Q:

10/4/2013
I have a two part question.

First question - Oral antihistamine tachyphylaxis

Is oral antihistamine tachyphylaxis a clinical problem?

I am continuing to see new patients in my clinic who have been told by primary care or others that oral antihistamines should not be used daily for prolonged periods because patients lose sensitivity to these medications over time. As best as I have been able to tell the only evidence for this idea is approximately 20 or so years old and involved a few poorly controlled studies with first generation H1 antagonists looking at central nervous system sedation and lower airway responses only. As far as I am aware there have been multiple larger and better controlled studies and analysis over the past 20 years that have looked at all manner of outcomes from wheal and flare, histamine release assays, receptor binding, symptom scores, intranasal challenge responses, etc that have long since discredited this idea.

Further I have never read a professional society position statement from any Internal Medicine, Pediatric, Allergy, ENT, or Dermatology society suggesting that tachyphylaxis is a concern for second generation H1 use or that chronic H1 use should be avoided in otherwise uncontrolled moderate to severe allergic disease with suboptimal response to nasal steroid, immunotherapy, or other targeted therapies.

Are you aware of any support for the idea that chronic second generation oral antihistamine use causes tachyphylaxis or should be avoided?

Second Question - The use of clinic spirometry alone, without any other clinical criteria, to guide diagnosis and management of asthma.

Should office spirometry results be used as an absolute and unassailable standard for asthma diagnosis and treatment, or is there a role for clinical judgment and therapeutic trial as well?

We have many patients with respiratory symptoms consistent with asthma that have no specific evidence of significant obstruction on clinic spirometry but show marked improvement in there clinical symptoms including cough, wheeze, SOB, ER visits, etc, on trials of ICS therapy (with or without LABA), sometimes with long term resolution of symptoms after completion.

Some of these patients have not had pre/post bronchodilator or challenge evaluations before the therapeutic trials are started for a variety of reasons including age, comorbidities, or other reasons including not being willing or able to go to a separate center for full pulmonary function or challenge analysis in our rural, high volume and high uninsured area.

Some of these patients may have only restriction on spirometry that resolves after their ICS trial. Some of these trials last many months because we are sometimes not able to see some patients back in clinic as often as we would like, or patient compliance issues increase the duration between visits.

It has been occasionally suggested by some not familiar with the details of each patient’s case that if patients don’t have irrefutable evidence of asthma by clinic spirometry they should not be on trials of ICS regardless of their clinical history. And if they are on an ICS trial that they should be stepped down every 1-3 months, a frequency of visits sometimes not possible with our practice volume or patient compliance, citing ATS guidelines.

Given the multiple variables associated with accurate performance and interpretation of clinic spirometry in the context of multiple patient medical history variables, acute illness, comorbidities, practice, staff, and equipment limitations, and many other factors, is there any role for clinical judgment or therapeutic trial as adjuncts to strict interpretation of clinic spirometry in patients with asthma symptoms?

A:

Thank you for your inquiry.

Re: Question 1:
You are correct; clearly, the weight of evidence in the literature indicates that tachyphylaxis does not occur with antihistamine treatment. For your convenience, copied below are some studies which illustrate this point.

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

Otolaryngol Pol. 2007;61(5):898-901. doi: 10.1016/S0030-6657(07)70551-6.
[Does new antihistamines characterize tachyphylaxis phenomenon?].
[Article in Polish]
K³os K, Kruszewski J.
Source
Klinika Chorób Infekcyjnych i Alergologii CSK MON Wojskowego Instytutu Medycznego w Warszawie.
Abstract
The Aim: of the Study: was to estimate the skin microcirculation reactivity after histamine administration in patients treated with 10 mg daily dose of cetirizine for 180 days.
Material and Methods: Thirty seven young men age 27+12 year, patients suffering from persistent rhinitis were randomized into three groups which received 10 mg/day of cetirizine, 5 mg/day of levocetirizine or placebo respectively. Twenty eight completed the study. The skin microcirculation reaction after 10 mg/ml histamine administration was estimated visually on the forearm (diameter of wheal and flare) and by laser Doppler flowmetry before and after study drug or placebo administration 24 hours and every 30 days during the time of the study. The blood flow was measured by Periflux PF3, using a skin probe 5 mm away from the histamine-induced point.
Results: Statistically significant inhibition of skin reaction (over 92%) and blood flow (over 85%) in relation to the start values in cetirizine group as well as between the groups which received cetirizine or placebo (p<0.001), remained at the same level all the time during the examination.
Conclusion: Tachyphylaxis phenomenon for antihistamine effect of 10 mg/day cetirizine and 5 mg/day levocetirizine was not observed during the whole 180-days treatment.

Pol Merkur Lekarski. 2005 Dec;19(114):758-60.
[Inhibition of histamine-induced wheal, flare and doppler laser flowmetry during long-term (180 days) of cetirizine 10 mg per day treatment].
[Article in Polish]
Kruszewski J, K³os K, Su³ek K.
Source
Wojskowy Instytut Medyczny CSK MON w Warszawie, Klinika Chorób Infekcyjnych i Alergologii.
Abstract
The Aim: of the study was to estimate the skin microcirculation reactivity after histamine administration in patients treated with 10mg daily dose of cetirizine for 180 days.
Material and Methods: Twenty six patients suffering from persistent rhinitis (28+11 years) were randomized into two groups which received 10 mg/day of cetirizine or placebo respectively. Twenty patients completed the study. The skin microcirculation reaction after 10 mg/ml histamine administration was estimated visually on the forearm (diameter of wheal and flare) and by laser Doppler flowmetry before and after study drug or placebo administration 24 hours and every 30 days during the time of the study. The blood flow was measured by Periflux PF3, using a skin probe 5 mm away from the histamine-induced point.
Results: Statistically significant inhibition of skin reaction (over 90%) and blood flow (over 80%) in relation to the start values in cetirizine group as well as between the groups which received cetirizine or placebo (p<0,001), remained at the same level all the time during the examination.
Conclusion: Tachyphylaxis phenomenon for antihistamine effect of 10 mg/day cetirizine wasn't observed during the whole 180-days treatment.

Ann Allergy. 1986 Oct;57(4):253-6.
Suppression of histamine-induced wheal response by loratadine (SCH 29851) over 28 days in man.
Roman IJ, Kassem N, Gural RP, Herron J.
Abstract
Five groups of 12 healthy volunteers each received in double-blind, randomized fashion oral b.i.d. doses of 10, 20, or 40 mg loratadine, 12 mg chlorpheniramine maleate (CTM), or placebo for 28 days. Histamine and saline were injected intradermally into opposite arms at baseline and at specified times following treatment on days 1, 3, 7, 14, 21, and 28. Notable suppression of adjusted wheal formation (histamine-induced minus saline-induced) occurred within two hours after the first dose of each active treatment on day 1. In general, throughout the treatment period, suppression of adjusted wheal formation by all doses of loratadine was significantly greater than by placebo. Suppression by 10 mg loratadine was comparable to CTM, and 20 and 40 mg loratadine were significantly greater than CTM. Suppression of wheal formation by loratadine during the treatment period and during five days posttreatment were dose related. The continued effectiveness of loratadine throughout the 28 days suggests that tolerance to loratadine did not develop in this study. Sedation occurred in 8 of 12 subjects receiving CTM, 1 of 12 receiving 10 mg loratadine, and 1 of 12 receiving placebo.

Also, thank you for your second question.

Re: Question Number 2:
There are volumes written about this issue. However, what I personally feel is the present standard guide that deals with this issue is the NAEPP3 (the National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program). This document is available at no charge online.

It can be searched by word. That is, right-clicking on the document will allow you to pull down a menu entitled “Find”. You can then type in the search word (e.g. spirometry) into the search box, and every sequential entry for that word will appear.

As expected, there are a number of entries dealing with spirometry. The first is under Section 3, with an entire subchapter on “pulmonary function testing (spirometry).” There is another section on spirometry under “monitoring pulmonary function,” and this section also includes peak flow monitoring. Much of this is summarized and quite easily seen in Box 32 entitled “importance of spirometry in asthma diagnosis.”

Then there are a number of sections on the use of spirometry to grade severity. Although it may initially seem like a daunting task to pull up all of these entries, it can actually be done quite easily and would probably take less than an hour or so of your time.

Basically, the expert panel recommends that spirometry measurements be taken at the time of the initial assessment, after treatment is initiated and symptoms and peak expiratory flow have stabilized, during a period of progressive or prolonged loss of asthma control, and at least every one to two years to assess maintenance of airway function. They also state that spirometry may be indicated more often than every one to two years depending on the clinical severity and the response to management.

The document itself goes through, in greater detail, the reasons for obtaining spirometry.

Thus, there is no question that performance of spirometry based on both expert opinion and the best evidence available, is a key element in the ideal care of the asthmatic. However, it is necessary to put these statements into perspective in relationship to your specific question and your practice environment. Spirometry or no other study or single means of an evaluation is ever “an absolute and unassailable standard for asthma diagnosis and treatment.” There is always room for “clinical judgment and therapeutic trial.” That stands true for any disease in medicine, and is of course not the issue in question. The issue in question is, what is the best and most desirable tool or tools for diagnosis and treatment, and at this time, FEV1/FVC certainly vies for that spot.

So, given a single tool, it is, at least at this time, the most time-tested objective measurement. It is simply done and studies have shown that results, if the test is performed properly, are highly reproducible. Usually it can serve this function in children over the age of 6 years. Thus, under ideal situations, it would be your best choice to accompany your clinical judgment and clinical trials with objective assessment if possible. And if you chose a single objective assessment, I believe the consensus of opinion would say that office spirometry would be the ideal choice.

There are more reasons to do spirometry than just to help one make “an irrefutable diagnosis.” We know, for example, that asthmatics are more prone to loss of lung function over time and that this can occur insidiously unbeknownst to both patient and clinician.

But, coming back to the situation in your practice, one of the issues that always affects the decision to perform a test is cost. For example, the weight of evidence supports the use of FENO as another viable measurement to diagnose and manage an asthmatic. However, in many instances, this test is not reimbursable, and therefore is probably used far less than it would be employed under reimbursable conditions. So, economic factors and other issues as you expressed in your question do limit, not infrequently, the ability to perform tests which have clearly been shown to be helpful, and which under ideal situations should be used. The only person who can make this judgment is the physician in charge of caring for the patient, who is aware of the “insurance climate” and other economic issues. Therefore one can sympathize with your inability to obtain spirometry and your reluctance to employ it. But the failure to use it cannot be based upon the fact that it would not be helpful. It is universally accepted as indicated. You could only justify its exclusion on the basis of social or economic issues.

Thank you again for your inquiry and we hope this is of help to you.

Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology