. We found that the rate of osteolysis in this series was not notably higher than that in other series reported in the orthopaedic literature. Although many possible factors may influence the rate of osteolysis in total hip arthroplasty, this finding suggests that the potential increase in osteolysis theoretically associated with this modular femoral implant was not observed at intermediate-term follow-up. Although longer follow-up is warranted so that the potential for osteolysis can be evaluated fully, no osteolytic lesions were evident distal to the stem-sleeve interface at the time of intermediate-term follow-up. This finding suggests that there is a circumferential seal at the modular junction of the stem that prevents the distal egress of wear debris.

Development of an experimental model of Microsporum canis infection in cats.

An experimental infection model was developed for reliable induction of Microsporum canis skin infections in cats, using a defined number of macroconidia harvested from the fungus in culture. The strain of M. canis used produced highly fluorescent hairs under ultraviolet illumination. Kittens 8 to 9 weeks of age (n = 6) received 10(5) macroconidia applied topically to a closely-shaved area of skin. Sites were dressed with an occlusive bandage for 3 days, then grooming was restricted for an additional 4 weeks. Lesions were first observed 2 weeks after inoculation, enlarged over the following 6 to 8 weeks, then decreased in size and appeared healed at 12 to 14 weeks after inoculation. Cats often developed satellite lesions on the face, ears, or other body regions. The experimental infections strongly resembled moderately severe cases of naturally-occurring feline dermatophytosis in clinical patients. This experimental infection model will be useful for evaluation of topical and systemic treatments for feline M. canis infection.

The ACVD task force on canine atopic dermatitis (III): the role of antibodies in canine atopic dermatitis.

Although an important pathogenic role for IgE is established in the case of allergic asthma and rhinitis in man, its role in atopic dermatitis is less clear. There are many studies where allergists and immunologists have provided evidence in favour of such a role, whereas dermatologists are less than convinced. In dogs, however, there is an abundance of clinical evidence implying that atopic dermatitis is antigen driven, and recent studies suggest that there may be a role for IgE, not only in the effector pathway, but also in antigen capture. Although an IgG response often accompanies an IgE response in dogs with atopic dermatitis, there is little evidence in support of a pathogenic role in respect of the former isotype.

The ACVD task force on canine atopic dermatitis (IV): environmental allergens.

Numerous environmental allergens have been incriminated in the pathogenesis of canine atopic dermatitis (AD). These include dust and storage mite antigens, house dust, pollens from grasses, trees and weeds, mould spores, epidermal antigens, insect antigens, and miscellaneous antigens such as kapok. In this paper, we review the literature concerning the allergens that have been reported to contribute to canine AD. We conclude that attempts to identify the relevant canine antigens in the past have been plagued by a lack of standardisation of extracts and techniques, and the presence of false-positive and -negative reactions in allergy tests. Until these problems are rectified, it is unlikely that we will be able to provide a list of major and minor antigens for dogs. Hence, we recommend that future studies should be aimed at determining the major patterns of reactivity and cross-reactivity to specific protein allergens within antigenic extracts using electrophoresis and immunoblotting techniques. Once this information becomes available, it may be possible to use a selection of genetically engineered, highly pure antigens for both diagnostic and therapeutic purposes in canine allergy investigations. The use of such antigens will allow standardisation of canine allergy testing and immunotherapy so that the reliability and efficacy of these procedures can be objectively assessed.

The ACVD task force on canine atopic dermatitis (XII): the relationship of cutaneous infections to the pathogenesis and clinical course of canine atopic dermatitis.

Dogs and human beings with atopic dermatitis (AD) frequently exhibit concurrent skin infections with Staphylococcus sp. bacteria or Malassezia yeast, and treatment of such infections is an important facet of managing these patients. Staphylococci appear to colonize atopic skin readily, and bacterial products on the skin could augment cutaneous inflammation via immediate hypersensitivity responses to the bacteria, by superantigen-mediated lymphocyte activation, or other non-specific mechanisms. Similarly, skin colonization by Malassezia yeast could contribute to clinical signs of AD; yeast components could induce inflammation via non-specific mechanisms, such as alteration in mediator release, or via antigen-specific hypersensitivity reactions. Clinical and experimental evidence exists that secondary microbial infections can both initiate and perpetuate episodes of AD in dogs and humans, and could even participate in promotion of pro-allergic immunologic responses. Mechanistic details of these complex interactions are under extensive investigation in human beings; only a few observations have been extended to include dog with AD.

The ACVD task force on canine atopic dermatitis (XIV): clinical manifestations of canine atopic dermatitis.

Canine atopic diseases, including those with skin lesions, have been described for many years. Unfortunately, early descriptions often failed to establish definitive guidelines for considering a patient atopic, and criteria for diagnosing atopic dermatitis (AD) have varied from author to author. Larger case-series published from the 1960s to the 1980s suggested that the most common clinical manifestation of AD was pruritus, particularly of the face, ears, paws, extremities, and/or ventrum. It is not always clear that testing to eliminate other differential diagnoses was always carefully performed on patients in early reports; therefore, some descriptions could include patients affected with diseases other than or in addition to AD. Points of consensus regarding clinical manifestations of AD in case-series include the presence of pruritus beginning at a young age, possibly seasonally; and a prominent lesional involvement of the face, extremities, axillae or ventrum. Conflicting information on breed and sex predispositions is present, perhaps representing regional or temporal variability. Clinical reports vary, in regard to the description of lesions seen in dogs with AD. This reflects a possible confusion with lesions of secondary complications, and highlights the fact that the existence and nature of primary lesions of canine AD are not truly known.

The ACVD task force on canine atopic dermatitis (XV): fundamental concepts in clinical diagnosis.

The clinical signs of atopic dermatitis (AD) in man and in dogs are variable, and there is no single physical or historical feature that, if present, indicates the presence of AD. The initial diagnosis of AD is made clinically with the fulfillment of a combination of criteria that are strongly associated with the disease. Several schemes have been proposed in an attempt to define uniform clinical criteria for diagnosing canine AD, but no system is perfect. Once AD is considered as a possible diagnosis, other important differential diagnoses must be methodically eliminated from consideration. As a final step, once the clinician is certain that AD is probable, "allergy" tests may be conducted to provide additional evidence to "substantiate" the diagnosis. It is important to understand that allergy testing, in whatever form, is not appropriately used early in the patient evaluation as a screening test. Rather, it should be reserved, after a firm clinical diagnosis of AD has been made, to implement allergen avoidance schemes or to select allergens to be incorporated in immunotherapy formulations.

The ACVD task force on canine atopic dermatitis (XVI): laboratory evaluation of dogs with atopic dermatitis with serum-based "allergy" tests.

Serum-based in vitro "allergy tests" are commercially available to veterinarians, and are widely used in diagnostic evaluation of a canine atopic patient. Following initial clinical diagnosis, panels of allergen-specific IgE measurements may be performed in an attempt to identify to which allergens the atopic dog is hypersensitive. Methodology for these tests varies by laboratory; few critical studies have evaluated performance of these tests, and current inter-laboratory standardization and quality control measures are inadequate. Other areas where information is critically limited include the usefulness of these tests in diagnosis of food allergy, the effect of extrinsic factors such as season of the year on results, and the influence of corticosteroid treatment on test results. Allergen-specific IgE serological tests are never completely sensitive, nor completely specific. There is only partial correlation between the serum tests and intradermal testing; however, the significance of discrepant results is unknown and unstudied. Variation in test methodologies along with the absence of universal standardization and reporting procedures have created confusion, varying study results, and an inability to compare between studies performed by different investigators.

The ACVD task force on canine atopic dermatitis (XVII): intradermal testing.

Intradermal testing has been practiced for decades in human and veterinary medicine. The primary utility of intradermal testing is in the demonstration of IgE-mediated allergen hypersensitivity. The presence of a positive reaction on an intradermal test is not always indicative of allergy, as it may sometimes be an indication of sub-clinical hypersensitivity. Despite its widespread use by veterinary dermatologists, the usefulness of the intradermal test would be greatly enhanced by the use of standardized allergen extracts and homogeneous criteria for the interpretation of results. Irrespective of these shortcomings, intradermal testing is regarded as a valuable tool in the demonstration of allergen-specific hypersensitivity when performed according to accepted guidelines.

The ACVD task force on canine atopic dermatitis (XXI): antihistamine pharmacotherapy.

Antihistamines frequently are recommended by veterinary dermatologists for symptomatic treatment of pruritus associated with canine atopic dermatitis (AD), perhaps because of their moderate success in some human patients with AD. A critical review of the literature describing antihistamine use in canine AD reveals that the majority of published, peer-reviewed studies are open, uncontrolled or partially-controlled trials. Such studies vary widely in reported efficacy, from perhaps 0 to 75% of patients, even using the same drug. The few blinded placebo-controlled trials available have failed to confirm efficacy of these drugs to relieve the pruritus of canine AD. Some studies indicate that synergistic effects could occur with concurrent use of essential fatty acid supplements. Consequently, at the time of this writing, there is insufficient evidence to conclude for or against the efficacy of antihistamines for treatment of canine AD. Additional blinded, randomized and controlled trials with larger numbers of patients are necessary to establish which of the antihistamine drugs currently available, if any, are truly efficacious for canine AD. Nevertheless, present clinician consensus suggests that several different antihistamine drugs should be evaluated in sequence, for 7-14 days each, in canine patients with AD.

Concentrations of total serum IgE, IgA, and IgG in atopic and parasitized dogs.

Concentrations of total serum IgE, IgA, and IgG were measured in 36 atopic and 16 parasitized dogs, and compared them with 30 healthy control dogs. IgE was measured using enzyme-linked immunosorbent assay. IgA and IgG were measured using radial immunodiffusion assays. Mean total serum immunoglobulin (Ig) E concentrations in healthy, atopic and parasitized dogs were 7.1 units (U) ml-1, 5.8 U ml-1 and 14.3 U ml-1, respectively. Mean total serum IgA concentrations in the same groups were 103.3 mg dl-1, 63.2 mg dl-1 and 67.3 mg dl-1, respectively. Mean total serum IgG concentrations were 1066 mg dl-1, 1621 mg dl-1 and 1480 mg dl-1 in the three groups. There was no significant difference in IgE concentrations between these groups of dogs. IgA levels were significantly lower in atopic and parasitized dogs compared with healthy dogs (P < or = 0.05), whereas IgG levels were significantly higher in the atopic and parasitized dogs (P < or = 0.005). These results suggest that measurement of total serum IgE would be of no benefit in the preliminary clinical investigation of a suspected atopic dog. The lower IgA and higher IgG concentrations in both atopic and parasitized dogs suggest that similar regulatory mechanisms governing immunoglobulin synthesis occur in canine allergic and parasitic disease, promoting IgG synthesis but down-regulating IgA production.