Intranasal flunisolide in the treatment of perennial rhinitis: Correlation with immunologic parameters

Gary Incaudo,

Lieutenant Commander, (MC) UWR, M&imel Sclwtz, M.D., Frank Yamamoto, M.D., Michael Melon, M.D., Seymour Cre~ea, M.D., and Jerry D. Johnson, Ph.D. San Diego and Palo Alto, Calif.

The effectiveness and safety of 200 pg lduy of intrunusul jlunisolide in the treatment of perennial rhinitis was studied in 56 patients in a 6 wk double-blind porullel vehicle controlled clinicul trial. In addition. patients failing to respond to placebo were entered into a 6 wk open triul wilh the active drug. Forty-six percent of the Junisolide-treuted patients uchieved total or substantiul control of their nusal symptoms tampared to I I % of the plucebo-treated group in the double-blind study (p = 0.031). Eighty percent r$ patients achieved total or substantial control qf their nasal symptoms in the 6 wk open study. No adverse effects attributable to junisoiide were observed. Parameters of IgE-mediated reactivity, including immediate-type skin test reuctivity. total serum and nasal secretion IgE, speciJc serum and nusal secretion IgE. and nasul eosinophiliu, were also assessed in these patients. Although benejt from jlunisolide signtficuntl~ correlated with all of these parumeters except specr$ic’ serum IgE, the absence of these findings did not preclude significant benefit from the drug. This S&J demonstrates the in the treatment of perenniul rhinitis, especially but .ejficacy and safety of intranasal junisolide not exclusively in those patients with evidence of IgE-mediated reacti\*ity.

Efforts have been recently directed toward the development of topically applied glucocorticosteroids capable of effecting a high degree of potency while being &sorbed in insufficient amountssystemically to cause adreIlal suppression or cellular toxicity. Beclomdbasune diproprionate is such an agent whose saf@yand potency have been demonstratedin reversible obstructive lung diseasewhen administered as an aerosol.1 Similar successhas been reported with intramsal betamethasonevalerate and beclomethasone From the Allergy Clinic, Departments of Pediatrics and Internal Medicine and CIinicaI Investigation Center, Naval Regional Medical Center, and the Akgy Department. Kaiser-Perrnanente Medical Center. San Diego, and Syntex Corporation, Palo Alto. Sum by Bunau of Medicine and Surgery Clinical Investigation Program Fwject CI 7-16-964. Received for pubkakon Match 9, 1979. AccepodforpubJicationJune 11, 1979. ~&~w~ichael Schatz, M.D., Allergy Department, ’ Rammeate Medical Group, 7060 ClairemoatMesa Dr., San Diego, CA 92111. *The opinions or aswtions expressed herein are those of the authors and prc not to be cmstrued as official or as reflecting the views of the Navy Depamnent or the naval service at large.

diproprionate” in the treatment of rhinitis. These agents have proved uniquely devoid of si@icant adverse effects when compared to earlier trials using topical hydrocortisorte, prednisoione, and dexamethasone.4-6 Flunisolide, a member of a group of acetoaidesof fluorinated corticosteroids, is the most recent corticosteroid agent to prove of benefit in the tmtment of rhinitis without causing demons&able adrerur) suppressionor local toxicity. In two studies7uwof patients with seasonalallergic rhinitis causedby ragwee&pollen, significant improvement compared to placebotreated controls was demonstrated.Two further studiesg*lo of perennial rhinitis patients with positive skin tests, and a third study” using both positive and negative skin test individuals revealedsir&r benefit. As a corollary, the latter authors” and others** 9. **-I5 have suggestedthat benefit from intmnasal steroids may be closely tied to the atopic statusof the patient. The present study was undertaken to exrmiae the efficacy and safety of incrpnaiEelflunisolide in a population of allergic and nonallergic patients with pctennial rhinitis whose atopic status was extensively characterized. Vol. 65, No. 1, pp. 4149

42 lncaudo et al.

J. ALLERGY

CLIN. IMMUNOL. JANUARY 1980

TABLE I. Comparison of treatment groups in baseline period Treatment Flunisolide

No. of subjects Mean (yr) age (range) Duration of perennial rhinitis (yr) 2-5 5-10 P-10 Other allergic diseases Seasonalrhinitis Asthma Eczema Hives Complicating past nasal disorders Chronic sinusitis Nasal polyposis Nasal surgery Concomitant nasal medication Antihistamines Any nasal medication (oral, spray) None Severity of nasal symptoms(averagescore)* Sneezing Stuffy nose Runny nose Nose-blowing Postnasaldrip Overall rhinitis severity

group Placebo

Combined

28 34.7 (20-62)

28 34.6 (19-58)

56 34.7 (19-62)

5 8 15

6 6 16

11 14 31

14 7 0 4

24 10 2 5

3 0 2

10 4 10

10 3 2 1 7 4 8 16 (57%) 20 (71%) 7 (29%)

15 (56%) 19 (68%) 8 (32%)

2.5 3.2 2.5 2.9 2.5 3.1

2.9 3.6 2.9 3.1 2.8 3.3

* 1 = absent;2 = mild, 3 = moderate;4 = severe.

MATERIALS AND METHODS Patients Fifty-six men more than 18 yr of age with known perennial rhinitis consisting primarily of nasal stuffiness, rhinorrhea, or sneezing for a duration of at least 2 yr were admitted to the study group. The patients chosenhad symptoms severeenough to require medication on the majority of days during the 3 mo prior to the study. Management of causative factors and medication were completed to the point where the clinical syndrome had been stabilized, and no further alteration in these parameterswas contemplated which might affect the pattern of response.All patients on immunotherapy were at maintenance levels of dosage and frequency for at least 3 mo prior to the study and were continued on theseprogramswithout changethroughout the study except when levels were decreaseddue to intolerance. Patients with nasal polyps present on the initial physical examination were excluded. Informed consentwas obtained from each patient prior to entrance into the study.

Study design Patients were entered into the study in three phasesat 3 wk intervals beginning in the middle of September.The history, physical examination, laboratory, and special pro-

cedures(seebelow) were completedduring a 2 wk baseline period. Thereafter, the patients were issued in a doubleblind fashion either the active drug or the vehicle control in identical plastic bottles. The patients were askedto continue their usual symptomaticmedication schedulethroughout the baseline and double-blind periods of study, and the type of drug and frequency of use were recorded. Increasesor decreasesin symptomaticmedication, if desired by the patient during the double-blind period, were allowed and recorded. During the baseline period and the ensuing 6 wk, the patients were askedto keep daily symptom and medication diaries. The symptom severity scores and symptomduration data (in hours per day) from the daily records were analyzed with the Mann-Whitney U test by comparing the two treatmentgroups with respectto average change in symptom severity and duration in the doubleblind period relative to the baseline. In addition, the patients were seenby a physician for evaluation at 2 wk intervals. At the completion of 6 wk of therapy, each patient graded the efficacy of the study drug as providing (1) total control, (2) substantial control, (3) minor but definite control, (4) no control, or (5) aggravatednasal symptoms. After the study procedureswere completed, the code was broken. Patients obtaining substantial or total control from the active drug

lntranasal flunisolide

VOLC vlE 65 NUMt?ER 1

were enteredinto a long-term open trial, the results of which will be reported elsewhere. Those responding significantly to the vehicle control were dropped as participants. All others on vehicle control were allowed the opportunity to usethe active drug in an open fashion for three 2 wk periods and, if they benefited, were given the opportunity to enter into rhe long-term open study. Dwl FI uiisolide was delivered to the noseas a coarsedroplet spra! via a pump-activated, non- Freon-propelled device. The -pray solution contained 0.025% flunisolide in aqueous propylene glycol/polyethylene glycol. On the average, 200 kg/cay of flunisolide was administered as two sprays in each nostril twice daily. Labmatory

tests

The following laboratory testswere performedduring the 2-wk baseline period, during the last week of the doubleblind phase, and at the end of the open phase for those pat&Its who first had the vehicle control: (I) Complete blood count (CBC); routine urinalysis; serum eiectrolytes, calcium and phosphorus, total lipids and cholesterol, total protein, albumin and globulin, blood urea nitrogen (BUN), fasthig blood glucose. alkaline phosphatase,uric acid, creatinine, serum gIutamic oxaloacetic transaminase(SGOT). lactic dehydrogenase(LDH), total bilirubin, and T,; (2) three separate morning cortisols; and (3) nasal fungal cultues. Irnmu~gk

studies

The following immunologic studies were performedduring the baseline period and as indicatd: TCWI serum Ige. The total serum IgE was performed by the double-antibody radioimmunoassay method’” and reportell in international units (IU). A definitely elevated serum IgE was considered to be any value ~-100 W/ml. To:ni nasal secretion IgE. Total nasal secretion IgE was determined using the PRIST method (Pharmacia Diagnostics) f&r values ranging from 0.5 H-l/ml (the lowest detectable I#E standard by this method) to 100 IUlml. The double-antibody radioimmunoassaymethodi was used for all values of IgE > 100 IU/ml. Serum radioaifergctsorbent tesf {RAST). RAST was performed on undiluted serumusing bluegrass,ragweed,Alternaria, and house dust disks and lPSI-laheledantihuman IgE. According to the manufacturer’s (Pharmacia Diagnostics) referenceseraand disks, the test was scored l-4+ for each antigr-1. As negative controls. the radioactivities bound by heated cord sera (1gE 4 [U/ml) and antigenic disks incubatedwithout serawere determinedfor eachrun of the test. Nasal RAST. During the baselineperiod the patients were instructed to discharge their nasal secretions over a several-dayperiod into a sterile plastic container kept in the home freezer when not being used. All secretionswere then returned to the laboratory during the baseline period and kept frozen at -20” C until analysis. Sime both the gel and fluid phasesof secretions have

43

TABLE II. Comparison of treatment groups in baseline period: Skin test results (No. positive/ No. negative) TSkin test

Hmkoiida

group Phmbo

-ed

l3/28 Ragweed 9/25 22/53 Grass 9/2s 15/28 ?4/53 Trees g/25 13/2x ?I/53 I I /‘7 Mold 9/2.5 20/52 10/2X Dust IO/25 20/53 At least I posi- l4/25 (56%,) 17/2X (61%) 31/53 (58%) tive skin test beenfound to contain equal amountsof IgE.” only the fluid phase was chosen for analysis to facilitate specimen handling. Undiluted, unconcentratednasal fluid secretionswere incubated for 3 hr with identical disks as described in the serum RAST. The disks were washedand incubated for Ig hr with L2’I-labeIedantihuman IgE before countmg. Heated cord serum (IgE 4 X/ml) was run concurrently as a negative IgE control for each disk, using identical incubation periods. The individual counts of all specimensfor each antigenic disk which were lessthan the cord serumcontrol for that disk (“negative experimental counts”) were pooled and the arithmetic mean and standarddeviation determined. Since three standard deviations (SD) above the mean of these negative experimental counts approximated 20% above the meanof the pooled cord serumcontrols for all four disks, a definitely positive RAST for any nasal secretion-incubated disk was defined to be counts greater than 20% above the cord serum control for that antigenic disk. In addition, the counts from any nasal secretion-incubated disk had to be at least two SD above the mean of the negative experimental counts for that disk to be considereddetinitely positive. Nusul smearfor eosinophils. A nasal smearwas obtained during the baselineperiod and after 6 wk of drug treatment. A total of 100white blood cells were countedfrom a slide of nasal mucus. The percentageof eosinophils was recorded. and any value 210% was consideredelevated. Skin rastirtg. Skin testing by prick-puncture (I : IO or 1 :20 w/v, Cler Labs.) to a battery of grasses, weeds, trees. molds, house dust, and cat and dog dander was performed during the baseline period. A positive test was considered any reaction greater than or equal to the histamine control. RESlJLTS The ages and histories of the 56 patients entered into the double-bii& phaseof the study are shown in Table I. The flunisolide and placebo groups demonstrated no statis&aIIy significant differences with respect to age, duration of symptoms. or concomitant medication. Although in the month prior to the study the placebo group tended toward symptoms of greater

44

J. ALLERGY

lncaudo et al.

III. Significances double-blind period

TABLE

of differences

between

the average

Difference

change

from baseline

between

flunisolide

Symptom

Sneezing Stuffy nose Runny nose Nose blowing Postnasaldrip Overall rhinitis symptoms Concomitant medication use Final assessment:total or substantial control

groups

(p)

Skin test-negative

Duration

Severity

to

and placebo

Skin test-positive

CLIN. IMMUNOL. JANUARY 1980

Severity

Duration

0.039

0.04

0.47

0.17

0.0052 0.0038 0.0006

0.43 0.013

0.16 0.84 0.74 0.63

0.41 I .oo 0.35 0.94

0.010 0.85

0.010 0.042 0.023* 0.002

0.17 0.76* 0.89

*Second week of observationonly.

severity than the flunisolide group (statistically significant only for stuffy nose, p = 0.029), a past history of complicating nasal disorders was more frequent in the tlunisolide group (Table I). Furthermore, during the baseline period the two groups were not significantly different regarding individual symptom or overall symptom severity (Fig. 1). Thirty patients, 14 in the flunisolide group and 16 in the placebo group, had at least one positive skin test (Table II). Three patients were not tested. Double-blind

study

For analysis of individual symptom scores, both treatment groups were divided into those with and those without at least one positive skin test. Patients with positive skin tests respondedto flunisolide significantly better than to placebo, with a decreasein severity and duration of nose-blowing and the final assessment being the most significant responses (Table III). Significant overall differences in severity and duration of sneezingand runny nose, and severity of stuffy nose, postnasal drip, and overall rhinitis symptoms were also noted in the skin test-positive flunisolide-treated patients compared to the skin test-positive placebo-treatedpatients (Table III and Fig. 1). The decrease in concomitant medication usage also showed a significant difference between the treatment groups in skin test-positive patients but only during the second week of observation (Table III). In the smaller group of skin tes~negative patients, little symptomatic responsewas noted (Table III and Fig. l), despite the lower overall baseline severity scores for the flunisolide-treated skin test-negative group (Fig. 1). The final assessmentof the degreeof control at the

conclusion of the double-blind phasefor all patients is shown in Table IV. Forty-six percent of the flunisolide-treated group experienced total or substantial control of their nasal symptoms as comparedto 11% of the vehicle control group, a difference that was statistically significant (p = 0.031). When skin test-positive patients and skin test- negative patients were considered separately regarding their final assessment,only among skin test-positive patients was a significant benefit from flunisolide compared to placebo observed (Table III). Mild, transient nasal burning or stinging was reported by 43 patients (71% of flunisolide group, 82% of placebo group) after nasal spray use. In no casedid this effect preclude the use of the drug. Open short-term

study

All 25 of the patients using the vehicle control who reported no significant benefit during the double-blind phasewere entered into an open 6 wk study using the active drug. Twenty (80%) reported significant benefit from flunisolide. Therefore, in the combined study under either the double-blind or open protocol, 33 patients (62%) experiencedsubstantialor complete control of their nasal symptomsduring a 6 wk reporting period, while 16 (30%) did not benefit at all (Table V). Laboratory

studies

The routine hematologic, urinary, and biochemical datarevealedno significant abnormalities during the 6 wk double-blind or open phase studies. Changes in patient meancortisol levels from baseline sampling to the end of the double-blind study were examined for the active and placebo groups. Adjusted for baseline levels, there were no statistically significant differ-

VOL.lME NULlHER

65 1

lntranasal

flunisolide

45

OVERALL SEVERITY OF RHINITIS Pationtt with Om or Mom Paltiw Tmtt

A

Flunisolidrgmup

0

PlesfJo ~IouP n - 17

n = 14 I

Mod. (31 AmrOe scorn Mild Ii!)

Abnm

(1 1

Brrlim 1 2

I 6

I 4

I 6

1

End of Wak

l Matn.Whitnq

U-test

Patimtt with All Tottt Negative

0.97

I

l MmwWhitrwy

I

A

Flunitokk6rou~

0

Pkabo

group

0.97 n = 13 ” =6

U.Mr

ffi. 1. The overall rhinitis symptom severity in patients with end without positive skin tests at the end of each 2-wk observation period. The end of week 2 is the end of the baseline period.

ences between the two treatment groups (p = 0.99). Over a period of 6 wk. sequential fungal cultures wen performed on 31 patients being treated with active drug. Two cultures changed from negative to positive, growing actinomyces and penicillium, respectively. In contrast, six patients had positive nasal fur@ culmres at the onset of the study which subsequently becamenegative after 6 wk of active drug treatment.

Not all laboratory studies were obtained on each patient. Three patients did not complete the akin testing appropriately, 12 patients did not provide nasal secretions, and in one patient a nasal smear for eosinophils was not obtained. Thirty-seven patients completed ali six prooedures. Correlations of the immunologic parameters with significant benefit from flunisolide are summarized in

46

J. ALLERGY

lncaudo et al.

IV. Flunisolide vs vehicle control in the double-blind study: Final assessment*

TABLE

Results

Total or substantialcontrol Minor benefit No benefit or aggravated symptoms

Flunisolide

Vehicle control

13/28 (46%) 3/28 (11%) 3/28 (11%) 5/28 (18%) 12/28 (43%) 20/28 (71%)

*p = 0.031 (Mann-WhitneyU test).

Table VI for the double-blind phaseand in Table VII for the combined study. Skin tests. Among the 52 patients with perennial rhinitis who were skin tested, 30 (58%) had at least one positive reaction (Table II). In the double-blind phaseof the study, significant benefit from flunisolide was more likely to be found in the skin test-positive group as compared to the skin test-negative patients (75% vs 30%, p = 0.03). The difference loses its statistical significance when the data of the doubleblind and open study are combined, since 78% of the skin test-positive patients benefited comparedto 61% of the skin test-negative group in the combined study. Total serum ZgE. Total serum IgE ranged from 14 to 6,750 III/ml with a mean value of 292 IUlml. Benefit from flunisolide correlated significantly with a total IgE ~100 IUlml in the combined study only (p = 0.03), although it nearly reachedsignificance in the double-blind phase (p = 0.06). Total IgE in nasal secretions. Total nasal IgE varied from undetectableconcentrations(co.5 III/ml) to 800 IU/ml. Overall, 30 of the samples tested had some detectable IgE by the PRIST method. In four patients, total nasal IgE was greater than the total serum IgE. Benefit from flunisolide correlated significantly with detectable nasal IgE (~0.5 IU/ml) in the combined study only. Specific serum ZgE. Specific serum IgE against at least one antigen was found in 16 of 56 patients tested (29%). Overall, 21 of 224 tests (9%) performed were positive, with grass (9) and short ragweed (8) being most frequently positive. Specific serum RAST positivity did not correlate significantly with benefit in either the double-blind or combined study groups. Specific nasal IgE. The presenceof specific nasal IgE against at least one antigen was found in 17 of 44 patients studied (39%). Overall, there were 30 positive reactions in the 154 testsperformed (19%). Most positive reactions were observed to grass antigen (14), followed by ragweed (9), house dust (4), and altemaria (3). Benefit was significantly correlated

CLIN. IMMUNOL. JANUARY 1980

with the presence of specific nasal IgE in both the double-blind and combined phasesof the study. Nasal eosinophilia. Nasal eosinophilia rangedfrom 0 to 61% of the total number of white blood cells counted. A statistically significant relationship to benefit from flunisolide was found in the combined study (Table VII) when nasal eosinophils were 210%. Nasal eosinophil smearswere obtained from 2 1 patients before and after 6 wk of flunisolide treatment. There was no statistically significant eosinophil reduction or correlation between changes in nasal eosinophil counts and responseto flunisolide spray. Combinations of parameters. Patients with both negative skin tests and an IgE < 100 IU/ml were significantly less likely to benefit from flunisolide than those who had either one or the other positive (Table VI). Although most of the patients who benefited from flunisolide had one or more positive immunologic parameters, having one or more positive tests did not insure successwith flunisolide, nor did lacking one or more positive tests insure failure (Table VII). Similarly, although most patients with all six immunologic parameters positive benefited, one such patient did not (Table VII). DISCUSSION The use of an intranasal corticosteroid capable of relieving symptomswithout inducing detectableadrenal suppression was first reported by Czamy and Brostoff2 in 1968. These authors demonstrateddefinite benefit in a double-blind crossover trial in perennial rhinitis from instilling 0.4 mg daily of betamethasone-17-valerateas a nasal spray. One out of 12 patients who received the active drug demonstrated transient adrenal suppressionas measuredby plasma cortisol concentrations and ACTH stimulation. Of the seven patients with suspectedvasomotor rhinitis, only one improved in this study. The same authors 1 yr later reported 82% benefit in patients with allergic rhinitis who received 0.28 mg of the drug per day with no demonstrable adrenal-suppressive or local toxic effect.I8 The emergence in 1972’ of beclomethasone dipro-

prionate as an aerosolizedsteroid effective in treating asthma while causing limited or no adrenal suppression promptedits study in patients with rhinitis. Using 400 pg per day, Mygind3 reported an 86% benefit in seasonalallergic rhinitis with no change noted in urinary 17-ketogenic steroid excretion. Such a significant effect on nasal symptomswas later substantiated by Brown and Storey,ls who used the same dosagein 72 patients with allergic rhinitis.

lntranasal

VOLI. ME 65 NUPF3ER 1

TABLE V. Overall

benefit

from flunisolide

in the double-blind, DoubkMnd

-.

47

open, and combined study comblMddata

ml--

13 (46%) 3 (I I%) 12 (43%) 28

Total or substantial benefit Minor benefit No benefit or aggravated symptoms Total

flunisolide

33 (62%) 4 (X0/) i h (3W& ) 53

20 (80%) I (4%) 4 (16%) 25*

*Three patients who attained total or substantial control on vehicle during double-blind phase were not entered into open phase.

TABLE VI. Double-blind study: Correlation immunologic parameters with significant benefit from flunisolide* -..

TABLE WI. Combined double-blind study: Correlation of immunologic parameters with significant benefit flunisolide*

of

SiiIfkent benefit from Yes

No

At least 1 positive skin test

No

9 3 8 5 8 2

3 7 3 9 4 5

Total serum IgE 5 100 W/ml Total nasal IgE 2 3.5 W/ml

At Ir,ast 1 positive serum RAST At Last 1 positive nasal RAST

Yes

5

No

8 6 5 5 7 3 9

Nasitl smear for eosinophils ~10%

Negativeskin tests and IgE < 100

-.

Yes No Yes No

Yes

Yes No Yes No Yes No

x’

I 8 3 9 7 3

from flunlwllde

PVdW

Yes 4.46

0.03

I .46

0.23

6

II

7

21

5

No Yes No Yes No Yes No Yes

I2 22 4 I3 20 13 I4 19

II 4 5 3 I3 I 0 3

4.54

0.03

5.65

0.02

2.09

0. IS

4.51

0.03

eosinophils z 10% No

I3

12

6.36

0.01

Yes

22

5

six immunologic No parameterspositive

2

2

I .98

0.16

L

0.63

0.43

0.1 I

3.11

0.08

4.10

0.04

0.75

0.39

IgE z 100 Wml Total nasal IgE 20.5 lu/ml At least I positive serum RAST At least I positive nasal RAST Nasalsmearfor

4.46

0.03

One or more of the

tranasal beclomethasone in patients with perennial rhin tis, relating the responseto somemeasureof “allergy. ’ ’ The results of intranasal beclomethasone trea:ment in perennial rhinitis were first reported by Hansen and Mygind in 1974.‘* Among 21 patients with perennial rhinitis, the majority of whom had positive skin tests and nasal eosinophilia, 71% preferred intranasal bectomethasoneover placebo. The authors believed that the drug was most effective in those with watery rhinorrhea and nasal eosinophilia, but no data were given. In a double-blind crossover study, Gibson et al. l3 used 200 pg of beclomethasone dail:, in 25 patients with perennial rhinitis characterized as “extrinsic” or “intrinsic” by history and skin test positivity. Eighty-one percent of the former

pvdue

21

2.57

Several studies have investigated the effect of in-

x2

Yes No Yes

0.06

*Siytificant benefit includes patients experiencing substantial or tol:+l control on flunisoiide. Data excludes three patients who experienced minor but definite control of symptoms on Bunkolid,..

No

At least 1 positive skin test Total serum

3.38

I II

from

S@iBwnt

flunisolide -.

and open

All six immunologic parameters positive

Yes

7

No

I7

*Significant benefit includes patients experiencingsubstantialof total coowol on flunkolide. Combined data exc&&s fw patients who experienced minor but definite benefit on flunisolide and three patientswho attained total or substuntiiid control on vehicle alone.

group benefited, contrasted with 67% of the latter group. In 1975, Smith et al. I4 reportedon the effect of 400 pg per day of intranasal beclometbasonein 58 patients, 45 of whom had perennial rhinitis with positive skin tests to house dust mite and 13 of whom were pollen sensitive. Sixty-nine percent of the pollen-sensitive patients and 75% of the perennial rhinitis patients with positive nasal provocation challenges to mite extract improved in contrast to 47% of the perennial rhinitis patients with negative nasal prc+ vocation tests. Ruff et a1.15in 1975 demonstratedbenefit from beclomethasonein 89% of patients with

48 lncaudo et al.

J. ALLERGY

seasonal allergic rhinitis but in 67% of patients with “chronic rhinitis. ” In 1977, Tarlo et a1.20studied 26 patients with perennial rhinitis using skin tests, total serum IgE, and nasal and serum R4ST to house dust to define their allergic status. After 3 wk of beclomethasonediprop-

rionate intranasal aerosol treatment, similar benefit was demonstratedin “allergic” vs “nonallergic” patient groups (53% vs 55%). However, after 6 mo of treatment, 75% of patients with allergy benefited in

contrast to 67% of the group of patients who were not allergic. These results compare favorably with Liifkvist and Svensson,2Lwho found a 64% successrate with beclomethasone treatment in 39 patients with

perennial rhinitis and intracutaneous skin test negativity (defined as vasomotor rhinitis). The present study shows that instilling 200 pg of flunisolide intranasally daily over 6 wk produced

substantial symptomatic improvement without adrenal-suppressive, systemic, or local toxic effects in

CLIN. IMMUNOL. JANUARY 1980

ence to intranasal flunisolide response. Benefit from flunisolide correlated significandy (p 5 0.05) with skin test positivity in the double-blind phase and with

nasal RAST reactivity in both the double-blind and combined studies. The combined study additionally demonstrated a significant relationship to total serum IgE, total nasal IgE, and nasal eosinophilia.

We interpret these data as indicating that an active allergic diathesis is most likely to respond to intranasal steroids. Eosinophils within the nasal mucus have been associatedwith local IgE-mediated events and have been acceptedas evidence of allergic rhinitis.22An elevated total serum IgE has been shown, in the absenceof dermatitis or parasitic infestation, to be a good indication of atopic potential.23 Immediate skin test positivity carries similar significance and is more specific. The presence of detectable total nasal IgE has been suggested as characteristic of an atopic individual,24, 25and the presence of specific nasal IgE

in the

(nasal RAST) may most directly reflect the potential for intranasal immediate-type hypersensitivity. It is

double-blind study and in 62% of patients in the

thus interesting that the presence of a positive nasal

combined double-blind and open study. Greater success with flunisolide in the treatment of seasonal al-

RAST was the only immunologic parameter to be

lergic’, 8 and perennials-” rhinitis has been reported by others. This may partially relate to the dosage of flunisolide used, in that our study used 200 pg daily, while two other studies of patients with perennial rhinitis used300 pg daily. lo, l1 Another reasonfor the

double-blind and combined phasesof our study. Although the presenceof atopic indicators substantially increasesthe probability of a favorable response to flunisolide, the absenceof these indicators did not exclude, nor did the presenceguarantee,successwith the drug. Two of four patients with all negative tests benefited also (Tables VII, G), while one patient possessing all six positive immunologic parameters did not (Table VII, H).

46% of patients with

perennial

rhinitis

differences in our results compared to the results of others may relate to the atopic status of the patients

studied. The patients with seasonalallergic rhinitis’, * and those in two studies of perennial rhinitisg, lo all had positive skin teststo inhalant antigens, while 42% of our patients had all negative skin tests. Since studies with intranasal beclomethasone had

suggesteda relationship between drug effectiveness and the atopic statusof the patient, such a relationship hasbeen soughtusing flunisolide. Schulz et al. l1 studied perennial rhinitis patients with both positive and all negative skin tests. Although many patients in both skin test groups improved, these authors found statis-

tically significant improvement compared to placebo only in the skin test-positive group. Similarly, Bloom et al .s noted that atopic indicators such as serum IgE, total peripheral eosinophil count, and number of positive skin tests were somewhat predictive of improvement with flunisolide, although these relationships did not achieve statistical significance in their study. In an attempt to define immunologic indices most predictive of intranasal steroid benefit, we studied skin test reactivity, nasal secretion and serum RAST to four specific antigens, total serum IgE, total nasal IgE, and nasal eosinophilia in our patients with refer-

significantly

associated with

benefit in both the

We wish to thank Dr. Donald Hoffman for kindly supplying the antigen disks used in the RAST procedure, Dr. Robert Hamburger for performing the double-antibody radioimmunoassay for total IgE, Carol Lipinski and Andrea

Peronefor their invaluabletechnicalassistance, andWanda Mendoza for her excellent secretarial assistance. REFWENCES

1. BrownWM, StoreyG, GeorgeWHS:Beclomethasone dipropionate:A newsteroidfor thetreatmentof allergicasthma.Br Med .J1:585,1972. 2. CzamyD, BrostoffJ: Effectof intranasalbetamethasone-17valerateon perennialrhinitis and adrenalfunction. Lancet 2~188,1968. 3. Mygind N: Local effect of intranasalbeclomethasone dipropionateaerosolin hay fever. Br Med J 4:464, 1973. CS:Hydrocortisone alcoholin thelocaltreatment 4. Pennypacker of hayfever:A preliminarystudy.J ALLERGY 25:513, 1954. snuff in hayfever:A 5. GodfreyMP, MaunsellK: Prednisolone controlledstudy.Lancet1:757,1957. 6. Aaron TH, Muttitt ELC: Effect of intranasaldexamethasone phosphateon the adrenalfunction of Patientswith perennial allergicrhinitis. Ann Allergy 23:100, 1965. 7. Turlceltaub PC, NormanPS,CrepeaS: Treatmentof ragweed

VOLCiklE NUMBER

65 1

lntranasal

h.1): fever with an intranasal spray containing flunisolide, a new .;/nthetic corticosteroid. J ALLERGY CLIN hiMUNO1. 58597, l’J76. 8. Kammermeyer

9.

IO. I I.

12.

13.

14.

15.

TK,

Rajtora

DW,

Anuras

J. Richerson

in normal and allergic Med 77:690, 17. Ishizaka

HB:

Clinical evaluation of intranasal topical tlunisolide therapy in 59:287, 1977. allergic rhinitis. J ALLERGY CLIN IM~~NOL B,oom FL. Cohan RH, Leifer KN, Spangler DL. Rhoades RB. \T’ittig HJ: Flunisolide aerosol in the treatment of perennial allergic rhinitis. Ann Allergy 38:408, 1977. I* xan JD, Johnson JD: Flunisolide nasal spray in the treatment 01 perennial rhinitis. CMA J 119:334, 1978. S:hulz JI, Johnson JD. Freedman SO: Double-blind trial comparing flunisolide and placebo for the treatment of perennial rhinitis. Clin Allergy 8:313, 1978. H msen J, Mygind N: Local effect of intranasal beclonr:thasone dipmpionate aerosol in perennial rhinitis. Acta AlIt c-gologica 29~28 I. 1974. <; bson GJ. Maberly DJ. Lal S, Ali MM, Butler AC: Double b Ind crossover trial comparing intranasal beclomethasone d xoplonate and placebo in perennial rhinitis. Br Med J 4:503, I 74. S lith JM, Clegg RT, Cook N, Butler AC: Intranasal becI( nethasone dipropionate in allergic rhinitis. Br Med J 1:255. 11.75. R. ff F. Boutaric P. Salem A, Brouet G: A two-stage clinical

as’*essment of beclomethasone diproprionate aerosols. PostII id Med Sl(Suppl 4):54. 1975. 16. G :ich GJ. Auerhcck AK, Swedhmd HA: Measurement of IgE

18.

19.

20.

2 I.

flunisolide

serum by radioimmunrra.say

49

J Lab Clin

1971.

K, NewcombRW:

Presence of IgE in nasal washings

andsputumfromasdunaticpatients. JAUERGY &:lY7. 1970. Brostoff J, Czamy D: Effect of intranasal betamethasone- 17valerate on allergic rhinitis and adrenal function J Al.1 t;RGt’ 44:77. l%9. Brown HM, Storey G: Beclornethasone dipropionate aerosol in the treatment of seasonal hay asthma and ha> fever. C1.r~ At I.ERCY 4:33l. IY74. Tarlo SM. Cockcroft DW. Dolovich 1. Hargreavc FE: Beclomethasone dipropionate aerosol in perennial rhinitis. J AI I ERGY CI.IN IHSIUNOI. 59:232, 1977. Liifkvist T. Svensson G: Treatment of vasomotor rhinitis with intmnasal beclomethasone dipropionate. Acta Allerpol 31:

227. 1976. Viner AL. Jackman N: Retrospective survey of 1271 patients diagnosed as perennial rhinitis. Clin Allergy 6:25 I, 1976. 23. Spitz E. Celfand EW, Sheffer AL, Austen KF: Serum IgE in clinical immunology and allergy. J AI.I.~..H(;~ CI I\ IMCII.\OI 49~337. 1972. 24. Yunginger JW, Gleich GJ: Seasonal changes In serum and nasal IgE concentrations. J At.1 FRGY Cr IY IWMI.NOI 51: 174. 1973. 25. Nakajima S. Gillespie DN, Gleich GJ: Differences between IgA and IgE as secretory proteins. Clin Exp Immunol 21:306. 197.5. 22.

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