Apoquel safety: how Apoquel is like fine wine – Part 2

By Jon Plant, DVM, DACVD

How much do we know about Apoquel’s safety? Quite a lot, I would argue.

Allergic dermatitis AEThe short-term safety profile, based on the data collected during multiple randomized-controlled trials at recommended doses looks good.  In a 28-day study of 436 dogs , the prevalence of diarrhea, vomiting, anorexia, and polydipsia were low (1.4-2.3%) and similar to the placebo-treated group (0-1.8%).  In most cases, the signs resolved with continued dosing of Apoquel. Similar results were found in other RCTs.

In a 28-day study of 123 dogs comparing Apoquel to prednisolone (0.5-1.0 mg/kg, once daily for 7 days, then every other day for 3 weeks), Apoquel compared favorably in terms of speed of onset, efficacy, and prevalence of adverse reactions.  In the Apoquel group, about 10% developed pyoderma, versus 6.5% in the prednisolone group.  This is probably not a statistically significant difference (6 dogs vs. 4 dogs) and a lower prevalence than I would expect in a population of dogs with allergic dermatitis. The prednisolone group had a higher prevalence of elevated liver enzymes (18%) than the Apoquel group (5%), as we might expect.  Three dogs (5%) in the Apoquel group were reported to develop Malassezia dermatitis. Other adverse events in this study were infrequent (0-2 dogs) in the Apoquel group.

Apoquel vs Atopica AEAn 84-day RCT comparing Apoquel to Atopica® (cyclosporine) in 226 dogs found that vomiting and diarrhea occurred with a greater frequency in the Atopica group (44 and 15%) than the Apoquel group (14 and 4%). I suspect that the higher rate of vomiting seen for Apoquel in this study compared to some other studies relates to its longer duration.  I have personally prescribed Apoquel for more than 50 dogs representing thousands of doses and have had very few clients contact our office regarding suspected adverse reactions.

So, if these clinical studies all sound good, why is there still concern amongst some about prescribing Apoquel? It stems from the target safety laboratory studies, often using 3 or 5 times the recommended dose, or giving it to young dogs, for which it is neither recommended nor approved. These are the studies that led to the recommended age restriction and dosing of a drug which admittedly represents a balancing act between the right amount and too much! Remember, Apoquel is like fine wine or anything else you are can overdo!

In the target safety studies, some of the concerning findings are dermatitis, interdigital furunculosis (apparently common in laboratory beagles), demodicosis (in 6-month old dogs), pneumonia (in young dogs treated with high doses), lymphadenopathy, decreased cellularity of other lymphoid tissue, and mild hematological effects.  Of the 4 dogs euthanized during the target animal safety studies, infection played a role in each.  Their Apoquel dosing for all of them was 6 to 12 times the recommended daily dosing and they all initiated treatment at less than 6 months of age.  Is this risk too great to use Apoquel?  I don’t think so. What if a pharmaceutical company was doing a similar target safety study as required by the FDA with prednisone, giving it at 6-12 times the recommended dose to young dogs for an extended period of time?  Wouldn’t you expect that we would see some immunosuppression related infections as well as other side effects?  Does that stop you from ever prescribing prednisone to alleviate a pet’s suffering? No, because you use the correct dose in practice!

Finally, what about the issue of neoplasia and cancer? It is thought that immunomodulating drugs can, in general, predispose patients (humans and dogs) to some forms of cancer, thus the FDA has certain labeling requirements concerning immunomodulating drugs. The Apoquel package insert carries a warning that Apoquel “may exacerbate neoplastic conditions.” There is no way to disprove this statement, so although no neoplasms were observed in the laboratory safety studies, and the causality of some of the tumors that developed in the field trials were ruled out based on a very short period of time between starting the drug and tumor diagnosis, the statement sticks. Here is the information available regarding the open-label, long-term continuation study (239 dogs) in the Freedom of Information Summary:

“Six dogs were euthanized because of suspected malignant neoplasms: including one dog each with thoracic metastatic, abdominal metastatic, splenic, frontal sinus, and intracranial neoplasms, and transitional cell carcinoma after 17, 120, 175, 49, 141, and 286 days of oclacitinib maleate administration, respectively. Two dogs each developed a Grade II mast cell tumor after 52 and 91 days of oclacitinib maleate administration, respectively. One dog developed low grade B-cell lymphoma after 392 days of oclacitinib maleate administration. Two dogs each developed an apocrine gland adenocarcinoma (one dermal, one anal sac) after approximately 210 and 320 days of oclacitinib maleate administration, respectively. One dog developed a low grade oral spindle cell sarcoma after 320 days of oclacitinib maleate administration.”

Ideally we would evaluate the prevalence of each diagnosis against a database of dogs with a comparator group with similar demographics.  But of course that isn’t readily available.  So we are left to consider whether the prevalence of neoplasia in these 239 dogs (5%) is unusually high. My local veterinary oncologist and I don’t find the prevalence unusual, although we don’t have all the demographic data that would help us evaluate it.

For the record, I do not have any financial conflicts of interest concerning Zoetis. I’m just a fan of Apoquel. For me, Apoquel is living up to expectations and I am very glad we can help out so many dogs. It needs to be used at recommended doses and under careful veterinary supervision. Let’s not forget how miserable it is to be itchy and how that negatively impacts quality of life and the human-animal bond!

In future posts I’ll discuss the patient monitoring that I recommend for Apoquel and how I incorporate it into my treatment with RESPIT to manage the underlying allergy. 

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Apoquel safety: how Apoquel is like fine wine – Part 1

By Jon Plant, DVM, DACVD

Apoqpinot-noir-glassesuel® (oclacitinib) is the new Zoetis drug for the treatment of atopic and allergic dermatitis in dogs at least 12 months of age. I’ve been prescribing Apoquel for almost 3 months now and I must say, wow, am I impressed with the efficacy! But, more on that another time.  My purpose today is to summarize some of the safety data on Apoquel.

Apoquel is a selective janus kinase (JAK) inhibitor.  JAKs are components of some cell receptors that receive instructions from other cells through molecules called cytokines.  There are many cytokines (interleukins and others) and different types of JAKs. By selectively targeting some of those involved in the itch and inflammation of allergic and atopic dermatitis, Apoquel reduces itch and inflammation, while having less of an impact on other aspects of the immune system.

How does Apoquel do this? It exerts its inhibitory effect on JAK-1 and JAK-3 at lower concentrations than it takes to inhibit JAK-2.  This is important because it allows the drug to target pruritogenic (creating itch) IL-31 and pro-inflammatory (IL-2, IL-4, IL-5, IL-6, IL-13) cytokines at concentrations lower than that at which it inhibits cytokines involved in hematopoiesis that are dependent on JAK-2 (IL-12, IL-23, EO, GM-CSF). It also means Selective JAK inhibitionthat we should follow the recommended dosing (0.4-0.6 mg/kg), even in those cases where it is not helping as much as we’d like.  Apoquel is like fine wine. Too little leaves you wanting more, but too much will make your head throb. The key is to aim for the sweet spot where we are inhibiting the “bad” cytokines but leaving the “good” cytokines to do their thing.

Apoquel appears to be safe when given with other medications. The risk of metabolic drug-drug interactions due to Apoquel inhibition of hepatic CYP450 enzymes is low, as it has minimal inhibitory effect on canine CYP450 enzymes.  The use of Apoquel concurrent with glucocorticoids, cyclosporine, and other immunosuppressive therapies is not recommended and hasn’t been investigated in any meaningful way so far.  There have been some (about 30 I believe is what I heard from a Zoetis dermatologist) patients in a long-term continuation study that did receive glucocorticoids for one reason or another, and no issues arose (this is how I remember it, at least).

The manuscript describing this long-term continuation study (the mean time on study = 402 days as of May 2013) was in preparation the last I heard.  A common concern expressed by veterinarians and pet owners alike is whether we know the long-term effects of this new drug. I suspect that we don’t know everything about it, but I do think that we know more than for most drugs that hit the market. When drugs are given to hundreds of thousands of patients after a drug is launched, uncommon adverse effects might turn up, such as toxicity due to a specific genetic mutation affecting its metabolism.  That is why the FDA requires drug companies to perform pharmacovigilence, monitoring for adverse reactions after going to market.  And why practicing veterinarians should take it upon themselves to report suspected adverse drug reactions.

More details in Part 2

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APOQUEL: will it live up to expectations?

Jon D. Plant, DVM, Dipl. ACVD

If you haven’t already, you will soon be hearing a lot about APOQUEL® for the management of allergic dermatitis and atopic dermatitis in dogs at least 12 months of age. APOQUEL® is a new drug from Zoetis that controls pruritus and inflammation by inhibiting janus kinase enzymes, and is therefore known as a JAK inhibitor.

APOQUEL significantly reduces itch within 24 hours, with continued improvement during the first 7-14 days of therapy. In clinical trials, APOQUEL-treated dogs with atopic dermatitis were evaluated after 28 days by the owners and veterinarians.  66% of dogs treated with APOQUEL and 4% of dogs treated with placebo were judged to have a significant reduction of itching.  Significant improvement was defined (in collaboration with the FDA) as a 2 cm reduction on a 10 cm pruritus visual analog scale (PVAS). Is this a case of what epidemiologist John Ioannidis calls “significance chasing?” Are the findings statistically significant, but clinically trivial?

The percent of dogs that achieved a “normal dog” level of itch (< 2.0 on the PVAS) has not been made available to us. This is, of course, the outcome measure than would mean the most to the owner of a pruritic dog, and the one that I am most interested in determining, even if the FDA was not.

I have had the opportunity prescribe APOQUEL to 20 dogs in the past 3 weeks, with follow-up examinations planned after 4 weeks of treatment. I’ve asked each owner to grade pruritus daily with the PVAS and am curious to see how many get into the “normal dog” range on the pruritus scale.  Will APOQUEL live up to the hype?  I hope so! But, I think we will all be more confident after we have some first-hand experience. APOQUEL is scheduled to be launched in January.

In my next post I’ll discuss the safety of APOQUEL and the patient monitoring that I am recommending to my clients.

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Veterinarian assessment of RESPIT for canine atopic dermatitis

Allergen-specific immunotherapy (ASIT) is frequently used to manage canine atopic dermatitis (AD). The selection of allergens for ASIT is based on intradermal testing (IDT), allergen-specific immunoglobulin E (IgE) assays, patient history, and aerobiological data. In theory, an optimal allergenic extract mixture would contain only antigens which elicit clinical signs upon natural exposure, but no others. There is no means of assessing how closely current practices approximate this optimal mixture. However, it is increasingly clear that the choice of allergy test technique, method or assay has the potential to influence the composition of ASIT.1

Despite poor agreement between testing techniques, the efficacy of ASIT does not correlate with a certain testing method or assay type.2 Our inability to discriminate between these allergen selection methods in terms of ASIT efficacy may reflect the paucity of prospective studies comparing ASIT based on different allergen selection techniques, or may indicate that they are indeed equivalent. If the techniques and methods that produce disparate test results are equivalent in terms of ASIT efficacy, this suggests that factors such as patient history, likely allergen exposure, and other parameters that may influence the antigens selected for ASIT (e.g. cross-reactivity) are as influential in determining the efficacy of an ASIT mixture as are allergy test findings. In this case, region-specific immunotherapy (RSIT) based on predicted allergen exposure may have efficacy similar to ASIT. This benefit could stem from the inclusion of some, if not all of the allergens to which a dog is sensitized, the influence of pan-allergens, or non-specific effects on the immune system.

There are two unpublished studies examining the efficacy of RSIT. In a double-blinded study, Garfield found a 76% “good” to “excellent” response rate to a stock mixture of 32 allergens in 29 dogs, not significantly different from those that received ASIT based on IDT results.3 In contrast, using a mixture consisting of four alum-precipitated allergens (house dust, dog dander, human dander, and grass mix), Willemse found that the response rate in 15 dogs was inferior to that obtained with ASIT.4 I would like to report the results of a survey of veterinarians who prescribed commercially-available RSIT mixtures that were selected based on a dog’s geographic location and predicted exposure rather than individual allergy test results.

All 160 veterinarians who had purchased the injectable form of RESPIT® (SkinVet Products, Lake Oswego, OR, USA) between March 2010 and September 2012 were contacted by mail in June 2013 and asked to review their patients’ records. Each aqueous allergen mixture contained 20 house dust mite and regional pollen antigens. Surveys were accepted up to a predetermined deadline of July 31. Veterinarians were asked to complete one survey per dog treated with RESPIT fulfilling defined inclusion criteria, estimating pruritus and lesion severity at Day 1 of RESPIT therapy and again at the time of the most recent follow-up examination.

Veterinarians graded the overall effectiveness of RESPIT for each dog on a categorical scale (poor = 0-24% reduction in itching, no reduction in additional medications; moderate = 25-49% reduction in itching, some reduction in additional medications; good = 50-74% reduction in itching, some reduction in additional medications; excellent = 75-100% reduction in itching, receives no additional medications).

Fifteen veterinarians completed surveys based on chart reviews of 50 dogs (24 males, 26 females, mean age of 6.7 years). Sixty-three percent of follow-up examinations took place during the months from April to September. No follow-up was available for 2 dogs. The majority of dogs had been treated for at least 12 months with RESPIT at the time of the follow-up examinations (median 382, range 27 – 920 days). The 15 veterinarians who completed the survey were located in seven states (California, Florida, Illinois, Nevada, Oregon, Tennessee, and Texas). The allergen mixtures were different for each of these states.

The median pruritus severity and lesion severity were lower at the time of follow-up than on Day 1 (Figure 1). PruritusLesions

Figure 1. (a) Pruritus severity and (b) lesion severity (median, range, interquartile range) in 48 dogs with atopic dermatitis pre-treatment and post-treatment with region-specific immunotherapy (RESPIT). The median interval between the two retrospective evaluations was 382 days.

Veterinarians assessed the overall efficacy as “good” or “excellent” in 69% of dogs evaluated beyond 90 days (29/42) and in 61% of all dogs treated (31/50). Adverse reactions (increased pruritus) were reported in 4/50 dogs resulting in the discontinuation of RESPIT in one dog.

The retrospective nature of this survey, the low participation rate and the likelihood of self-selection bias are significant limitations that affect the generalizability of these findings. It is, however, interesting that the response to RESPIT reported by 15 veterinarians for these 50 dogs is similar to the response rates often reported for ASIT in retrospective studies and for RSIT in the randomized-controlled trial by Garfield. Prospective studies are required to verify these findings.

1. Plant JD, Neradilek MB, Polissar NL, et al. Reproducibility of allergen-specific IgE assays and ensuing immunotherapy recommendations from four laboratories. In: Abstracts of the 26th Annual Congress of the ECVD-ESVD, 19-21 September 2013, Valencia, Spain. Veterinary Dermatology 2013;24:391.
2. Miller WH, Griffin CE, Campbell KL, et al. Muller & Kirk’s Small Animal Dermatology. 7th ed. St. Louis: Elsevier/Saunders, 2013;380.
3. Garfield R. Injection immunotherapy in the treatment of canine atopic dermatitis: comparison of 3 hyposensitization protocols. 8th Annual Members Meeting of the American Academy of Veterinary Dermatology & the American College of Veterinary Dermatology 1992;7-8.
4. Anderson R, Sousa C. Workshop report 7. In vivo vs. in vitro testing for canine aotpy. In: Ihrke P, Mason I,White SD, eds. Advances in veterinary dermatology. New York: Pergamon Press, 1992;425-427.

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Veterinarians recommend RESPIT

RESPIT, regionally-specific immunotherapy, is the practical allergy immunotherapy alternative that you can prescribe for atopic dermatitis in dogs and cats without allergy testing.  I recently conducted a survey of all 160 veterinarians who had prescribed RESPIT Injectable prior to September 30, 2012.  (That number is now over 500, but we wanted to hear from those that had had a chance to follow up patients for at least 9 months.)  I asked veterinarians to assess the efficacy and safety of RESPIT in each of their patients meeting certain inclusion criteria, and also asked some questions concerning their overall impression of RESPIT.  I am going to share the patient-specific information elsewhere, but here are the overall impression results from the 15 veterinarians who completed the survey.

  • 100% of veterinarians responded that RESPIT is equal to or more effective than allergy-test based immunotherapy.

Efficacy blue

  • 80% of veterinarians responded that they are very likely or extremely likely to recommend RESPIT to a colleague.

Recommend blue

  • 100% considered adverse reactions with RESPIT to be equal to or less frequent than with immunotherapy customized based on allergy test results.AE blue
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Why aren’t there more randomized controlled trials on allergy immunotherapy in dogs?

By Jon D. Plant, DVM, Dipl. ACVD

Long before I developed regionally-specific immunotherapy (RESPIT), I was interested in studying the efficacy of allergen-specific immunotherapy (ASIT) in dogs. Why? shutterstock_33136963 The only placebo controlled study on ASIT, although a noble effort, had some serious limitations.1 First, there were no validated outcome measures available to the investigators at the time. Ad hoc pruritus scores (0-9) and lesion scores (0-8) were combined into a single score. Whether or not the investigators accurately captured what they were trying to measure cannot be known.

Medications for the control of secondary infection were not permitted. And most importantly, there was no intent-to-treat (ITT) analysis performed. By the time (15 months) that a significant difference in clinical scores was found between the groups, only 5/24 dogs remained in the placebo group and 11/27 dogs remained in the treatment group. ITT analysis, whereby the last score of cases that dropped out is carried forward, may have led to a different conclusion.  Those that failed to respond would seem to be the most likely to have dropped out, so this is a significant flaw.

By 24 months, 5 dogs in the placebo group would be characterized as 100% improved at some point in the trial. This study also utilized a form of allergens (with an aluminum adjuvant) not generally used in the United States, where we use aqueous allergens in canine subcutaneous immunotherapy. So when dermatologists in the US cite this study as proof of what they are doing, that is taking some liberty.

I don’t mean to pick on this report, because it is the best that we have. It nicely illustrates, however, the challenge we face in trying to study immunotherapy. We’ve had to take some steps back before we could proceed.  I have gone through multiple fits and starts trying to design an immunotherapy study myself. One difficulty has now been surmounted.  We have validated methods for scoring canine pruritus and lesions in atopic dermatitis. But even the first validated lesion scoring system (CADESI-03) was so cumbersome (248 evaluations per dog) that it prompted me to develop a more rapid scoring system (CADLI) rather than begin an immunotherapy study with the CADESI-03.2,3  The International Committee on Atopic Diseases of Animals, on which I serve, is still working on a medication scoring system that would allow us to provide and account for much needed concurrent treatment during lengthy atopic dermatitis clinical trials.

Do we need more studies on ASIT?  I think so.  There is a good bit of variability in how veterinary dermatologists perform and interpret intradermal tests, which is bound to affect immunotherapy prescriptions.4  There is no consensus among us as to which serum allergy test (SAT) is more accurate (VARL Liquid Gold with lots of positive reactions in general, Heksa’s Allercept with few positive reactions and more altogether negative tests, Idexx/Greer’s Aller-g-complete with a medium number of positive reactions, or one of the other laboratories). Some dermatologists claim that IDT-based immunotherapy is more effective than SAT-based immunotherapy, while the 2010 Practice Guidelines of the ITFCAD (the ICADA precursor) states that either can be used as there is no strong evidence supporting one method over the other.5

The bottom line is that studying immunotherapy is difficult, but we are slowly getting the necessary tools in place to design more meaningful studies in the future.

1.            Willemse A, Van den Brom WE, Rijnberk A. Effect of hyposensitization on atopic dermatitis in dogs. J Am Vet Med Assoc 1984;184:1277-1280.

2.            Olivry T, Marsella R, Iwasaki T, et al. Validation of CADESI-03, a severity scale for clinical trials enrolling dogs with atopic dermatitis. Vet Dermatol 2007;18:78-86.

3.            Plant JD, Gortel K, Kovalik M, et al. Development and validation of the Canine Atopic Dermatitis Lesion Index, a scale for the rapid scoring of lesion severity in canine atopic dermatitis. Vet Dermatol 2012;23:515-e103.

4.            Hensel P. Differences in allergy skin testing among dermatologists within the same geographical region in the USA. Abstracts of the 7th World Congress of Veterinary Dermatology. July 24-28, 2012. Vancouver, Canada. Vet Dermatol 2012;23 Suppl 1:60.

5.            Olivry T, DeBoer DJ, Favrot C, et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol 2010;21:233-248.

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The efficacy of oromucosal or sublingual immunotherapy in dogs

by Jon Plant, DVM, DACVD

Two routes of administration may be used for allergen immunotherapy: subcutaneous injection or oromucosal  / sublingual.  The subcutaneous route has been in use in humans and animals for more than 50 years.  After an initial up-dosing schedule, maintenance injections are typically given every one to two weeks.

The sublingual route has been gaining favor in Europe for the past 15 years in human allergy practice.  It is now the predominant route of administration in some countries.  Numerous high quality studies have demonstrated that sublingual immunotherapy reduces symptoms and the need for medications without adverse effects.1  The degree of benefit is similar to that obtained with subcutaneous IT.

One of the primary functions of the mucosal immune system is to develop tolerance of foreign proteins that we (or our patients) ingest. The sublingual and buccal mucosa provide access to the privileged immune system of the oral cavity to induce environmental allergen tolerance.  The plentiful dendritic cells in the mucosa process antigens and present them to T-cells, which go on to modulate cytokines including IL-10 and TGF-β.  The oral mucosa displays unique immunological features which make it an attractive target for immunotherapy.

Several companies now offer oromucosal immunotherapy for dogs in the United States.  My company, SkinVet®, offers regionally-specific immunotherapy (RESPIT®), in a pediatric spray device for daily administration in the cheek of dogs.  Allergy testing need RESPIT Oromucosal Spraynot be performed first, as the allergens are standardized to the geographic region. (Read some of my previous posts to learn why I don’t ask my clients to spend their money on allergy testing). The build-up dosing schedule common to injection immunotherapy is not needed for RESPIT®  Oromucosal Spray therapy, because of the  wide margin of safety.

Two reports on oral immunotherapy in dogs were presented at the 2012 World Congress of Veterinary Dermatology in Vancouver, B.C.  In a laboratory model of canine atopic dermatitis, the clinical effect of allergen challenge in sensitized dogs was diminished after treatment with oromucosal spray immunotherapy.2  Corresponding cytokine changes were demonstrated in this University of Florida study.  The customized allergen extracts evaluated were produced by Nelco Vet, the manufacturer of RESPIT®.  It is sold under the name AllerPaws.

A third product is offered by Heska.  A large, uncontrolled case series by Doug Deboer  found clinical improvement and potentially meaningful changes in allergen-specific IgE and IgG in SLIT-treated dogs.2 The cases were enrolled by numerous veterinary dermatologists and extracts were customized based on the testing method of their choosing. Few details were presented regarding the testing actually used, but these presumably included intradermal testing with various techniques and serum IgE testing by various laboratories.  Yet, despite the variability in testing methods, the overall efficacy of the ensuing SLIT was still promising, if not definitively proven in this uncontrolled study.

The oromucosal spray or SLIT routes are nice options to have. That said, most of my clients still opt for once weekly injectable administration over daily oromucosal spray.

1 Radulovic S, Wilson D, Calderon M, et al. Systematic reviews of sublingual immunotherapy (SLIT). Allergy 2011;66:740-752.

2 Abstracts. Veterinary Dermatology 2012;23:2-104.

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Controlling Staphylococcus in the veterinary hospital

With the rapid emergence of methicillin-resistant strains of Stapylococcus pseudintermedius (MRSP), the potential for nosocomial infections should be addressed by every veterinary hospital with a formal, written infection control program.  Most of the control measures for MR staphylococci are applicable to control of many other pathogens. These recommendations are of particular importance when dealing with veterinary dermatology patients, which have a relatively high prevalence of MRSP infections in many geographic regions.

Here is a brief outline of the components of an infection control program of MRSP:

  1. Surveillance.  The most practical method of surveillance for veterinary hospitals is the passive surveillance of available data.  A step that all veterinary hospitals can readily implement is compiling all culture data in order to identify disease trends.  Environmental cultures, on the other hand, are a waste of resources.
  2. Cleaning and disinfecting the environment. Although we don’t yet know the role of environmental transmission of MRSP, it makes sense to treat the hospital as a possible source. Using disinfectants effective against methicillin-susceptible staph will kill MRSP as well.  Products should be used at proper dilutions and with adequate contact time. Take special care to clean after patients known or suspected to carry MRSP.
  3. Personal protective equipment.  Laboratory coats, disposable aprons and gloves are examples of PPE that is intended to prevent contamination of the wearer’s clothing or skin.  These items may be underutilized in veterinary hospitals because we are afraid to offend owners.
  4. Hand hygiene.  Either hand washing or alcohol-based hand sanitizers should be used before handling patients, after contamination of the hands, after removing gloves, and after patient contact.
  5. Patient flow and design. Ideally, dermatology patients, with a relatively high rate of MRSP infection, should be kept separate from other patient groups.  This is not feasible in many hospitals, but one should consider environmental cleaning of common areas after dermatology patients.
  6. Judicious use of antimicrobials. Exposure to antibiotics is a risk factor for developing MRSP.  Ideally, antibiotics are prescribed when needed, for only as long as needed, and at effective doses based on culture and susceptibility testing.

A more detailed infection control discussion is available at www.wormsandgermsblog.com/promo/services.

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Non-specific effects of immunotherapy in asthmatic cats

An interesting study pertinent to RESPIT was brought to my attention by my friend Dr. Dean Gebroe of Culver City Animal Hospital.  You may have noticed the capsule report in the September 2012 Clinician’s Brief entitled “One Allergen to Treat Another Allergy?”  Here is my summary of the original article:1

Hypothesis:  immunotherapy with allergens not completely matched to sensitizing allergen(s) in experimentally-induced feline asthma can reduce aberrant immune responses.

Methods:  In phase I, 19 cats were sensitized to Bermuda grass (BG), housedust mite (HDM), or given a placebo.  All cats then received BG immunotherapy for 6 months, beginning with a rush protocol. In phase II, 17 cats were sensitized to both BG and HDM, then received either placebo, BG, or HDM immunotherapy for 6 months.

Bronchoalveolar lavage fluid eosinophils, antigen-specific lymphocyte proliferation, number of IL-10 producing cells, and percentage of regulatory T-cells were measured.

Results:  Both BG and HDM immunotherapy resulted in significantly decreased eosinophilic airway inflammation in BG-sensitized cats (p < 0.001), but not the placebo controls (p=0.221).  In dually sensitized cats, single allergen immunotherapy with either HD or BG, but not placebo, significantly reduced airway eosinophilia (p = 0.038).  Differences in IL-10 and regulatory T-cells were found between cats receiving placebo and single-allergen immunotherapy.

Conclusions:  Immunotherapy with allergens which do not completely match the allergen(s) used in asthma induction provided some degree of cross-protection.  The mechanism may differ from that when immunotherapy is matched to sensitizing allergens.

Comment: These findings are similar to a study in humans which found that imperfectly matched immunotherapy can be beneficial in the management of rhinitis and bronchial hyperactivity.2 Thus, there is mounting evidence that some of the benefits of immunotherapy are, at least in part, non-specific. This may partially explain why standardized immunotherapy for canine atopic dermatitis is similar in efficacy to customized immunotherapy, and how widely discrepant allergy test results lead to similar immunotherapy efficacy.

1.            Reinero C, Lee-Fowler T, Chang C-H, et al. Beneficial cross-protection of allergen-specific immunotherapy on airway eosinophilia using unrelated or a partial repertoire of allergen(s) implicated in experimental feline asthma. The Veterinary Journal 2012;192:412-416.

2.            Marogna M, Spadolini I, Massolo A, et al. Effects of sublingual immunotherapy for multiple or single allergens in polysensitized patients. Ann Allergy Asthma Immunol 2007;98:274-280.

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Serum allergy test reliability in dogs

If you are recommending that your client spend several hundred dollars on an allergy test for their dog, it would be nice to have confidence that the test is reliable.  It should demonstrate both test-retest reliability (repeatability) and inter-lab reliability (reproducibility).  In human medicine, allergy testing companies are required to participate in an interlaboratory proficiency program using standardized serum pools. Unfortunately, such a program has not yet been adopted in veterinary medicine, although the International Committee for Atopic Diseases of Animals is working on it.  This leaves us with relatively little information about which serum allergy test (SAT) to recommend.

Over the years, most studies examining SAT reliability, including one I presented to the ACVD in 1994, have found most to be less reliable than desired. Since then, many of the companies have changed their methodology, although some do not readily disclose their anti-IgE antibody source or enzyme conjugate, which can profoundly influence results.

Two more recent studies have been published. Thom et al. evaluated the reliability of three independent European allergen-specific IgE testing laboratories all employing Heska techniques and reagents. In terms of differences in reporting positive versus negative reactions, they reported a 3% intralaboratory discrepancy rate and a 9% interlaboratory discrepancy rate for the 3 labs.  What I am unable to glean from this study, is how this would have differed from chance alone.  If positive reactions were either very common or very uncommon, that would have a significant effect on the expected agreement. The kappa statistic is often used to account for this, but was not reported in this paper.

In the second report, SAT results were compared between two labs that employ Greer macELISA methodology and also between Greer’s reference lab and Heska’s fceELISA test. Pools of sera were created from samples of known macELISA reactivity and duplicate samples submitted for each of the comparisons.  Agreement was reported in terms of percent concordance of positive and negative reactions, and it was found to exceed 90% for both interlaboratory comparisons. Kappa was not reported, nor was the proportion of the 18 serum pools that had high, intermediate, or low (negative control) reactivity.  Again, if the samples were skewed to very high or low reactivity, positive/negative agreement would look better than for samples with reactivity closer to the cutoff value.

Following the second report, I submitted duplicate samples from two atopic dogs, with one sample going to Heska and the other to Greer. From one dog, both samples were negative.  From the second dog, one of the samples showed no positive reactions, while the other lab reported several highly positive reactions to mites and one weed.  I have since followed up on this finding by evaluating the agreement of four commercial allergen-specific IgE testing laboratories, both in terms of reported positive allergens, and allergens recommended for immunotherapy by laboratory personnel. A colleague submitted four identical samples from each of four dogs to different laboratories. Since each lab tests for a unique set of allergens, I examined the results a) as tested (ungrouped) and b) treating similar or cross-reacting allergens as the same (grouped).  Figure 1 shows the total number of pairwise agreements and disagreements.

The relatively high number of disagreements compared to positive agreements results in kappa values that are for the most part in the poor range (< 0.2), with just 1/6 lab comparisons displaying agreement in the fair range for treatment recommendations.  I’m not able to present the entire study here, since I hope to publish it.

Another way of putting it, 81% of the allergens recommended for treatment for these four dogs in their treatment sets were recommended by only one of four laboratories, and just 4% were recommended by 3 or 4.

My bottom line:  if you choose to send in a blood sample for serum allergy testing, your choice of labs has a major influence on their immunotherapy prescription recommendation, yet we don’t know which test is more accurate. Most clients are not keen on spending hundreds of dollars on a test if given that bit of information.

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