Q:

9/10/2012
I have a retired male patient on immunotherapy for a number of years with sleep apnea who does not wish to discontinue immunotherapy and in the past 6 months had some fatigue/weakness. An EKG showed a. fib. He saw a cardiologist, was placed on Pradaxa, flecanide and Bystolic x 1 month and successfully cardioverted. He is now in sinus rhythm adn his Bystolic is being weaned. His last stress test was 15 years ago. He now has more energy, but doesn't wear his CPAP mask. Sleep apnea and ischemia are both risk factors for a. fib. He plans to get a stress test in the near future. Post cardioversion he now is reduced to 2.5 mg Bystolic. Bystolic is Beta-1 selective at doses less than or equal to 10 mg and non-cardioselective above this dose. He also is on an ACE inhibitor, Lisinopril.

Questions:
1) Is a cardioselective Beta blocker a contraindication to allergy immunotherapy even if administered at a low dose? Does being on an ACE inhibitor have an additive effect?
2) Is recent a fib a contraindication to immunotherapy in case Epi administration could cause the return of a fib, or exacerbate it if it came back unknowingly to the patient?
3) Would continuing immunotherapy be a risk in this or any patient with history of either current or past arrhythmia or current or past heart disease in general such as CAD, etc. even if the cardiac issue has been treated or corrected?
4) An unrelated question - when are asymptomatic asthma or COPD patients not allowed to get immunotherapy? Is there a cutoff FEV1?

A:

Thank you for your inquiry.

Before answering each of your specific questions, I need to make it quite clear that you will not get a definitive answer to any of the ones that you’ve asked simply because these issues are in essence matters of clinical judgment. The Guidelines are written quite carefully to state that in the final analysis, all that we can do is cite the available evidence in the literature dealing with these issues, but how to employ this evidence should remain in the hands of the individual physician conducting the immunotherapy. Also, each of these issues are dealt with in detail in Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter, third update. The Journal of Allergy and Clinical Immunology, January 2011; Volume 127 (1), Supplement, pages S1-S55. This document is available to you free of charge online through the Joint Council of Allergy, Asthma, and Immunology website, or via your subscription to The Journal of Allergy and Clinical Immunology. Since the issues are dealt with in detail, employing several paragraphs for many of the questions that you asked, I will not be able to copy and paste the entire discussion for you, but will copy only a few of the summary statements. I would suggest that you read the appropriate sections to gain insight into the reasons that the summary statements were made.

In addition, there are several entries on our “Ask the Expert” website which have dealt with some of the issues about which you are inquiring on Beta-Blockers and various contraindications to immunotherapy which deal with the principles involved in assessing such contraindications.

Having said that, I will deal with one of your last questions first. That is, is there a minimum baseline FEV1 recommended for starting immunotherapy in patients with asthma.

It is clear that the most severe non-fatal reactions to immunotherapy have occurred in patients with a baseline FEV1 of less than 70% predicted value. Therefore, recommendations have been made by some authorities that the cutoff for allergen immunotherapy be 70% of FEV1. In addition, FEV1 has been known to be a predictor for systemic reactions. In patients receiving rush immunotherapy, an FEV1 of less than 80% of predicted was found to be associated with an increased incidence of systemic reactions. However, I have not been able to find in either the 2007 or the most recent Allergen Immunotherapy Parameter any officially recognized cutoff point. A more detailed discussion of this can be found in the previous entry on this topic noted above.

But, in summary, to my knowledge there is no officially mandated cutoff level of FEV1 that would preclude immunotherapy. As noted, in the final analysis, the judgment remains in the hands of the physician administering immunotherapy, with recognition of the potential dangers stated above. These are discussed in more detail in the Practice Parameter under Summary Statement 32 on Page S21.

While we are on the topic of FEV1, your Question Number 4 also asks whether or not asymptomatic asthma or COPD patients are excluded from immunotherapy. Clearly they are not. The Parameters deal with the issue of asthma, and state that uncontrolled asthma is a risk factor for fatality, and that patients should be evaluated for the presence of asthma symptoms prior to the administration of an injection. Again, the nuances of this recommendation and the role of asthma severity in whether or not one should administer allergen immunotherapy are too detailed to present to you in-depth. This issue, however, is discussed in the Practice Parameters mentioned above. There is an entire section on “Special Precautions in Patients with Asthma”. There is also a table (Table Number 4) devoted to this issue.

In brief, the Parameters state that “Allergen immunotherapy in asthmatic patients should not be initiated unless the patient’s asthma is stable on pharmacotherapy.” Also the Guidelines state that “Allergen immunotherapy should not be initiated in patients with poorly controlled asthma symptoms.”

The issue of whether or not a patient with COPD, current or past arrhythmia, current or past heart disease in general such as coronary artery disease and recent atrial fibrillation, are all issues which fit under a generalized statement appearing in the aforementioned Guidelines. Once again, there is no “simple” or dogmatic approach to these issues. I think the wording of the Guidelines, since these words were carefully chosen, is the best way to approach your question. Since the wording is reasonably succinct, I have copied below the statement from the Guidelines for your convenience (Summary Statement 44).

"Summary Statement 44: Medical conditions that reduce the patient's ability to survive the systemic allergic reaction or the resultant treatment are relative contraindications for allergen immunotherapy. Examples include severe asthma uncontrolled by pharmacotherapy and significant cardiovascular disease. C

Alternatives to allergen immunotherapy should be considered in patients with any medical condition that reduces the patient's ability to survive a systemic allergic reaction. Examples include patients with markedly compromised lung function (either chronic or acute), poorly controlled asthma, unstable angina, recent myocardial infarction, significant arrhythmia, and uncontrolled hypertension. Under some circumstances, immunotherapy might be indicated for high-risk patients, such as those with Hymenoptera hypersensitivity and cardiac disease being treated with beta-blocker medications".

You can see from reading this, there is mention of conditions such as poorly controlled asthma, recent myocardial infarction, significant arrhythmias, et cetera. However, there are no mandates in this regard. The wording is quite clear that these are “relative contraindications” and that they “should be considered”. Therefore, once again, it would be left up to the prescribing physician to assess the risk/benefit ratio and discuss these issues with the patient. However, as noted above, having asthma itself is not a contraindication.

Finally, you asked about beta-blockers and ACE inhibitors. In my opinion, in regards to anaphylaxis, as you can see from my previous entry noted above, there is no distinction between cardioselective and non-cardioselective beta-adrenergic blockers in regards to anaphylaxis. For asthma, a cardioselective beta-blocker would of course be considered less risky than a nonselective beta-blocker. However, in anaphylaxis, we are not only dealing with pulmonary symptoms, but also with shock. In addition, the Guidelines do not make definitive distinction between cardioselective and non-cardioselective beta-blockers.

As far as anaphylaxis in general, I do feel that an angiotensin-converting enzyme inhibitor might prevent the patient’s compensatory response to anaphylactic shock. However, for allergen immunotherapy, there are no data to my knowledge to support restriction of the use of an ACE inhibitor. There is distinction in this regard between venom immunotherapy (where an angiotensin-converting enzyme inhibitor is contraindicated) versus allergen immunotherapy (where there is no present admonition in this regard).

There is, of course, as mentioned above, a far more nuanced and detailed discussion of the use of beta-adrenergic blocking agents as well as ACE inhibitors in the Parameters. In fact, there is an entire subsection devoted to this topic entitled “Beta-blockers and ACE inhibitors” under Summary Statement 37. This discussion is far too long to copy and paste here, but I think that you would find it quite helpful, in order to understand the rationale behind the above noted comment, to read this section.

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

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology