TH
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`AL RGY
`CLINICAL
`IMMUNOLOGY
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`AND
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`INCLUDING
`ALLERGY ABSTRACTS
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`INDEX I SSUE
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`VOL. 75, NO. 6
`JUNE, 198~EALTH_ SCi~,,iCES UBRP.1RY
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`THE JOURNAL OF
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`ALLERGY
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`AND
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`MOSBY
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`CLI NICAL IMMUNO'LOGY
`l!II!
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`VOLUME 75
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`A CME article that has servep as a self-assessment tool since June 1983 is not published in this issue of
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`CONTENTS
`June, 1985
`
`Editorial
`
`Atopy in infancy and early childhood: Natural history and role of
`skin testing
`
`633
`
`Robert S. Zeiger, M.D., Ph.D., San Diego, Calif.
`
`Contents continued on page 7A
`
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`June, 1985
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`Page 5A
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`

`

`CONTENTS
`
`CONTINUED
`
`Original articles
`
`Acquired deficiency of the inhibitor of the first component of
`complement: Report of five additional cases with commentary on
`the syndrome
`
`Albert L. Sheffer, M.D . , K. Frank Austen, M.D., Fred S. Rose11 , M .D. , a11d
`Douglas T. Fearon, M.D., Boston , Mass .
`
`Skin test reactivity in infancy
`
`Jean Luc Me11ardo, M.D. , Jean Bousquet, Michel Rodiere, Jacques Astruc, and
`Franr;ois-Bernard Michel, Montpellier, France
`
`Levels of immunoglobulin G, M, A, and E at various ages in
`allergic and nonallergic black and white individuals
`
`Fred J. Grundbacher, Ph.D. , and F. Standorf Massie , M .D. , Peoria, Ill., and Richmond, Va .
`
`Reactivity of lgE and lgG serum levels to chymopapain after
`chemonucleolysis
`
`Michael A. Sagona, Ph.D., George V. Bruszer, M .S. , John C. Nelson, M .S.,
`Carmine Mascoli, Ph.D ., and Kenneth Serkes, M.D ., Morton Grove, Ill.
`
`Detection of lgE-mediated respiratory sensitization in workers
`exposed to hexahydrophthalic anhydride
`
`David R. Moller, M .D .. Joan S. Gallagher, Ph.D ., David I. Bernstein, M .D ..
`Thomas G. Wilcox, M.D., H . E. Burroughs , C.I.H ., a11d I. Leonard Bernstein , M .D . ,
`Cincinnati, Ohio
`
`Anaphylaxis after contact with a jellyfish
`
`Alkis G. Togias , M.D . , Joseph W. Burnell, M.D. , Anne Kagey-Sobotka, Ph.D ., and
`Lawrence M . Lichtenstein, M.D ., Ph.D . , Baltimore, Md.
`
`A collaborative study on the first international standard of
`Dermatophagoides pteronyssinus (house dust mite) extract
`
`Annelle Ford, B .Sc., Valerie Seagroa/1, M.Sc .. Thomas A . E . Plaits-Mills, M .D .. Ph .D ., and
`Henning L¢wenstein, Ph .D ., D .Sc., London , England, Charluttesville, Va ,. a11d
`Copenhagen, Denmark
`
`Allergens of the house dust mite Dermatophagoides farinae(cid:173)
`lmmunochemical studies of four allergenic fractions
`
`Michiko Haida, M.D., Hirokazu Okudaira, M.D., Ph.D .. Tadaatsu Ogita, M .D., Ph.D . ,
`Koji Ito, M .D . , Ph .D . , Terumasa M iyamoto, M .D .. Ph.D. , Toshilwru Nakajima, B.S. , and
`Osamu Hongo, M.D. , Ph.D., Tokyo , Japan , and Winnipeg , Ma11itoba, Canada
`
`Toxic oxygen products alter calcium homeostasis in an
`asthma model
`
`Earle B . Weiss, M.D ., and the technical assista11ce of Prakash C . Mullick, Ph .D .,
`Worcester, Mass.
`
`640
`
`646
`
`651
`
`659
`
`663
`
`672
`
`676
`
`686
`
`692
`
`June, 1985
`
`Continued on page 9A
`
`Page 7A
`
`

`

`CONTENTS
`
`CONTINUED
`
`A placebo-controlled trial of procaterol: A. new long-acting oral
`beta2-agonist in bronchial asthma
`
`698
`
`Sheldon C. Siegel, M.D., Roger M. Katz, M.D .. Gary S. Rachelefsky, M.D.,
`Milan L. Brandon, M.D .. and Lowell A. Borgen, Ph.D .,
`Los Angeles and San Diego, Calif., and Ann Arbor, Mich .
`
`The occurrence of multiple physical allergies in the same patient:
`Report of three cases
`
`Lee Sonin, M.D., Leslie C . Grammer, M.D ., and Roy Patterson, M.D., Chicago, /II.
`
`Theophylline and fibrocystic breast disease
`
`Michele C. Hindi-Alexander, Ph.D. , Maria A. Zielezny, Ph.D., Naris Montes, R.N., M.S.,
`Bonnie Bullough, Ph.D., Elliott Middleton, Jr., M.D., Dutzu H. Rosner, M.D., and
`William M. London, Ed.M., Buffalo, N. Y.
`
`705
`
`709
`
`The effect of phenobarbital on theophylline disposition in children
`with asthma
`
`716
`
`Consuelo L. Saccar, Pharm.D .. Michele Danish, Pharm .D., Marie C . Ragni, M.S ..
`Mario L. Rocci, Jr. , Ph.D., Jeffrey Greene, M.D., Sumner J. Yaffe, M .D., and
`Herbert C. Mansmann, Jr., M.D., Philadelphia, Pa.
`
`Effect of the nonsedative H,-receptor antagonist astemizole in
`perennial allergic and nonallergic rhinitis
`
`B. Nuchel Petersen, L. Nuchel Petersen, G. Gundersen, J-A Wihl, K. Bresson, and
`N. Mygind, Hellerup and Copenhagen, Denmark, and Malmo, Sweden
`
`Skin testing in chymopapain anaphylaxis
`
`Frederick C. Cogen, M.D., Marc Goldstein, M .D ., and Burton Zweiman, M.D .,
`Philadelphia, Pa.
`
`The relationship of cerebrospinal fluid and plasma theophylline
`concentrations in children and adolescents taking theophylline
`
`William A. Auritt, M.D., Stephen J . McGeady, M.D., and Herbert C. Mansmann, Jr. , M.D.,
`'
`Philadelphia, Pa.
`
`Stinging insect allergy: Natural history and modification with
`venom immunotherapy
`
`Robert E . Reisman, M.D ., Donald J. Dvorin, M.D ., Christopher C. Randolph , M.D. , and
`John W. Georgitis, M.D., Buffalo, N. Y.
`
`Brief communication
`
`Factitious snee~ing
`
`Deborah Wiener, M.D., Kris McGrath, M.D ., and Roy Patterson, M .D., Chicago, Ill.
`
`720
`
`728
`
`731
`
`735
`
`741
`
`June, 1985
`
`Continued on page I IA
`
`Page 9A
`
`

`

`CONTENTS
`CONTINUED
`
`Correspondence
`
`Announcements
`
`Allergy abstracts
`
`Asthma and hay fever-Immunology-Miscellaneous allergies-
`Pediatrfcs-Pharmacology, physiology, and pathology
`
`Index
`
`743
`
`744
`
`23
`
`747
`
`CME calendar-American Academy of Allergy and Immunology on page 27A
`
`Newsview-:American Academy of Allergy and Immunology on page 40A
`
`Information for authors on page 23A
`
`Professional opportunities on page 96A
`
`Index to advertisers on page 98A
`
`With this June issue, the JOURNAL initiates several changes that should shorten the lag time between
`acceptance of a manuscript and its publication. First, additional space has been picked up by the run-in
`technique that eliminates unused blank space. Second, the executive committee approved the addition of
`20 extra pages to each issue.
`
`-Elliott Middleton, Jr., M.D.
`
`Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by The C. V.
`Mosby Company for libraries and other users registered with the Copyright Clearance Center (CCC) Transactional Reporting Service,
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`June, 1985
`
`Page 11A
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Effect of the nonsedative H,-receptor
`antagonist astemizole in perennial allergic and
`nonallergic rhinitis
`
`J-A Wihl,* B. Nuchel Petersen,** L. Nuchel Petersen,** G. Gundersen,**
`K. Bresson, *** and N. Mygind***
`Hellerup and Copenhagen, Denmark, and Malmo, Sweden
`
`We studied the efficacy and side effects of the H,-antihistamine astemizole in perennial rhinitis.
`We also defined subgroups of responders and examined the added effect of a steroid spray.
`Fifty-five adults completed a JO- to 14-week controlled trial. Astemizole reduced the number of
`sneezes to 41% (p < 0.001) and the number of nose blowings to 55% (p < 0.001) of the
`placebo values. The added use of beclomethasone dipropionate caused a further reduction to
`14% (p < 0.001) and 37% (p < 0.05), respectively. Nasal blockage was only marginally
`affected by the antihistamine, but it was reduced to 64% by the steroid spray (p < 0.001).
`"Sneezers" responded better to the antihistamine than "blockers," with "nose blowers" in an
`intermediate position. The effect was equal in allergic and nonallergic patients. Astemizole
`was completely nonsedative but increased appetite and body weight. An open I-year study of 17
`patients demonstrated that astemizole maintained its efficacy and that further weight gain did
`not occur. It is concluded that astemizole is a highly effective nonsedative H,-antihistamine suitable
`for continuous therapy of perennial rhinitis. (J ALLERGY CLIN IMMUNOL 75:720-7, 1985 .)
`
`Perennial rhinitis is a heterogeneous group of
`chronic noninfectious disorders. 1 In childhood it usu(cid:173)
`ally results from allergy, but in adults its cause in
`many cases is unknown. 2• 3 In nonallergic rhinitis,
`symptomatic medication is the only therapeutic pos(cid:173)
`sibility, and corticosteroids, which are becoming in(cid:173)
`creasingly used as nasal sprays, are beneficial for most
`patients. 4 Antihistamines are frequently prescribed for
`allergic rhinitis, but the rationale for their use in non(cid:173)
`allergic rhinitis is questionable. Results of an open
`study by Mullarkey et al. 3 have indicated, however,
`that antihistamines can also be of value in nonallergic
`rhinitis associated with nasal eosinophilia.
`Astemizole is a potent H 1-antihistamine with some
`unique properties. It has a very long duration of action
`(half-life= 4 to 18 .days), 5 • 6 so that 24-hour protec-
`
`From the *Department of Otorhinolaryngology, Malmo Hospital,
`Malmo, Sweden, **Department of Lung Diseases, Gentofte Hos(cid:173)
`pital, Hellerup, Denmark, and ***Otopathological Laboratory,
`Department of Otorhinolaryngology, Rigshospitalet, Copen(cid:173)
`hagen, Denmark.
`Supported in part by Janssen Pharmaceutica, Beerse, Belgium.
`Received for publication July 2, 1984.
`Accepted for publication Oct. 20, 1984.
`Reprint requests: J-A Wihl, M.D ., Department of Otorhinol~n(cid:173)
`_gology, Malmo Hospital, Malmo, Sweden.
`
`720
`
`Abbreviation used
`BDP: Beclomethasone dipropionate
`
`tion can be easily attained. It is almost a pure H 1-
`receptor antagonist and has no anticholinergic and
`local anesthetic effects. 5• 6 The drug effect can there(cid:173)
`fore be taken as indirect evidence of the involvement
`of histamine in the inflammatory reaction. Astemizole
`is reported to be nonsedative. 5•8
`The objectives of our study were as follows: (1) to
`test the value of a new method of exact symptom
`recording, (2) to study efficacy and side effects of
`astemizole, (3) to define subgroups of antihistamine
`responders, (4) to provide indirect evidence of the role
`of histamine in nonallergic rhinitis, and (5) to analyze
`the additive effect of an antihistamine and a topical
`steroid. ·BOP was chosen for this purpose because it
`is the most widely used steroid spray.
`
`MATERIAL AND METHODS
`Design of short-term study
`In the controlled trial, which consisted of four periods,
`patients were randomized to two parallel groups (Table I).
`The trial was undertaken at three centers from October 1982
`to February 1983, a period that does not include the pollen
`season.
`
`

`

`VOLUME 75
`NUMBER 6
`
`TABLE I. Design of short-term study
`
`Astemizole in rhinitis 721
`
`Period 1*
`(Open design)
`
`Period 2t
`(Double-blind design)
`
`Period 3t
`(Double-blind design)
`
`Period 4t
`(Patient single-blind design)
`
`Group 1 No treatment
`
`Astemizole tablets
`
`Group 2 No treatment
`
`Placebo tablets
`
`Astemizole tablets
`and BDP aerosol
`Astemizole tablets
`and placebo aerosol
`
`Astemizole tablets and BDP
`aerosol
`
`*Of 2 weeks' duration.
`tOf 4 weeks' duration.
`
`Patients
`Consecutive adult patients referred to departments of lung
`medicine and otorhinolaryngology for perennial rhinitis en(cid:173)
`tered the study. They all complained of nonseasonal nasal
`symptoms that were present on most days, required daily
`therapy, and had lasted for at least 1 year. Patients were not
`included if they (1) were pregnant, (2) used other types of
`medicine that could affect trial results, (3) had large polyps,
`or ( 4) had gross anatomic abnormalities hindering the use
`of intranasal medication. All patients gave informed consent
`to participate, and the protocol was approved by the relevant
`ethical committees. Fifty-six patients entered the trial, and
`55 (28 in group 1 and 27 in group 2) completed it. One
`patient was excluded because he failed to complete the diary
`cards. The mean age was 37. 9 yr (range 18 to 70 yr); 27
`were women and 28 were men.
`
`Pretreatment examinations
`All patients completed a detailed symptom questionnaire.
`Skin prick testing was done with a routine battery of 10
`inhalant allergens (ALK, Copenhagen, Denmark) and eval(cid:173)
`uated according to the recommendation of the Scandinavian
`Allergy Society.9 An ordinary ear, nose, and throat exam(cid:173)
`ination was performed, and a nasal smear was taken for
`cytology at the first and second visits (i.e., before treatment).
`The smear was coded, and the number of eosinophils was
`evaluated blindly by one of the authors (J-A W.) according
`to a semiquantitative scale.' Body weight was determined
`before treatment and after each treatment period.
`
`Drugs
`Astemizole and placebo tablets were supplied in coded
`vials by Janssen Pharmaceutica, Beerse, Belgium. The daily
`dose was one 10 mg tablet taken as early as possible in the
`morning, preferably 30 min before breakfast. BDP pres(cid:173)
`surized aerosols and placebo aerosols were supplied by
`Glaxo Laboratories, Greenford, England. The final coding
`was done by a representative from each company.
`
`Effect parameters
`Diary cards were completed during the entire study pe(cid:173)
`riod. Patients recorded the numbers of sneezes and nose
`blowings continuously in 2-hour periods, assessed nasal
`blockage (Tables II and III), evaluated sedation (100 mm
`visual analog scale from O = completely alert to 100 =
`
`TABLE II. Self-assessment method for
`recording of nasal blockage*
`
`Assessment
`
`Score
`
`Breathing through the nose/nostril is:
`Free and easy
`Uneasy but can be continued
`Difficult and cannot be continued
`Completely abolished
`
`0
`1
`2
`3
`
`* After examination of both nasal cavities together, each cavity is
`assessed separately by occluding the other nostril gently but
`tightly with a thumb beneath.
`
`TABLE Ill. Blockage index based on the
`patient's self-assessment (see Table II)
`
`Self-assessment score
`
`Both sides One side Other side Blockage index
`
`0
`0
`
`I
`2
`2
`3
`
`0
`0-1
`
`1-2
`I
`2
`2
`3
`
`0
`1-3
`I
`2
`3
`2
`3
`3
`
`2
`3
`4
`5
`6
`7
`8
`
`very sleepy), and completed a questionnaire about possible
`side effects (see Table V) in the morning and evening.
`
`Statistics
`Neither number of sneezes nor number of nose blowings
`follows a normal distribution, and the nonparametric Wil(cid:173)
`coxon test with two-sided alternatives was therefore used.
`To reduce random day-to-day variation in symptoms and
`the risk of mass significance, comparisons were made only
`between median values for the last 2 wk of each period.
`
`Long-term study
`In one of the centers, 23 of 41 patients continued in an
`open long-term assessment of effect and possible side ef-
`
`

`

`722 Petersen et al.
`
`J . ALLERGY CUN. IMMUNOL.
`JUNE 1985
`
`u,
`Q)
`N 10
`
`Q)
`Q)
`C
`
`0
`L.
`Q)
`
`u, - 8
`.0 6 E
`
`:::,
`C
`C 4
`C,
`Q)
`~
`
`2
`
`0
`
`o--o Placebo
`
`6·· ··· ·6 Astemizole +BOP
`
`0
`
`0
`
`\ □---□ Astemizole
`□, \
`I\
`
`\
`
`'□ '
`, ,
`0
`I
`0
`I
`'o-o-0
`\
`,
`0
`I
`□,
`0
`0
`I
`',
`'o......
`'-o--□- - --,
`o, 6 ····6..
`··6 ·-·-C!.···6····6-. .
`0
`·6····6····6
`
`.··
`I
`/
`_,Q
`I .··
`- ~fl"
`
`8
`
`12
`
`16
`
`20
`
`24
`Hour
`
`FIG. 1. Diurnal variation in the number of sneezes and effect of treatment.
`
`TABLE IV. Results of short-term study
`
`Comparison
`
`Symptom
`
`No. of
`patients
`
`Effect of placebo
`
`G2,Pl vs . G2,P2
`
`Effect of astemizole
`
`Gl,Pl vs. Gl,P2
`
`G2,P2 vs. G2,P3
`
`Effect of BDP
`
`Gl,P2 VS. Gl,P3
`
`G2,P3 vs. G2,P4t
`
`Sneezing
`Nose blowing
`Blockage
`
`Sneezing
`Nose blowing
`Blockage
`
`Sneezing
`Nose blowing
`Blockage
`
`Sneezing
`Nose blowing
`Blockage
`
`Sneezing
`Nose blowing
`Blockage
`
`27
`
`28
`
`27
`
`28
`
`14
`
`Statistical comparisons are between median values for symptoms in the last 2 weeks of each period.
`G = Group; P = period (see Table I); NS = not significant.
`*Difference still significant when patients with allergy are excluded.
`tG2,P4 studied only in one of the investigation centers.
`
`p value
`
`NS
`NS
`NS
`
`<0.01*
`<0.05*
`NS
`
`< 0.001*
`<0.001*
`< 0.01*
`
`<0.001 *
`<0.05
`=0.01 *
`
`NS
`< 0.05
`=0.001 *
`
`fects. They were treated with 10 mg astemizole daily and,
`in 18 cases, also with BDP. Symptoms and side effects were
`recorded in 14-day periods every 3 mo. Seventeen patients
`·
`completed a I-year treatment period.
`
`RESULTS
`Value of exact symptom recording
`The subclassification of patients based on exact
`symptom recording (number of sneezes, number of
`
`

`

`VOLUME 75
`NUMBER 6
`
`Astemizole in rhinitis
`
`723
`
`PLACEBO
`
`ASTEMIZOLE
`
`ASTEMIZOLE +
`BECLOMETHASONE
`DI PROP IONA TE
`
`•
`• • 3
`
`2
`
`•
`
`4
`
`--...
`
`6
`
`5
`
`4
`
`3
`
`2
`
`0
`
`" GROUP I
`• GROUP II: PE. I
`
`PE. I
`
`PERIOD 2
`
`PERIOD 2
`PERIOD 3
`
`WEEKS
`PERIOD 3
`PERIOD 4
`
`FIG. 2. Drug effect on the daily number of sneezes (2-week medians). The four squares show
`the values for 17 patients receiving long-term therapy (1 = 3 months; 2 = 6 months; 3 = 9
`months; 4 = 12 months).
`
`PLACEBO
`
`ASTEMIZOLE
`
`ASTEM IZOLE +
`BECLOMETHASONE
`DI PROP ION~ TE
`
`14
`
`12
`
`10
`
`8
`
`6
`
`4
`
`2
`
`• •
`2
`I
`
`•
`
`4
`
`•
`3
`
`0
`,. GROUP I
`• GROUP I I,
`FIG. 3. Drug effect on the daily number of nose blowings (2-week medians). See Fig. 2 for legend.
`
`PE. I
`
`PERIOD 2
`
`PE. I
`
`PERIOD 2
`PERIOD 3
`
`WEEKS
`PERIOD 3
`PERIOD 4
`
`PLACEBO
`
`ASTEMIZDLE
`
`ASTEM I ZDLE +
`BECLOMETHAS0NE
`DI PROP IONA TE
`
`•
`
`3
`
`•
`4
`
`7
`
`6
`
`5
`
`4
`
`3
`
`2
`
`" GROUP I ,
`• GROUP I I:
`
`PE. I
`
`PERIOD 2
`
`PE. I
`
`PERIOD 2
`PERIOD 3
`
`WEEKS
`PERIOD 3
`PERIOD 4
`
`FIG. 4. Drug effect on the blockage index (2-week medians for morning and evening index). See
`Fig. 2 for legend.
`
`

`

`724 Petersen et al.
`
`J . ALLERGY CUN. IMMUNOL.
`JUNE 1985
`
`TABLE V. Possible adverse effects presented as the percent of patients having the symptoms and the
`percent of all days with the symptom (in parentheses)
`
`No treatment
`(G1 + G2,P1)
`N = 55
`
`Placebo (G2,P2)
`N = 27
`
`Astemizole
`(G1,P2 + G2,P3)
`N= 55
`
`Astemizole + BDP
`(G1,P3 + G2,P4)
`N = 55
`
`Nausea
`Headache
`Diarrhea
`Abdominal pain
`Dryness of mouth
`Dryness of nose
`Artralgia
`Palpitation
`Dizziness
`Decreased appetite
`Increased appetite
`Uneasiness
`Nose bleeding
`
`18 (4.4)
`65 (24.6)
`15 (1.7)
`24 (4.5)
`38 (16.3)
`36 (24.5)
`18 (13.0)
`7 (0.4)
`11 (4.2)
`11 (2. 7)
`15 (2.5)t
`38 (13.5)
`5 (0.9)
`
`G = Group; P = period (see Table I) .
`*With BDP in most cases.
`
`10 (2 .6)
`36 (20.0)
`10 (1 .2)
`17 (6.1)
`32 (18.1)
`29 (20.0)
`32 (14.8)
`I (0. I)
`22 (5 .0)
`12 (4.6)
`5 (2.3)t
`27 (15.2)
`2 (0.1)
`
`22 (2.2)
`58 (21.0)
`16(1.4)
`22 (5.3)
`44 (20.8)
`47 (26.3)
`25 (1 7 .1)
`7 (1.4)
`3 I (6.5)
`22 (5 .2)
`20 (6.2)t
`44 (15 .8)
`13 (2.4)
`
`7 (3.4)
`46 (17 .7)
`7 (2.1 )
`20 (8.4)
`44 (22.2)
`39 (23.9)
`27 (16.5)
`12 (5 .9)
`27 (7 .0)
`15 (4.0)
`29 (8.9)t
`34 (8.2)
`7 ( 1.2)
`
`TABLE VI. Mean body weight (kg) in 17
`patients before, during, and after astemizole
`therapy for 1 year
`
`Before
`therapy
`
`After
`short-term
`study
`
`After long-term study
`
`3
`mo
`
`6
`mo
`
`9
`mo
`
`12
`mo
`
`71.3
`
`74.0
`
`74.o
`
`73.s
`
`72.9
`
`73.9
`
`nose blowings, self-assessment of blockage) can be
`used for prediction of the response to antihistamine
`treatment (see below). Exact symptom recording also
`demonstrated that patients who retrospectively com(cid:173)
`plete a symptom questionnaire tend to overestimate
`their symptoms ( + 90% for number of sneezes,
`+ 20% for nose blowings). Most important is the dem(cid:173)
`onstration of considerable inhomogeneity of the pop(cid:173)
`ulation studied. The daily number of nose blowings
`in our patients, who claimed to suffer from nasal dis(cid:173)
`charge, ranged from 1 to 300. We find the exact symp(cid:173)
`tom monitoring we used to be of considerable value
`for the characterization of the treatment groups in
`controlled trials and for evaluation of an individual
`patient in daily clinical practice. It is, however, more
`time consuming than the usual semiquantitation of
`symptoms in a value range of zero to three.
`in sneezing demonstrated a
`Diurnal variation
`marked morning peak, a small peak in the evening,
`
`and virtually no symptoms during the night (Fig. I).
`Sneezing was reduced by astemizole and further re(cid:173)
`duced by BDP, but only the steroid tended to smooth
`the response curve and eliminate the morning peak.
`Nose blowings demonstrated similar diurnal variation
`that was less influenced by the steroid.
`
`Placebo effect
`There was no placebo effect with the use of exact
`symptom recording ( Figs. 2 to 3). This is an advan(cid:173)
`tage because it allows statistical comparison within
`the single-treatment group.
`
`Effect of astemizole
`The antihistamine had a marked effect on the num(cid:173)
`ber of sneezes, which was reduced to 41 % of the
`placebo level (Fig. 2; Table IV) , and on the number
`of nose blowings, which fell to 55% of the placebo
`level (Fig. 3; Table IV). The effect on blockage index
`was marginal (Fig. 4) but statistically significant for
`one treatment group (Table IV). Astemizole also re(cid:173)
`duced the number of sneezes and nose blowings in
`the patients with nonallergic rhinitis (Table IV). Rel(cid:173)
`evant allergy was demonstrated in only 10 of 55 pa(cid:173)
`tients.
`
`Effect of BOP
`When the steroid spray was added to the antihis(cid:173)
`tamine, the number of sneezes dropped from 41 % to
`14% (Fig. 2; Table IV) and the number of nose blow-
`
`

`

`VOLUME 75
`NUMBER 6
`
`Long-term study*
`
`Astemizole
`(3 mo)
`N = 23
`
`Astemizole Astemizole Astemizole
`(6 mo)
`(9mo)
`(12 mo)
`N = 17
`N = 19
`N = 17
`
`0 (0)
`61 (26. 7)
`17 (6.4)
`17 (7.8)
`26 (7 .5)
`43 (34.5)
`30 (18.3)
`0
`22 (5.2)
`13 (4.6)
`13 (8.1)
`35 (11.3)
`26 (10. 7)
`
`11 (2.6)
`37 (23.2)
`11 (4.9)
`16 (10.~)
`26 (14.0)
`37 (28.4)
`21 (15.8)
`5 (0.4)
`21 (7. 7)
`11 (6.0)
`16 (4.9)
`16 (10.5)
`11 (3.9)
`
`12 (1.2)
`47 (22.7)
`24 (7.1)
`24 (10.6)
`29 (16.9)
`29(23.1)
`18 (9.8)
`0
`18 (7.5)
`18 (7.1)
`6 (1.2)
`29 (9.4)
`6 (2.0)
`
`12 (2.7)
`53 (22.0)
`18 (7.1)
`29 (13. 7)
`29 (20.4)
`29 (26. 7)
`18 (11.8)
`12 (0.8)
`24 (11.0)
`18 (7. 1)
`12 (1.6)
`35 (13.0)
`12 (4.3)
`
`ings fell from 55% to 37% (Fig. 3; Table IV) of the
`placebo value. There was a pronounced steroid effect
`on the nasal blockage index, which fell from 100%
`in the antihistamine period to 64% after addition of
`BDP (Fig. 4; Table IV).
`
`Effect of long-term therapy
`Continuous treatment for I yr demonstrated no evi(cid:173)
`dence of a diminished antirhinitis effect of astemizole
`with BDP (13 patients); only four patients were treated
`with astemizole alone (Figs. 2 to 4).
`
`Adverse effects
`There was no change in the score for sedation dur(cid:173)
`ing therapy with astemizole alone or with BDP
`( Fig. 5).
`Body weight increased during the first treatment
`month in both group 1 (astemizole; mean increase 0. 85
`kg; p < 0.001) and group 2 (placebo; mean increase
`0.32 kg; p < 0.01). The latter was probably related
`to seasonal changes (Christmas eating). The inter(cid:173)
`group difference was not significant, but a further
`increase in weight during continuous astemizole ther(cid:173)
`apy in the short-term trial (mean increase 0.91 kg/
`mo) was highly suggestive of increased weight as an
`adverse effect of astemizole. This was supported by
`an increase in appetite as reported in the daily symp(cid:173)
`tom questionnaire (Table V). When the "Christmas
`increase" in body weight was taken into account, 18
`of 28 patients gained weight during the first month of
`astemizole therapy. Four patients refused to participate
`in the long-term study for this reason. In the 17 pa(cid:173)
`tients who received daily therapy for 1 yr, there was
`
`Astemizole in rhinitis 725
`
`PLACEBO
`
`ASIDIZDI.E
`
`ASIDIZDI.E •
`IIECLDMETHASONE
`OIPROPl[)lATE
`
`20
`
`15
`
`10
`
`s
`
`0 +--+--1---+-+---!-f--+--+--+--+--+---i,--+---i
`WEEKS
`PERIOD 3
`PERIOD •
`
`PERIOD 2
`PERIOD 3
`
`., GROLi' I ,
`• CROUP II, PE. I
`
`PE.1
`
`PERIOD 2
`
`FIG. 5. Drug effect on the sedation index (2-week
`medians).
`
`no further weight gain (Table VI), probably due to
`awareness of this side effect.
`There were no other significant side effects from
`astemizole or BDP in the short-term or long-term stud(cid:173)
`ies (Table V).
`
`Classification of subgroups
`All patients who sneezed an average of five or more
`times a day in the run-in period were classified as
`"sneezers." Patients who were not "sneezers" and
`blew their noses more than 10 times a day were called
`"nose blowers." The remainder were classified as
`"blockers," provided they had an average nasal
`blockage index of 8 or more (morning plus evening) .
`Seven patients had too few symptoms to be included
`in any of the groups, but they were not excluded from
`the analyses of drug effect.
`
`Definition of response to treatment
`A patient was defined as a ''responder'' if the num(cid:173)
`ber of sneezes and/or nose blowings was reduced by
`at least 50% and/or the blockage index was reduced
`by at least 2 degrees (morning plus evening).
`
`Antihistamine responders
`Under the above criteria, 26 of 48 patients with
`symptoms were classified as antihistamine responders.
`As seen from Fig. 6, more "sneezers" than "block(cid:173)
`ers" were responders (p = 0.002; Fisher's exact
`test), with the "nose blowers" in an intermediate po(cid:173)
`sition. Neither a positive skin test nor a relevant al(cid:173)
`lergy could predict the response to astemizole. Nasal
`eosinophilia and concomitant asthma or polyps were
`suggestive of antihistamine responsiveness (Fig. 6).
`
`DISCUSSION
`A series of double-blind studies has demonstrated
`that astemizole is effective in the treatment of allergic
`rhinitis5· 7
`10
`11 and that it compares positively with
`•
`•
`
`

`

`726 Petersen et al.
`
`Blockers (N=ll)
`
`B¼
`
`Nose-blowers (N=B I
`Skin test positive•
`(Na12)
`Nasal eosinophilia
`(N:25I
`.
`Asthma or polyps
`(N:23I
`
`Sneezers ( N=28 I
`
`38¼
`
`50¼
`
`68¼
`
`O¼
`•> Some rl!'sult for poli@nts with ~levanl allergy (5 of tOpos)
`
`54¼
`
`76¼
`
`l00"/.
`
`FIG. 6. Positive response to astemizole (horizontal bars)
`and to additional BOP therapy (arrows). The dotted line
`gives the mean value for all patients.
`
`other antihistamines such as chlorpheniramine12 and
`mequitazine. 13 This is probably because of its unique,
`almost irreversible receptor binding properties, its ex(cid:173)
`tremely long duration of action, and high patient com(cid:173)
`8 The latter was
`pliance due to absence of sedation.5
`7
`•
`•
`confirmed in our present investigation.
`Our study of perennial rhinitis demonstrated that
`the effect of astemizole on the number of sneezes and
`nose blowings is pronounced, whereas the effect on
`nasal blockage is marginal. Trials with other antihista(cid:173)
`mines have also demonstrated a poor effect on nasal
`16 This is in accord with investigations
`stuffiness. 14
`-
`indicating that sneezing and hypersecretion are me(cid:173)
`diated by a histamine effect on nervous H1-recep(cid:173)
`18 whereas blockage is due to vasodilation and
`tors, 17
`•
`edema induced by stimulation of both vascular H1-
`and H2-receptors. 19
`20
`·
`It is of theoretic and therapeutic interest that we
`were able to demonstrate an effect of an antihistamine
`in nonallergic rhinitis; this had been suggested by an
`open study. 3 Since astemizole is reported to be a pure
`21 our results provide in(cid:173)
`H 1-receptor antagonist,5· 6
`direct evidence for the participation of histamine and
`mast cells in a large part of perennial nonallergic rhi(cid:173)
`nitis. An experimental model for the direct demon(cid:173)
`stration of mast cell involvement in rhinitis is now
`available, as Naclerio et al. 22 have demonstrated that
`a raised level of histamine, p-tosyl arginine methyl
`ester, and prostaglandin D2 in nasal secretions is a
`reliable sign of mast cell degranulation_. They also
`claimed that nonspecific stimuli can cause mediator
`release from mast cells in the nasal mucosa.
`The therapeutic message that emerges from our
`study is that antihistamines can be _tried in both allergic
`and nonallergic rhinitis. The character of the symp(cid:173)
`toms is more predictive of response to therapy than
`is the result of allergy testing. The large majority of
`"sneezers" will improve after taking an antihista(cid:173)
`mine, but an effect cannot be e;l(pected in' 'blockers.''
`
`•
`
`J . ALLERGY CUN. IMMUNOL.
`JUNE 1985
`
`10
`-
`
`Nasal discharge associated with sneezing will be re(cid:173)
`duced in most cases, but some patients with mono(cid:173)
`symptomatic rhinorrhea appear to respond neither to
`antihistamine nor to corticosteroid therapy. This is
`the target group for topical cholinoceptor antag(cid:173)
`onists .23
`Astemizole adequately controlled the symptoms in
`some of the patients, whereas others also required a
`steroid spray. The additive effect of astemizole and
`BDP is not surprising considering their different
`modes of action. The insufficient response to antihis(cid:173)
`tamine in some of the patients may be due to the
`participation of biochemical mediators other than his(cid:173)
`tamine, but we have little knowledge about their role
`in rhinitis. The increased nonspecific nasal respon(cid:173)
`siveness after provocation with allergen, 24 but not with
`histamine, 25 indicates that mediators other than his(cid:173)
`tamine are responsible for nasal hyperreactivity. This
`hypothesis gained some support from our data that a
`glucocorticoid, which probably acts in part by inhi(cid:173)
`bition of the formation of arachidonic acid metabo(cid:173)
`lites, smooths the curve of diurnal symptom variation,
`although this was not the case with an antihis(cid:173)
`tamine.
`A few cases of weight gain during astemizole ther(cid:173)
`apy were described by Wiison and Hillas, 8 although
`this has not been reported in other trials with the
`13 In a recent study, 129 British doctors
`drug. 5
`•
`were treated with astemizole for hay fever, and it was
`claimed that none of the "sneezing doctors" noted
`weight gain as an adverse effect. 26 Weight gain is
`mentioned as a possible adverse effect of a