Q:

10/11/2013
42 year-old F with allergic rhinitis, asthma, fire ant allergy, history of anaphylaxis to flu vaccine and elevated tryptase 13.8 and elevated 24 urine PGD2 (normal urine histamine) consistent with mast cell activation disorder. She has been seen by Heme-Onc but bone marrow biopsy has not yet been performed. She was recently given her first fire ant injection of 1:100,000 at 0.05ml. Within 10 minutes developed hypotension, nausea, itching requiring treatment with IM Epi x 2, IVF and Benadryl. She was monitored in ER and received additional fluids and sent home. She takes ranitidine, Singulair, Allegra, Advair daily. She is very fearful of retrying fire ant IT but obviously really needs lifelong VIT.

My questions:
1. How would you retry fire ant IT? I have seen reports using rush fire ant IT in hospital with premedication with steroids and possibly Xolair.
2. She is currently on maintenance aeroallergen IT with good control. Would you continue with regular IT?

A:

Answer:
Thank you for your inquiry.

As a prelude to my response, in my opinion, I think you might get different answers to your questions from different experienced allergists-immunologists depending on personal experience. Clearly, there is no universally accepted response to part of your inquiry, and therefore no truly “right or wrong answer” in many respects.

Secondly, I think the best reference in which to base our response is our most recent update to the Joint Task Force Immunotherapy Parameter (Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter, third update. Journal of Allergy and Clinical Immunology, January 2011; Volume 127 (1), Supplement, page S1-S55). Thus, I have copied below sections that deal with the issues brought up by your patient.

As you can see, there is clear evidence that pretreatment with antihistamines can be helpful. However, your patient evidently was already taking fexofenadine at the time of the reaction. Thus the only thing one could do would be to increase the dose of antihistamine to be potentially helpful in this regard. The data on the use of antileukotrienes are inadequate to make a judgment. There are data on pretreatment with oral corticosteroids summarized for you, but they do not allow us a definitive conclusion, especially in regards to immunotherapy with fire ant.

The other possible pretreatment that could be of help would be with aspirin or a nonsteroidal antiinflammatory drug since your patient demonstrates an elevated 24 hour urine PGD2. However, as you know, the administration of aspirin or nonsteroidal antiinflammatory drugs to a patient with mastocytosis can also provoke episodes. But based upon a report by Butterfield and Weiler (see abstract copied below), aspirin can be very helpful in the management of patients with mastocytosis who exhibit elevated levels of prostaglandins. In addition, it has been shown that patients who have reactions to allergen immunotherapy can also exhibit increased levels of prostaglandins during the event (1).

I think that this is the best summary we can employ to help you evaluate the role of pretreatment with medications, and based upon the available evidence, there is a rationale for increasing the antihistamine dose, adding aspirin, giving a trial of oral corticosteroids, and perhaps less rationale for an antileukotriene. However, this is a moot issue since your patient is already taking an antileukotriene.

As you can see from the sections copied from the Immunotherapy Parameter, there is clear-cut evidence that omalizumab can be helpful in the prevention of reactions occurring during immunotherapy, and therefore it would be, in my opinion, a worthwhile adjunct.

The other question you posed was whether it might be helpful to hospitalize your patient and employ rush immunotherapy. This is certainly an option, but one that I have no experience with and therefore cannot give you any expert opinion in this regard. However, I have copied below the statement from the Cox, et al., immunotherapy reference dealing with rush immunotherapy using fire ant extract. I believe in this situation one could either proceed with rush immunotherapy or continue an attempt at standard office immunotherapy. The “restarting dose” again is a matter of conjecture, but in such situations, I usually start with a concentration two logs more dilutes than the concentration at which the reaction occurred. Of course, beginning with such a dilute concentration would make one more strongly consider the implementation of rush immunotherapy since it would be “quite a while” until which time a protective maintenance dose was reached using standard immunotherapy.

All of the above depends upon the implication that fire ant venom is very important in your patient, and I agree with your analysis that it is.

Finally, if your patient has been on allergen immunotherapy for a minimum of three years, I would strongly consider discontinuing it, and if not, I would give it on an alternate day. One would like to avoid any possible confusion, should a reaction occur, that it was unrelated to increased allergen load presented by giving both injections at the same time.

Thank you again for your inquiry and we hope this response is helpful to you.

Premedication and immunotherapy-induced systemic reactions

Premedication and weekly immunotherapy Summary Statement 56: Premedication might reduce the frequency of systemic reactions caused by conventional immunotherapy. A

There is concern that antihistamines might mask a minor reaction that would otherwise alert a physician to an impending systemic reaction if taken before an immunotherapy injection during a conventional build-up. However, one randomized controlled study demonstrated that premedication reduced the frequency of severe systemic reactions caused by conventional immunotherapy and increased the proportion of patients who achieved the target maintenance dose.299

In the post hoc analysis of a study designed to investigate omalizumab’s effect on the tolerability of cluster immunotherapy in patients with moderate-to-severe asthma, there was a similar incidence of systemic reactions in the patients who received antihistamine premedication compared with those who did not; however, use of antihistamines was not randomized but rather based on the physician’s discretion.300 Thus patients might still experience systemic reactions despite antihistamine premedication treatment. Because many patients might take an antihistamine as part of their overall allergy management, it is important to determine whether they have taken it on the day that they receive an allergen immunotherapy extract injection for consistency in interpretation of reactions. It also might be desirable that they consistently either take their antihistamine or avoid it on days when they receive immunotherapy. Other attempts to reduce the occurrence of systemic reactions, such as the addition of epinephrine to the allergen immunotherapy extract or use of concomitant corticosteroids, are not justified and might delay the onset of a systemic reaction beyond the waiting time when the patient is in the physician’s office, thus increasing the risk (see summary statements 57 and 58 for further discussion on premedication).

Premedication with accelerated immunotherapy schedules Summary Statement 57: Premedication before cluster and rush immunotherapy with aeroallergens might reduce the rate of systemic reactions. Combination therapy is effective in reducing systemic and local reactions during accelerated immunotherapy build-up protocols. A

Oral antihistamines
Oral antihistamines have been shown to be effective in decreasing local and systemic reactions during rush VIT protocols.223, 224, 225 Premedication with a nonsedating antihistamine (loratadine) 2 hours before the first injection of each visit reduced both the number and severity of systemic reactions during cluster immunotherapy with birch or grass pollen extract.222 Although rush VIT–induced systemic reaction rates are typically low,293, 295, 296, 297 some studies have demonstrated that the addition of antihistamines decreased the frequency of systemic reactions compared with placebo.225 Antihistamines also decreased the frequency of LLRs over the first 4 weeks of treatment compared with placebo, although the addition of ranitidine to terfenadine did not provide additional benefit compared with terfenadine alone.225 Two additional rush VIT studies demonstrated that antihistamine pretreatment decreased LLRs and cutaneous symptoms of pruritus, urticaria, and angioedema but did not decrease the frequency of respiratory, gastrointestinal, or cardiovascular reactions.223, 224 Finally, a retrospective study reported that premedication with terfenadine during rush VIT might improve efficacy because the treatment group had fewer systemic reactions to field stings and sting challenges over an average of 3 years.301 However, this finding was not confirmed on prospective study.302

The effect of antihistamines in decreasing local and systemic reactions when using conventional schedules has been less documented. Antihistamine pretreatment was demonstrated to decrease the frequency of severe systemic reactions in a study using a conventional build-up schedule.299 The effect of oral antihistamines on LLRs in this study was not reported, although the antihistamine group more frequently attained the target maintenance dose. No other study has reported the effect of antihistamines on LLRs or systemic reactions during conventional build-up or maintenance injections with inhalant allergens. For VIT, pretreatment with antihistamines did not reduce LLR rates during conventional monthly maintenance injections after they decreased LLRs during the initial rush protocol.224, 225

Leukotriene antagonists
A pilot study demonstrates that premedication with montelukast delays the onset and decreases the size of local reactions during rush VIT, but no controlled studies have investigated the effect of leukotriene antagonists on the incidence of systemic reactions.226

Combination pretreatment
Combination pretreatment with ketotifen, methylprednisolone, and theophylline used during a 3-day rush treatment with pollen immunotherapy decreased the frequency of systemic reactions.303 Premedication with prednisone, an H1 histamine receptor antagonist, and an H2 histamine receptor antagonist before rush immunotherapy with inhalant allergens reduced the risk of a systemic reaction from approximately 73% to 27% of patients.229 The number of local reactions were also decreased, as was the size of the erythema and but not the wheal.

During a 2-day imported fire ant rush protocol evaluating the effect of combination therapy with antihistamines and steroids, there were no statistically significant differences in systemic reaction rates between the premedication group (3.6%) and the placebo group (6.7%).124 However, a recent 1-day imported fire ant rush protocol involving 37 patients performed without premedication reported higher systemic reaction rates (24.3%) than the 2-day regimen, with most reactions involving urticaria and pruritus.298

Because the risk of a systemic reaction from rush immunotherapy with the flying Hymenoptera venoms is relatively low, routine premedication is usually unnecessary. Further studies are needed to clarify the risk of fire ant rush immunotherapy, and premedication might be considered.

Omalizumab in combination with immunotherapy
Summary Statement 58: Omalizumab pretreatment has been shown to improve the safety and tolerability of cluster and rush immunotherapy schedules in patients with moderate persistent asthma and allergic rhinitis, respectively. Additionally, omalizumab used in combination with immunotherapy has been shown to be effective in improving symptom scores compared with immunotherapy alone. A

Omalizumab used in combination with immunotherapy 2 weeks before and during the grass season was compared with immunotherapy alone. The combination therapy improved symptom load and asthma control, with more patients reporting good or excellent efficacy.304 Additionally, omalizumab added to standard maintenance doses of birch and grass immunotherapy resulted in decreased rescue medication use and symptomatic days compared with omalizumab or immunotherapy alone.305

In addition to symptom improvement, omalizumab has also been shown to reduce systemic reactions to rush immunotherapy. The use of omalizumab 9 weeks before and in conjunction with ragweed rush immunotherapy improved symptom severity scores during the ragweed season compared with immunotherapy alone. Furthermore, omalizumab pretreatment resulted in a 5-fold decrease in the risk of anaphylaxis during rush immunotherapy.306 Additionally, a prospective study examined the effect of 16 weeks of treatment with omalizumab or placebo on the incidence of systemic reactions during cluster immunotherapy in 248 subjects with asthma.300 Eligible subjects were required to have perennial asthma that was not well controlled despite inhaled corticosteroids and to be sensitive to cat, dog, and/or house dust mite. After 13 weeks of pretreatment with omalizumab or placebo, subjects received immunotherapy to 1, 2, or 3 allergens (cat, dog, and dust mite) through a 4-week cluster regimen, which overlapped with continued omalizumab/placebo treatment for 3 weeks. This was followed by 7 weeks of maintenance injections during which the omalizumab or placebo was not given. Compared with placebo, omalizumab pretreatment reduced the rate of systemic reactions during cluster immunotherapy from 26.2% to 13.5%. There were no systemic reactions during maintenance therapy.

There have been a few case reports regarding patients with bee venom allergy who were unable to tolerate VIT because of anaphylaxis but were subsequently able to tolerate VIT with omalizumab.307, 308 There is also evidence that omalizumab might improve the tolerability of VIT in patients with mastocytosis.309, 310 Although not specifically approved as a pretreatment for allergen immunotherapy, the use of omalizumab in these scenarios might be beneficial for high-risk patients. It should be noted that omalizumab has been associated with anaphylaxis in 0.09% to 0.2% of patients.311, 312

RUSH IMMUNOTHERAPY TO FIRE ANT
"Rush protocols for administration of flying Hymenoptera venom have generally not been associated with a similarly high incidence of systemic reactions.293, 295, 296, 297 There has been some conflicting data on the safety of rush immunotherapy with imported fire ant venom. One study demonstrated no significant difference between the premedicated and placebo-premedicated group during a 2-day rush protocol.124 In another study conducted at the same medical center, 24% of patients experienced a systemic reaction during a 1-day rush protocol that did not include premedication.298."

Int Arch Allergy Immunol. 2008;147(4):338-43. doi: 10.1159/000144042. Epub 2008 Jul 12.
Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production.
Butterfield JH, Weiler CR.
Source
Division of Allergic Diseases, Mayo Clinic, Rochester, Minn. 55905, USA.
Abstract
Background: Patients with systemic mastocytosis have increased numbers of mast cells in the bone marrow and other organs, such as the liver, spleen, gastrointestinal tract and skin. Symptoms result from the local and remote effects of mediator release from mast cells and from the local effects of increased mast cell numbers in various organs. Patients with mast cell activation experience many of the same clinical symptoms as do patients with systemic mastocytosis from chronic or spontaneous release of mast cell mediators. We report 4 patients with mast cell activation symptoms from selective release of prostaglandin (PG) D(2), but not histamine, and their improvement with aspirin therapy.
Methods: Bone marrow biopsy specimens obtained from 4 patients with symptoms suggestive of mastocytosis were examined by tryptase immunostaining. Baseline levels of serum tryptase and urinary 11beta-PGF(2)(alpha) and N-methylhistamine were obtained. In 2 of the 4 patients, urinary 11beta-PGF(2)(alpha) and N-methylhistamine samples were also measured during acute symptoms.
Results: Baseline increase in urinary excretion of the PGD(2) metabolite 11beta-PGF(2)(alpha) was found in 2 patients. In the remaining 2 patients, baseline levels of urinary 11beta-PGF(2)(alpha) and N-methylhistamine were normal, but during acute symptoms, the excretion of 11beta-PGF(2)(alpha) increased markedly. Treatment with aspirin resulted in normalization of 11beta-PGF(2)(alpha) excretion in the 2 patients with elevated baseline levels and in prevention of symptoms in all 4 patients.
Conclusions: These results suggest that mast cell activation may be manifested by a selective excessive release of PGD(2). These patients respond to administration of aspirin but not to antihistamines.

Reference:
1.Rank MA, et al. Systemic reactions to allergen immunotherapy: a role for measuring a PGD2 metabolite? Annals of Allergy, Asthma, and Immunology 2013; 110(1):57-58.

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology