Antigen and methacholine children with asthma Hyman

ANTIGEN

Chai, M.D., F.R.C.P.(Edin.),

D.C.H.(Lond.)

CHALLENGES

Antigen inhalation challenges for clinical use have 2 essential purposes in my view. One of these, and perhaps the most important, relates to whether the ultimate goal of therapy is directed toward immunotherapy. The second establishes that the lung either is or is not a target organ, regardless of whether the skin test has demonstrated the presence of specific IgE to the antigen. It follows, therefore, that there should and must be clear-cut indications for antigen challenges, which are not without considerable risk in sensitive individuals. Any asthmatic, who clearly has a seasonal history related to his skin tests, probably does not require any antigen challenges. The role of the challenge is essentially twofold-first, the initial confirmation of the lung being sensitive to the antigen and hence responding as bronchospasm; second, following immunotherapy, the response to another challenge would provide pertinent information as to whether the therapeutic procedure (immunotherapy) is having the required benefit over time and hence whether or not the therapy should be continued. In the case of the patient who has clear-cut seasonal symptoms, related to his skin tests and to few of any other nonimmunologic precipitant mechanisms (parasympathetic hypersensitivity, exercise, cold, hyperirritability of the airways to nonimmunologic stimuli, etc.), antigen challenges should be unnecessary. The clinical and physiologic responsiveness during the next appropriate season would be sufficient to demonstrate the effectiveness of immunotherapy or the lack thereof. However, in those asthmatics in whom clear evidence of an immune system involvement is not apparent, despite positive skin tests, because of a noncorrelating history (such as a lack of increasing asthma during high pollen seasons or the presence of perennial asthma, making clear definition of a particular allergen difficult), antigen challenges may be the only

From the National Asthma Center. Reprint requests to: Hyman Chai, M.D., National Asthma Center,

1999JulianSt., Denver,CO 80204. 0091-6749/79/130575+05$00.50/0

challenge

0 1979 The C. V. Mosby

Derwr,

in

Cola.

procedure available to define the lung as a target organ related to the skin tests. If the allergic picture is so unclear, it could legitimately be argued that even if immunotherapy is indicated, the clinical effectiveness of a response or lack thereof would not be apparent because of the presence of multiple other nonimmunologic factors that might dominate the picture. This would be an acceptable argument if long-term corticosteroids were not included in medication required for control. The utilization of immunotherapy to remove one precipitant might be all that is necessary (should the immunotherapy succeed) to either remove steroids from therapy, maintain steroid therapy on an every-other-day basis if total removal is impossible, or, at worst, reduce the amount of steroids required. Immunotherapy would thus appear to be justified in some situations. Inhalation antigen challenges may be essential for delineating the lung as a responding target organ. METHACHOLINE (OR OTHER SIMILAR ANALOGUES) There are limited clinical indications for inhalation challenges to methacholine (or carbachol, acetylcholine, etc.). The major clinical indication is to determine, when doubt exists, whether the individual being treated is, in fact, an asthmatic. This arises when subjects demonstrate abnormalities in lung functions that are poorly or totally unresponsive to maximized therapeutic procedures. Additive medication varying from theophylline, a /3,-sympathomimetic, to cromolyn sodium, to inhaled and oral steroids in any combination might be used without much success in reversing obstruction. Sensitivity to inhaled methacholine in relatively small doses would be highly suggestive of the presence of at least an asthmatic component. Methacholine is used predominantly in research as a marker of airway lability. It is this latter aspect to which this paper is directed. BASIS FOR THIS STUDY Two events provided the opportunity to examine antigen and methacholine inhalation challenges seCo.

Vol. 64, No. 6, Part 2, pp. 575-579

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Chai

TABLE

I. Amount of inhaled methacholine

required to cause a sustained fall in FEV, of 25% or greater Methacholine

Premeasles Subject

Last wk

B. M.

0.375

P. R. A. S. c. I.

0.375 0.875 1.375

vaccine 2nd wk

0.300 0.400 0.875 1.250

CLIN IMMUNOL DECEMBtR 1379

(mg) Postmeasles

vaccine

1st wk

2nd wk

3rd wk

4th wk

9th wk

0.325 0.325 0.650 0.925

0.265 0.250 0.635 0.725

0.273

0.150

ND*

ND”

0.500 0.375 0.625 0.9so

0.215 0.700

0.275 0.320

From Molk and Kumar.’ *Test was not performed. Subject was clinically wheezing on both weeks.

quentially over a period of time. The ,ficvr was an investigation by Molk and Kumar,’ at this Center, of the sensitivity to inhaled methacholine in 4 subjects who had received measles vaccine in an effort to determine whether the vaccine itself (being a live, attenuated virus) would increase the sensitivity of the airways to inhaled methacholine. All subjects were children, and prior to the administration of vaccine, they were challenged twice with methacholine inhalation and thereafter each week for the first 4 weeks, with a final challenge at 9 weeks, a total of 5 challenges. The data are shown in Table I. All 4 subjects showed markedly increased sensitivity to inhaled methacholine, steadily increasing until the fourth week and recovering to normal values in 2 subjects (B. M., P. R.) and approaching baseline recovery in 2 others (A. S ., C. L.) (but still below prevaccine levels). The .srt~~rrdwas based on a clinic,ai finding some years later that did not match these initial postvaccine results. An outbreak of measles occurred at this Center, and despite a great deal of clinical evidence of bronchitis associated with the measles, asthma based on clinical and pulmonary function grounds was generally conspicuous by its absence. The unexpected clinical lack of asthma suggested that during the measles infection, these subjects’ airways were much less sensitive to external insult. The viruses, of course, were presumably different because of attenuation in the vaccine and virulence in the clinical outbreak.

target organ to antigen; therefore, regardless of whether other nonallergic mechanismsareoperative (parasympathetic,” exercise,” cold exposure, nonspecific irritation, etc.) immunotherapy might assist in alleviating part of the airway obstruction. Thus the 4 subjects (Figs. 1 to 4) had been tested with both methacholine and allergen before measles

occurred. and a baseline was available. With the consent of parents and the patients. IO days after cessationof symptomsof measles.weekly inhalations to methacholine and antigen, which had previously been positive at low concentrations, were repeatedat weekly intervals in order to determine(1) whether there had beenany change from the baseline premeasles data and (2) the degree of increaseor decreaseof sensitivity over time.

Method Challenges to antigen and methacholine were performed in a standard fashion at the time of the study. but as this had

occurred prior to the standardization recommendedby the committee on inhalation challenges of the American Academy of Allergy (AAA),’ this method was not used. The procedure used for this study was the same used for hun-

dredsof routine inhalation diagnostic challengesat this Cen-

MATERIAL AND METHODS Investigation

ter, prior to our change to the AAA standardized system. Methacholine and antigen had the following procedural methods in common: (I) an initial baseline challenge with diluent only-sterile water for methacholine, the actual diluent used for the antigen in allergen challenge: (2) an initial pulmonary function of at least 80% of predicted or better: (3) a drop in FEV, of 25% indicated positive test; no change after final concentration considered negative test; (4) a series of dilutions of both methacholine and antigen. each consisting of I ml total quantity and each succeeding dilution containing increasing amounts of either methacholine or antigen: (5) pulmonary functions measured consistently after every 5 inhalations until I dilution was completed; next concentration completed if no positive findings ob-

Methacholine inhalation challenges were a routine procedure at this Center when these events occurred. Antigen

tained-continued with eachsucceedingconcentrationprior to the final dilution; if no fall in pulmonary functions met

challenges were routinely performed to confirm the lung as a target organ if skin tests to antigens were positive and the history unclear. The antigen challenge was performed because immunotherapy as a therapeutic procedure was, and still is, based on confirmatory evidence of the lung being a

criteria for positive test, test considered negative: (6) if sustained fall of 25% in f%V, at any point of measurement, test consideredpositive and no further inhalations done: (7) results reported as “accumulated dose,” i.e., sum of each dilution was added; as example, final result might be ex-

VOLUME NUMBER

1.0

64 6, PWT

Challenge

in asthmatic

children

577

2

1

r

3000

pt. R

0.8z5

- 2000 0.6 Z

FIG. 1. Solid lines, antigen; broken lines, methacholine. Initial challenge, routine admission challenge to this Center; second challenge: approximately 10 days after cessation of active measles (post infection); subsequent challenges: repeated at intervals of 4 to 7 days.

-3

FIG. 3. See legend to Fig. 1

so00

zoo0

000

pt. B

z -2

IOOC’

000

Z

I

I 000

FIG. 4. See legend to Fig. 1. -C

1

FIG. 2. See legend to Fig. 1.

pressed as positive to “0.225 mg” inhaled methacholine or to “750 PNU” (protein nitrogen units) in the case of antigen. The challenges differ in relation to the dilutions and the expression of inhaled product. The following concentrations were used (in l-ml solution): merhacholine-0.01, 0.05. 0.1,0.5. 0.75, 1.O, 2.5, and 5 mg (final concentration); and atujg~~~--IO, 50, 100. 1,000, 5,000, 10,000 PNU (final concentration). If the subject’s response was positive, the final additive dose was determined by the milligrams of methacholine or the PNUs of antigen in the nebulizer at the start of the end-point concentration minus the amount remaining in the nebulizcr. This amount was then added to the previous amounts for each completed concentration and expressed as a total inhaled dose.

DISCUSSION The Subject A (Fig. 1) had an initial premeasles challenge that was positive at a total inhaled dose of 0.06 mg methacholine, the first challenge after measles had abated. His reaction was still positive, but at this point 0.45 mg was required. The initial antigen challenge (Altcmaria and Homodendrum

mix) was positive at a total administered dose of 150 PNU. The challenge done the day following the methacholine was also positive but required 1,500 PNU. By the fourth challenge (5 to 7 days between each challenge) sensitivity was back to the initial range (0.05 mg) and remained generally so over the next 5 challenges. Antigen sensitivity returned to 100 PNU, in parallel with the increased sensitivity to methacholine. Subject B (Fig. 2) essentially followed the same pattern initially but then diverged at the end. Positive methacholine testing at 0.05 mg was accompanied by positive antigen response at 1.50PNU, prior to infection. Following the infection, methacholine sensitivity decreased, requiring 0.75 mg by the third challenge, while the antigen-positive test now required 2,200 PNU. The following 3 challenges became divergent, with methacholine requirements increasing to 0.21 mg, while the antigen challenge returned to initial levels (180, 140, 160 PNU). Subject C (Fig. 3) indicated no apparent correlative evidence of methacholine-related allergen sensitivity. The baseline methacholine was 0.04 mg and this showed no essential change for the next 5 challenges. The subject was less sensitive to the antigen used for the challenge than were A and B (1,200 to 1.700 PNU

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pt. E

CLIN IMMUNOL DECEMBER 1979

the last few challenges occurred for no apparent reason that could be determined.

COMMENT

FIG. 5. routine imately sequent

Methacholine challenge only. Initial challenge, admission challenge; second challenge, approx10 days post active measles (post infection); subchallenges, 4 to 7 days between challenges.

were required for a positive response). The sudden increase in antigen sensitivity in early July (90 PNU produced a positive challenge) was reflected by a similar increase in methacholine sensitivity (a change from 0.22 to 0.1 mg) at this time, which was less severe than that reflected by the antigen (50% vs. 95%) but at least in the same direction. The antigen challenges continued to hover at the same level, despite a return of methacholine sensitivity to a high of 0.2 mg when the antigen challenge was positive at 160 PNU. Subject D (Fig. 4) showed total discrepancy between sensitivity to methacholine and to antigen. The initial methacholine challenge was performed well before (4 months) the antigen challenge and hence cannot be related. The postmeasles challenges to both demonstrated divergent sensitivities. Methacholine response was positive at 0.25 mg (admittedly far below the initial 0.8 mg done some months before) but the change is relatively small in comparison to PNUs required for the allergen challenge. More importantly, while sensitivity to antigen challenge had decreased considerably at the last challenge, from approximately 100 PNU to 1,490 PNU (an increase of some 900%), the methacholine challenge was still positive at 0.2 mg. the level present when antigen challenge was positive at 90 PNU. The graph for Subject E (Fig. 5) depicts 23 challenges to methacholine, performed in the same way each time over a period of 16 weeks at intervals of 4 to 7 days between challenges. The initial decrease in sensitivity was related to the postmeasles period, but the remainder presented surprising stability for a considerable period of time at a low dosage of inhaled methacholine. A return to decreased sensitivity during

The procedures used for challenges were different than those presently deployed. Nevertheless, the system used physiologic measures, which were the same for all the subjects depicted in the 5 figures. Whatever errors are inherent in the procedure were thus present in all the challenges, and even though more carefully controlled systems (such as the AAA Procedures now in use) may have made the procedure more reliable, it is unlikely that an outcome very different from that presented in this article would have been reflected. Asthma is a very complex disease in regard to the mechanisms that may be involved in the production of bronchospasm. Allergen-induced mediator release is only one of them and, in the subjects involved in this study, by no means the major precipitant. Other mechanisms totally unrelated to antigen-IgE mediator release prevailed in all the subjects. Exercise-induced asthma, various

a hypersensitive infections

of

parasympathetic viral

origin

(not

system, the least

of

which is the common cold), changes in temperature or barometric pressure or weather in general, irritable airways from any cause, allergic or nonallergic irritants (tobacco smoke, chlorinated swimming pools, perfumes, aerosols, nonallergic dust), cold air, emotionally aggravating factors, sympathetic “blockade,” and other factors as yet unearthed contribute to airway sensitivity and bronchial obstruction. Two of the subjects (Figs. 1 and 2) have a degree of methacholine and antigen parallelism that, in a clinical allergic response to the antigen used in the challenges, may well have been a major factor involved in the asthmatic picture. In the others (Figs. 3 and 4) it is possible that other factors were more important than the allergic factor. However, the production of bronchospasm with a very small amount of allergen which was not reflected in an increased sensitivity to methacholines in Subject D (Fig. 4) has 2 possible explanations. The antigen used was ash extract and the challenge was performed in September. No trees pollinate in September in Denver and hence the sensitivity to ash may well have been there on challenge with antigen, but presumably the state of the airways may be projected differently with continual methacholine challenge during the tree season but not when continuous season-related natural challenge is present. Hence the lack of correlation at this point may yet reflect the true state of affairs. The airways are much less sensitive because a major sensitizer has not been continually

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present, i.e., absence of ash pollen. Increasing sensitivity to allergen in seasonal ragweed hay fever as the season progresses is a correlative example. Apparently, methacholine confirms the probable presence of asthma when the issue is in doubt and the data published (by Townley et al.“) in regard to hay fever are not a complicating factor. All the challenges were positive at levels of inhaled methacholine considerably lower than the level shown by these investigators. It is also possible to conclude that sensitivity to methacholine may be an expression of airway sensitivity in general, regardless of the mechanism involved, and not especially related to allergen-IgE mediator release mechanisms. Assuming then that methacholine inhalation challenges merely reflect airway sensitivity regardless of cause, the variations found in this study may well suggest that, for an individual patient, factors other than allergy could be involved and need to be investigated. Finally, it is difficult to explain why the first study’s (Molk and Kumar’) result, showing nearly 9 weeks of increased sensitivity following attenuated measles vaccine, was opposite the result noted in a measles epidemic. Not only was there no clinical evidence of bronchospasm for many weeks, but the study also demonstrated an initial decreased, rather than an increased, sensitivity to methacholine. The nature of the virus has been altered in the attenuated measles vaccine and this may account for the difference.

Challenge

in asthmatic

children

579

Furthermore, the presence of airway sensitivity to methacholine by inhalation appears to be confirmed in asthmatics regardless of the clinical state. This is reinforced by the presence of airway sensitivity to methacholine [in some cases less sensitive (Figs. I and 2) and sometimes very sensitive (Figs. 3 and 4)] in these despite the total 4 subjects for a period post measles. absence

of symptoms

or clinical

and

physiologic

evi-

dence of bronchospasm, as well as by the continuous presence of sensitivity, not necessarily related to attacks of bronchospasm. in another subject (Fig. 5) during some 23 challenges over 16 weeks. REFERENCES Molk L. Kumar S: Methacholine challenges after measles vaccine. (Unpublished data.) Gold W: Cholinergic pharmacology in asthma. irr Austen KF, Lichtenstein LM. editors: Asthma: Physiology, immunopharmacology. and treatment. New York. 1973. Academic Press, Inc., p. 177. Godfrey S, Silverman M, Anderson SD: Problems of interpreting exercise-induced asthma. J All ERGL CI IN Ivnr~‘noL 52109, 1973. Chai H. Farr RS, Froehlich LA, Mathison DS, MacClean JA. Rosenthal RR, Sheffer AL, Spector SL, Townley RG: Standardization of bronchial inhalation challenge procedures. J AIUERGY CIJN IMMLINOI. 56:323, 1975. Townley RG, Ryo UY. Kolotkin EM, Kang B: Bronchial sensitivity to methacholine in current and former asthmatic and allergic rhinitis patients and control subjects. J Al I ~.Kc;\ CI.IN IMWNOL 56:429, 1975.

Antigen and methacholine challenge in children with asthma.

Antigen and methacholine children with asthma Hyman ANTIGEN Chai, M.D., F.R.C.P.(Edin.), D.C.H.(Lond.) CHALLENGES Antigen inhalation challenges f...
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