Q:

3/14/2017
Inherited patient, 9yoM, on fire ant IT for 5 years. Initial reaction was multiple stings, cyanosis and loss of consciousness (anaphylactic shock) within 30 minutes. A single fire ant envenomation last year - delay of 30-40 minutes and then given Epi and observed at ED without any signs or symptoms (recommendation has been epi and ED for all exposures regardless of symptoms). He has been receiving (on average) twice monthly IT of 1:40,000 at 0.1mL over the last 5 years. Lack of progression due to irregular visits and a conservative approach - no previous shot reactions. Current tryptase is 4.0, Total IgE 106, and Fire ant IgE 10.6.

Any data/consensus on an exit plan for immunotherapy in this case? Is accelerated immunotherapy in this case reasonable? After review of practice parameters, I am stuck between considering him no longer at risk based on a recent sting history despite a positive sepcific IgE, and trying to accelerate to maintenance with consideration for indefinite or another 3-5 years therapy based on his severe initial reaction at 4yo with a negative skin or serology test still not being a definitive end point. Any insight on data which might help in decision making in this case?

A:

Inheriting patients on a treatment plan I may not have selected is a challenge for me. The severity of the initial reaction, cyanosis and loss of consciousness, coupled with the high level of specific-IgE would make me uncomfortable with discontinuing therapy and not considering him at risk. The venom content of individual ants varies during the course of the year and difficulties for patients in identifying culprit insects leaves me with uncertainty as to the degree of protection. Certainly, allergic patients will lose their allergy irrespective of therapy we offer. I suspect the low dose of whole body extract your patient is receiving is not contributing to any improvement he may or may not have experienced. Dose response to imported fire ant treatment is not well established due to the use of whole body extracts, but I am confident a 0.1mg of 1:40,000 w/v vaccine maintenance dose is not sufficient to provide much benefit. The duration of fire ant immunotherapy is also less defined than for venoms. I have copied excerpts from the 2016 Insect Allergy Practice Parameter for you to review.

Once initiated, venom immunotherapy (VIT) should usually be continued for at least 3 to 5 years. Evidence suggests that despite the persistence of a positive skin test response, 80% to 90% of patients will not have a systemic reaction to an insect sting if VIT is stopped after 3 to 5 years. There are no specific tests that can distinguish which patients will relapse after stopping VIT, but there is a higher risk in some patients than in others. Relapse is less likely with 5 years than with 3 years of VIT. Although most patients can safely discontinue immunotherapy after this period of time, some patients with a history of severe anaphylaxis with shock or loss of consciousness still might be at continued risk for a systemic reaction if VIT is stopped, even after 5 years of immunotherapy. For this reason, some experts recommend an extended duration of immunotherapy, possibly indefinitely, in such patients. Other criteria suggested for stopping VIT include a decrease in serum venom-specific IgE to insignificant levels or conversion to a negative skin test response. Some patients have relapsed despite negative venom skin test responses. Repeat skin (or venom-specific IgE serum) testing is not required for consideration of discontinuing VIT. Measurements of venom-specific IgG antibodies have no predictive value when discontinuing VIT. The decision on stopping VIT requires a context sensitive flexibility based on the available evidence and the preference of the patient."

"The optimal duration of fire ant immunotherapy is less well defined. Most allergists consider stopping fire ant immunotherapy after a specified period (usually 3-5 years) either empirically or only when skin or in vitro test results become negative. Until further data are available, a definitive recommendation about the duration of immunotherapy for fire ant sting allergy cannot be made. Less is known about the natural history of fire ant venom hypersensitivity and the effectiveness of immunotherapy than is known about other stinging insects. Fire ant whole-body extract has been shown to contain relevant venom allergens, and evidence continues to accumulate, despite the lack of any placebo-controlled study, to support the effectiveness of immunotherapy with fire ant whole-body extract. Recommendations for immunotherapy with fire ant whole-body extract are generally the same as those for VIT."

Duration in the discussion above assumes that a therapeutic dose is being administered. I know of no evidence that extended duration of subtherapeutic doses has any greater effect than placebo.

I would favor increasing the dose to a more effective dose and administer for the foreseeable future. If he experiences additional stings without reactions and completes 3 years of appropriate dose immunotherapy, I would consider discussing with your patient and family the possibility of discontinuing therapy. The high probability of repeat stings, assuming you and your patient are in an endemic fire ant area, and the severity of initial reaction could be used to justify lifetime therapy. I would recommend that epinephrine autoinjector be carried in case of multiple stings. I would consider extending maintenance interval to every 6 weeks to make more convenient after he has tolerated a therapeutic dose (0.3-0.5 ml of 1:10 or 1:100 w/v) monthly for 6-12 months. If he is unwilling to come to clinic often regularly, you might consider a cluster program ( see Ask The Expert archive question below ) to reach maintenance more quickly.

In summary, I would not discontinue immunotherapy or consider your patient protected despite the experience with the single sting. I would try to reach a maintenance dose of 1:10 or 1:100 and continue indefinitely at monthly or 6 week intervals.

All my best.
Dennis K. Ledford, MD, FAAAAI

Q: 9/1/2015
Are there any validated fire ant desensitization protocols that are not a rush protocol?

A: The simple answer to your question is “yes” since almost all the protocols used for fire ant are either weekly or biweekly gradual build up or cluster (2-3 injections per visit). Rush protocols are described with all insect allergy immunotherapy. I also have a question as to what you meant by “validated”, since most of the schedules are developed by consensus and not formal validation.

Quotes related to imported fire ant immunotherapy from the current 2011 practice parameters on insect allergy (revision available within the next year but I do not expect a change) [2011 Insect Allergy Practice Parameter] are:

“The dosage schedule for fire ant immunotherapy is less well defined in terms of starting dose and rapidity of buildup. Although most experts recommend a maintenance dose of 0.5 mL of a 1:100 wt/vol concentration—and there is increasing evidence that this dose is protective—a 1:10 wt/vol maintenance concentration has been recommended by some. The interval between maintenance dose injections can be increased to 4-week intervals during the first year of VIT and eventually to every 6 to 8 weeks during subsequent years. Rapid VIT protocols have been used successfully and safely to treat flying Hymenoptera and fire ant sting allergy and can be considered for routine use. “

“The dosage schedule for fire ant whole-body extract immunotherapy is less well defined in terms of rapidity of buildup. However, most authors recommend a once- or twice-weekly buildup schedule until a maintenance dose is reached, and the interval between doses can then be increased. Two examples of dosage schedules are included in Appendix E2. Successful use of a rush immunotherapy protocol has been published.59 Most reports have recommended a maintenance dose of 0.5 mL of a 1:100 wt/vol vaccine/extract with either Solenopsis invicta or a mixture of S invicta and Solenopsis richteri extract, although there are some recommendations for a dose as high as 0.5 mL of a 1:10 wt/vol extract.13-15,55,56,59,68 A survey of practicing allergists found that 0.5 mL of a 1:200 wt/vol extract is the most widely prescribed maintenance dose.55 Evidence continues to accumulate to support the efficacy of this dose.14,15,59 Special dosing might need to be considered for treatment failures.”

I would equate “rush protocol” with “rapid VIT protocols”. Thus, rush protocols for fire ant are available but are not routine or the standard of care. The “conventional” schedules are not validated but reflect the general standard of care (see Appendix E2 in the link above to the Practice Parameter).

In summary, there are a variety of protocols for imported fire ant but the conventional protocols are weekly or twice weekly build up and maintenance intervals of 4-8 weeks. A cluster program, similar to that used for pure venom immunotherapy, is also utilized as well as rush protocols. Systemic reactions with rush protocols using imported fire ant whole body extract are approximately 5-6% (Tankersley). None of these protocols or schedules are validated, i.e. legally or officially sanctioned or confirmed by specific evidence based studies.

Tankersley, Michael S., et al. "Safety and efficacy of an imported fire ant rush immunotherapy protocol with and without prophylactic treatment." Journal of Allergy and Clinical Immunology 109.3 (2002): 556-562.

Duplantier, John E., et al. "Successful rush immunotherapy for anaphylaxis to imported fire ants." Journal of Allergy and Clinical Immunology 101.6 (1998): 855-856.

Cox, Linda. "Accelerated immunotherapy schedules: review of efficacy and safety." Annals of Allergy, Asthma & Immunology 97.2 (2006): 126-138.

I hope this information is of help to you and your practice.

All my best.
Dennis K. Ledford, MD, FAAAAI

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