ADRENAL
FUNCTION
IN ALLERGY
III.
Effect
of
Prolonged
Intermiffent
Steroid
Therapy
in Allergic
Children
By Sheldon C. Siegel, M.D., Bailey J. Lovin, Jr., M.D., Robert S. Ely, M.D.,
and Vincent C. Kelley, M.D., Ph.D.
Chikiren’s Medical Group, Los Angeles, Harbor General Hospital, Torrance, California, Department of
Pediatrics, University of Utah College of Medicine, and Department of Pediatrics, Unicersity of California at Los Angeles
(Accepted May 5, 1959; submitted February 9.)
This research was supported in part by grants from the Harbor General Hospital Attending Staff Association and the Upjohn Co.
ADDRESS: (S.C.S.) Children’s Medical Group, 58:30 Overhill Drive, Los Angeles 43, California.
PEDIATRICS, September 1959
434 DRENOCORTICOTROPIN and the adrenal
steroids have become recognized as
potent adjuncts in the treatment of atopic
hypersensitivities. However, because of the
possibility of serious deleterious side effects,
prolonged administration of these hormones
in the treatment of chronic allergic diseases
has been controversial and often rightfully
condemned. Obviously the development of
a steroid preparation, or regimen of therapy
with these hormones, which would negate
all or most of the harmful side effects of
these drugs would provide a welcome
addi-tion to the physician’s armamentarium.
Lange’ attempted to obviate the
unto-ward effects of prolonged hormone
ad-ministration in nephrotic patients by a
schedule of “interrupted” use of hormone
therapy; this subsequently became widely
employed in the treatment of patients with
the nephrotic syndrome. Despite its useful
application in the therapy of the nephrotic
syndrome, this regimen has not been
em-ployed generally in other chronic diseases
in which prolonged hormone treatment
often is used.
Furthermore, only a few meager reports
of the complications of administration of
intermittent hormone therapy in nephrosis
have appeared in the literature. None of
these reports includes definitive evaluation
of the effectiveness of this schedule of
ther-apy in reducing the potential hazard of
adrenal hypofunction that is known to be
induced by the administration of steroids.’9
Techniques for directly measuring the
levels of adrenocortical hormones in the
blood and urine following the
administra-don of a stimulating dose of
adrenocortico-tropin (ACTH) have provided an excellent
and sensitive means of assessing adrenal
re-sponsiveness. By utilizing one of these
di-rect methods-the technique of measuring
the increase in level of circulating
17-hy-droxycorticosteroids (17-OHCS) in response
to the administration of exogenous
ACTH-the authors’#{176} previously demonstrated that
while allergic children were receiving
ster-oids the adrenal response to ACTH was
im-paired markedly.
The present study was undertaken to
de-termine whether a schedule of intermittent
steroid therapy is effective in the treatment
of children with severe allergic disorders
and obviates some of the harmful effects of
continuous steroid administration. In an
attempt to evaluate further some of the
pos-sible deleterious side effects from
pro-longed steroid administration, the adrenal
responsiveness of most of these patients
was investigated before, and at varying
periods of time after, the introduction of
in-termittent steroid treatment.
SUBJECTS
The subjects were 42 children with severe
ARTICLES
California at Los Angeles and from private
pa-tients of the Children’s Medical Group. Only those allergic children who had failed to respond to orthodox methods of allergic man-agement were selected for intermittent steroid
therapy.
TREATMENT
The steroid used was prednisolone. This was administered either in the form of a
palatable suspension for the infants and
younger children (fluid Delta-Cortef#{174}) or in the form of tablets (Meticontelone#{174}). *
The drug was administered orally for 3
suc-cessive days of each week followed by a 4-day rest period, during which steroids were with-held. Initially the dose administered varied
with the age and size of the patient and with
the severity of the illness, but was always in
the realm of what the authors have found to be
a suppressive amount for atopic hypensensitivi-ties in children-usually 15 to 30 mg/day given in two or three divided doses.h1 Jf a good
clinical response was observed, the dose was tapered gradually to determine the minimum amount of hormone which would keep the pa-tient’s disease under satisfactory control. Thus, by this tapering technique, the patient re-ceived the least amount of hormone which would control the symptoms.
Each patient was observed at least once a
week, usually at the end of each nest period,
at which time the weight, blood pressure and
clinical status were noted. Based on these
weekly clinical evaluations, the patient’s
ne-sponse to therapy was classified into one of three categories: 1) excellent; 2) good; or 3) poor. Those patients classified as having an
“excellent” response had complete clinical
re-lief. Those classified as “good” had the symp-toms relieved to the extent that they could
participate in most normal daily activities.
Fi-nally, those subjects who had no change in
their clinical condition despite therapy were
considered to have “poor” responses.
EVALUATION OF ADRENAL FUNCTION
In the majority of the patients
adnenocorti-0 Dr. C. J. Donovan, Department of Clinical Investigation, the Upjohn Company, kindly sup-plied the fluid Delta-Gortef#{174}. The Meticortelone#{174} tablets were furnished through the courtesy of Dr.
Babcock, Schering Corp.
cal function was evaluated before and after in-stitution of the schedule of intermittent steroid therapy. The method of assessing adrenocorti-cal function consisted of a standardized
17-OHCS response test12 performed as follows:
Heparinized blood specimens were obtained by
venipunctune before and 2 hours after the in-tramuscular administration of 25 units of
lyo-philized ACTH. After the blood was
with-drawn, it was immediately centrifuged and the plasma frozen. Following this initial freezing, the specimens were packed in dry ice and shipped by air express to Salt Lake City where determination of the 17-OHCS concentration was made by the method of Nelson and Sam-uels .
As a further method of evaluating the effect of intermittent steroid treatment on
adrenocorti-cal function, 24-hour collections of urine were
obtained daily for a 1-week period from 16 subjects for determination of the total daily
excretion of 17-ketosteroids (17-KS) and
17-OHCS. During collections, hydrochloric acid
was used as a preservative, and the urine was
kept under refrigeration. After the total volume of the 24-hour urine collection was measured,
aliquots of 60 ml were removed from each and
frozen until analyzed for 17-KS by the method
of Klendshop et al.14 and for 17-OHGS by the method of Glenn and Nelson.’
RESULTS
Clinical Response to Schedule of
Intermittent Steroid Therapy
In Table I the clinical results observed
in the 42 patients treated with intermittent
hormone therapy are summarized. Most of
the subjects were patients suffering from
severe bronchial asthma (29 cases). Six
pa-tients were afflicted with atopic dermatitis
alone, and seven had both asthma and
atopic dermatitis. The initial suppressive
dose of prednisolone ranged from 15 to 30
mg/day, the average being 24.3 mg for all
42 patients. The duration of therapy varied
considerably; the shortest course was 1%
months and the longest, 20 months. As can
* The ACTH (Acthar))) for the response tests
was supplied through the courtesy of the Armour
TABLE I
CLINICAL OBSERVATIONS
Initial I)ose Total Pred- Duration of JJ ‘eight #{149}
. 1ge , . . * . . , . (‘linical
AO. Patient ‘es Diagnosis ofPrednis- nisoloiie Therapy (rai,i
(yr) , . Response
okine (rng) (iiven (rng) (mo) (Ib)
I R.A. 14 M BA 30 575 3 19 Excellent
2 C.B. 3 M AD 25 1,507 13 4 Good
3 I1.B. 7 M BA 15 517 24 2l Good
4 A.C. 11 F BA 30 3,892 17 16 Good
5 D.B. 15 %I BA 30 255 1 0 Good
6 B.C. 4 M AD 20 2,355 10 Good
7 D.C. 8 M BA 30 937 4 4 Excellent
8 S.C. 6 F BA 30 2,447 9 4 Good
9 D.C. 5 M BA 15 1,132 11 5 Good
10 F.D. 14 M BA 30 1,080 6 15 Excellent
11 J.E. 6 F BA 2(1 335 2 3 Excellent
12 S.G. ‘3 M BA 20 1,745 16 9 Good
13 R.G. 3 M BA 20 1,491 11 (1 Poor
14 AG. 10 M BA 20 517 5 10 Good
15 RH. 3 F AD, BA 20 705 3 (1 Good
16 D.K. 5 M BA, AD 30 2,287 7 3 Poor
17 BK. 8 F BA 25 887 6 4 Poor
18 B.L. ‘3 M BA, AD 15 1,236 11 2 Good
19 R.L. 8 M BA 30 2,302 13 6 Good
20 A.L. 88 F BA, AD 30 779 34 5 Excellent
21 G.L. 6 iI BA 30 474 4 3 Excellent
22 D.M. 3 M BA 20 361 41 3 Excellent
23 SM. 9 M BA 20 579 44 9 Good
24 C.M. 7 M BA, AD ‘20 675 3 0 Good
25 G.M. 8 M BA, AD ‘25 1,488 13 4 Good
26 J.M. 11 M BA 30 202 3 ? Good
27 W.N. 9 M BA 20 456 9 ? Good
28 J.O. 2 M AD 30 1,026 8 3 Good
29 C.P. 9 F BA 20 975 12 8 Excellent
30 KR. 10 M BA 20 507 11 23 Good
31 R.R. 10 M AD 30 3,199 14 9 Good
32 KR. 6 F BA 30 1,419 14 15 Excellent
33 T.S. 6 M BA 20 306 24 2 Good
34 L.S. 1 F BA 30 525 4 2 Good
35 CS. 11 F BA 20 564 3l 6 Excellent
36 MS. 10 M BA 20 2,649 ‘20 5 Good
37 5.5. 10 F BA 20 650 5 18 Good
38 J.S. 3 M BA 20 1,636 7 0 Good
39 G.T. 2 M Al) 30 1,551 9 1 Good
40 B.U.t 6 F BA 20 1,095 10 5 Good
40 B.U.t 20 1,395 8 4 Good
41 MW. 1 F Al) 30 1,047 6 4 Good
42 C.Z. 7 F BA, AD 30 546 41 9 Excellent
* BA-Bronchial asthma.
AD-Atopic dermatitis.
t Patient received two separate courses of therapy.
be observed in Table I, the majority of the In those asthmatic patients responding
patients treated had a favorable response favorably to treatment, a characteristic
to the intermittent therapeutic program; the clinical pattern was observed. Usually
with-response was classified as excellent in 11 in 12 to 24 hours after steroid
437
disappeared or were easily controlled by
other drugs. In most cases this “freedom”
from asthma persisted throughout the
re-maining period of time that the steroids
were administered and for another 24 to
72 hours after steroids had been
discon-tinued. Then the wheezing gradually
in-creased in intensity so that by the fourth
day of the rest period most of the children
required the use of other drugs to control
the asthma.
The patients with atopic dermatitis had
a similar sequence in their response.
How-ever, the pattern differed slightly in that
a longer period of time elapsed before the
dermatitis improved. Furthermore,
al-though the skin lesions improved greatly,
they usually did not disappear completely
or heal. As was noted in the asthmatic
chil-dren, on the third and fourth days after
discontinuance of steroids, a gradual
reap-pearance of the symptoms and findings was
observed. Although the dermatitis was not
completely controlled, the patients’
discom-fort was alleviated considerably, and it
be-came feasible to manage patients with
gen-eralized acute atopic dermatitis without
hospitalization.
Although the majority of subjects treated
with this type of therapy were improved,
there were three children whose symptoms
were not controlled adequately. In these
cases severe symptoms and signs of their
disease recurred almost immediately upon
discontinuation of the steroid.
Evaluation of Adrenal Function
ACTH-17-OHCS RESPONSE TEST: In
Table II the data from the
ACTH-17-OHCS response tests performed prior to the
introduction of intermittent therapy
(pre-therapy) and following the institution of
this treatment (post-therapy) are shown.
Response tests were done in 41 of the
sub-jects, and in some patients several
post-therapy tests were done. All post-therapy
response tests were performed on the last
day of the rest period.
In 27 of the subjects both pre- and
post-therapy response tests were obtained
(
asindicated in Table II). For statistical
pur-poses the results of the paired pre- and
post-therapy response tests in these 27
mdi-viduals were compared (Table III). In
making this comparison it was decided
an-bitranily to select only the first post-therapy
response obtained in any one subject. As
shown in Table III, the mean 17-OHCS
re-sponse in the pre-therapy tests on the 27
subjects was 17.4 p.g/100 ml as compared
to a mean of 9.8 .g/10O ml in the
post-therapy tests. The difference between these
mean responses is statistically significant at
a level of significance beyond 1% (as
deter-mined by the t-test [t 3.11] and the
signed rank test). On the other hand, the
mean 17-OHCS response observed in the
pre-therapy group (17.4 tg/100 ml) was
not statistically different from the mean
re-sponse of 17.8 i.g/ml found in 40
non-al-lergic children.
The results of these studies indicate that
prior to institution of intermittent hormone
therapy, there appears to be no impairment
of the adrenal response to ACTH. However,
once intermittent steroid therapy has been
initiated, the ability of the adrenals to
re-spond to ACTH is partially impaired. The
results also demonstrate that the
suppres-sion of the adrenal response to exogenous
ACTH is not alleviated completely by
with-holding steroids for a 4-day period.
Emcr OF DOSAGE AND DURATION OF
Tiiiw’y: To determine whether dosage
was a factor in the apparent suppression of
the adrenocortical response to ACTH, a
number of ACTH-17-OHCS tests were
performed while patients were receiving
variable amounts of prednisolone. Because
of the relatively small number of tests
oh-tamed for this purpose, the results were
grouped into only three dose categories:
2.5 to 5 mg; 7.5 to 19 mg; and 20 to 30
mg. As the dose of prednisolone was
in-creased, there was a definite trend for the
ACTH-17-OHCS response to decrease
(
Table IV). Even though the number ofpa-tients studied is relatively small and there
is considerable variability in the responses
observed in the 2.5 to 5 mg-dose category,
it appears likely that suppression of
Before Titerapi,
. 1 7-Ifydroxycorticoxteroids Dose
Pred-Patient
(g/lO() in!) nisolone
-______________
----
(nig/240 hr 2 hr Change hr)
After Therapy
Duration I 7-!!ydroxycorticosteroid.s
of (ig/lOO ml)
Therapy ----
-(mo) 0 hr 2 hr Change
1_R.A.* 0.0
---i
2.3 2.5 3 4.2 10.0 5.82C.B.* 0.0 26.1 26.1 2.5 4 0.0 15.7 15.7
20.() 2 0.0 6.6 6.6
1.3 17.4 15.9 25.0 1 7.? 9.9 ‘2.7
4-R.B. - - - 10.0 5 ‘2.5 21.0 18.5
0.0 ‘22.!) 22.9 30.0 3 7.3 17. 1 9.8
20.0 5 3.0 14.6 11.6
20.0 9 0.0 14.2 14.2
12.5 13 0.3 6.6 6.3
3.0 17 0.0 17.5 17.5
6_B.C.* 0.0 7.6 7.6 ‘20.0 3 0.0 6.8 6.8
7_1).C.* 3.8 ‘27.2 23.4 10.0 ‘2
5 0.0 1.6 I .6
18-A.L.
19-B.L. - - - 7.3
‘2 ‘2.0 ‘25.9 23.9
4 0.0 16.2 16.2
* Patients from whoni paired pre- and Post-therapY responses were obtained.
t Patient received two separate courses of therapy.
TABLE II
ACTII-l 7-OIICS HESPONSE TESTS BEFORE AND AFTER THEIIA I’Y
11.8 17.5 3.7
.5.0 4 2. 10.6
8_1).C.* 0.0 14.6 14.6 .5.0 3 6.1 27.0 20.9
9_J.C.* 1.8 20.7 18.9 20.0
10-Fl). 0.0 19.2 19.2
24.8 26.4
- -
-11-J.E. 2.4 - -
-12_A.G.* 0.4
13-R.G. 0.0
4.5 4.1 2.5 5 4.7 17.1
77.2 77.2 -
-12.4
-14-S.G. - - - 15.0 3 0.() 3.7 3.7
5.0 5 0.0 I .9 1 .9
5.0 7 0.0 17.3 17.5
5.0 9 0.0 9.0 9.()
10.0 17 4.5 33.5 29.0
-;ii--16-BK. 5.4 21.8 16.4 - -
-17-D.K. 4.0 10.7 6.7 - -
Before Therapy 1 7-Ilydroxycorticosteroids Patient (j.sg/lOO ml) 0 hr .lfter Therapy
2 hr Change
20_G.L.* 2.6 39.3 36.7 10.0 24 0.0 0.0 0.0
fl_R.L.* 6.1 24.6 18.5 25.0
15.0 10.0 7.5 1 l 7 94 8.8 0.0 0.0 0.0 19.4 6.9 0.0 11.0 10.6 6.9 0.0 11.0
2’2_1).M.* 4.7 14.2 9.5 5.0
2.5 24 54 0.0 13.9 10.6 12.1 10.6 -1.8
23-G.M. - - - 20.0
12.5 1 0.0 11 0.0 9.6 19.6 9.6 19.6 24_J.M.* 25_S.M.* 26_W.N.* 27_J.O.* 28_C.P.* 7.1 6.7 5.7 8.9 0.5
14.7 7.6 20.0
5.0
18.4 11.7 10.0
5.0
5.9 0.2 15.0
. 10.0
27.9 19.0 20.0
77.4 76.9 12.5
7.5 1 0.0 8 8.8 14.3 11.9 14.3 8.1 2 34
0.9 7.0 6.1
0.0 13.0 13.0
5 64 6.3 0.0 12.7 8.7 6.4 8.7
4 9.8 20.4 10.6
5 9 0.0 0.0 15.4 20.6 15.4 20.6
29_K.R.* 7.0 11.4 4.4 15.0
5.0 .5 44 9 11 9.7 0.0 6.8 9.9 U.2 0.2 12.2 17.4
30_K.R.* 8.4 29.9 21.5 25.0
7.5 2.5 24 84 15 1.2 0.0 0.0 18.0 0.0 29.9 16.8 0.0 29.9
31_R.R.* 9.2 32.8 23.6 30.0
30.0 15.0 14 6 13 0.0 0.0 0.0 16.1 11.7 16.8 16.1 11.7 16.8
32-J.S. - - - 20.0
5.0 2l 6 5.4 3.8 8.8 13.8 3.4 10(4
33_L.S.* 3.5 24.1 20.6 2.5 5 0.0 28.2 28.2
34_M.S.* 1.3 18.7 15.4 15.0
12.5 6 11 0.0 0.0 14.1 14.9 14.1 14.9
35_T.S.* 3.2 20.3 17.1 2.5 10 3.3 22.2 18.9
36-S.S. - - 10.0 5 0.0 15.2 15.2
(Continued on next page)
ARTICLES 439
TABLE II (C’ontinued)
l)ose Pred- Duration 1 7-Hydroxycorlicosteroids
nisolone of (Mg/lOU ml)
(ing/24) Therapy
Patient
Before Therapy
0 hr 2 hr
Dose Pred-nisolone
(mg/2.)
hr) Change
37-CT.
38_BJT.*
38-B.11.t
I)uration
of
Therapy (nio)
11.3 ‘27.3 16.0
11.6 30.6 19.()
39\I\\r* 0.0 8.5 8.5
40_C.Z.* 14.3 33.0 18.7
S Non-allergic children.
TABLE II (Continued)
1 7-ilydroxycorlicosteroids
(g/lOO ml)
After Therapy
I 7-Ilydroxycorticosteroids (g/1()O ml)
(4hr 2 hr Change
30.0 4 0.0 6.0 6.0
12.5 6 0.() 0.0 0.0
30.0 3 6.2 8.4 ‘2.2
10.0 S 3.8 6.4 ‘2.6
‘2.5 ii 0.0 54.7 .54.7
15.0 S I..5 8. 7 7.’2
‘25.0 ‘2 4.4 8.0 3.6
5.0 44 0.0 4.3 4.3
hormone therapy is related to dosage of
hormone received.
In contrast, duration of therapy did not
appear to affect the magnitude of the
ACTH-17-OHCS response. However, it
should be pointed out that any effect of
duration of therapy on the
ACTH-17-OHCS response test may have been masked
by the intentional alteration of the dosage
of hormone administered (the longer the
duration of therapy, the more likely a
smaller dose was administered). It is
con-ceivable that had the dose of prednisolone
been maintained at the initial level, the
duration of therapy might have been shown
to affect the magnitude of the
adrenocorti-cal response to ACTH.
TABLE III
COMPARISON OF 27 PAIRED ACTH-17-OHCS
RESPONSE TESTS, BEFORE AND AFTER
RE-CEIVING INTERMITTENT STEROID THERAPY
No. of Patients
No. of Tests
Mean 17-OHCS
Ex-cretion in Response to ‘25 units ACTII
g/lOO
SE.)!. mi
Pre-therapy Post-therapy
Controls*
27
Q7
40
27
27
40
17.4
9.8
17.8
2.8 1 .4
1.76
TABLE IV
RELATION OF ACTH-17-OHCS
RESPONSE TO DOSAGE
No. of Responses
Dose of
.
Prednisolone
(nig)
Mean
Response (j.ig/lOO ml)
‘ S. ..11.
10 ‘2.5-5 16.9 5.0
13 7.5-19 11.1 2.2
13 20-30 7.7 1.4
URINARY ExciuTIoN OF 17-OHCS AND
17-KS : In Table V are tabulated the data
concerning the urinary excretion of
17-OHCS and 17-KS by 16 patients during a
schedule of intermittent prednisolone ther-apy. It is apparent that although no
con-sistent change was noted in the excretion of
17-KS, a definite pattern of change in
ex-cretion of 17-OHCS was observed in most
of the subjects. During the 3 days
pred-nisolone was administered, increased
amounts of 17-OHGS were excreted in the
urine. However, the first day hormones
were withheld, only small or undetectible
amounts were excreted. Throughout the re-maining days of the rest period the amounts
excreted progressively increased
(
Fig. 1).As can be seen in Figure 1, on the first
day prednisolone was administered to the
patients the largest concentrations of
(Continued on next page)
ARTICLES 441
TABLE V
EFFECT OF INTERMITTENT PREDNISOLONE THERAI’Y ON URINARY EXCRETION OF
17-HYDR0XYc0RTIc0STEROIDs AND 17-KETOSTEHOIDS (io/24
Patient
Days
1 2 3 4 5 6 7
Patient
1)ays
‘2 3 4 5 6 7
T.S. HR. Prednisolone (mg) 17-OHCS 17-KS Prednisolone (ing) 17-OHCS 17-KS 15 1.9 1.5 20 3.6 1.2 15 2.7 0.6 20 2.1 0.9 15 2.6 1.6 20 3.1 1.1 0.4 2.2 0.4 0.4 1.1 1.3 1.’2 -1.2 1.4 1.6 1.8 1.0 2.0 1.6 2.1 M.S. Prednisolone (mg) 17-OHCS 17-KS ‘20 2.1 1.3 20 1.1 2.8 20 1.9 1.7 0.9 1.0 0.3 0.7 0.4 0.8 0.4 1.4 Means S.E.M. 17-OHCS 17-KS 17-OHCS 3.2 1.7 .64 2.4 1.6 .31 2.4 1.5 .40 0.3 1.3 .08 0.6 1.4 .15 0.9 1.7 .14 1.2 1.5 .18 RB. V.B. R.C. L.C. D.C. W.D. D.F. MG. DII. PH. K.K. AL. F.S. D.T. G.S. C.B.
TABLE V (Continued)
interpreted as being partly a reflection of
the administered prednisolone and partly
due to endogenous production of 17-OHCS.
On the second and third days of
pred-nisolone therapy, the production of
17-OHCS by the adrenal cortex probably was
suppressed. Thus, the levels were less than
those observed on the first day of treatment,
but were, nevertheless, still elevated due
to the administered steroid. On the fourth day, the first day prednisolone was
with-held, only minute quantities of 17-OHCS
were excreted in the urine; this probably
reflected a state of adrenocortical
hypofunc-lion induced by the previously administered
prednisolone. On the subsequent days the
concentrations of 17-OHCS excreted in the
urine progressively increased. However,
in spite of the apparent recovery of the
adrenals, the mean for excretion by the
controls was not attained by the fourth day
after steroid therapy was discontinued. The
difference between the excretion observed
on the last day hormones were withheld
(1.2 mg/24 hr) and the excretion by controls
(1.8 mg/24 hr) was statistically significant
as determined by the ranked sum test (p
.04) Thus, in accordance with the findings
in the standardized ACTH-17-OHCS
re-sponse test, these results also indicate that
some residual impairment of adrenal fune-.
tion remains even on the fourth day after
discontinuation of prednisolone.
Complications
No serious complications were observed
in any of these patients treated by this
tech-nique. Certain minor side reactions were
TABLE VI
URINARY EXCRETION OF 17-OHCS IN 16 ALLERGIc CHILDREN \\HO HAD NEVER RECEIVED
STEROID THERAPY
. 17-OUCS
Patient Age (yr) Sex (mg/24 hr)
5 M 1.7
7 F 1.6
6 M 2.1
3 F 1.6
3 M 0.9
7 M 1.3
5 M 0.8
7 1I 2.4
8 F 1.9
9 F 1.5
13 M 3.4
6 M 1.5
4 iI 3.3
6 1I 3.8
7 F 0.6
3 M 1.0
Mean 1.8
+
+
+
I.
mean control
value
6 children
.8 mg./24 hr.
I 2 3 4 5 6 7
noted in a few subjects. Those encountered
were : central nervous system stimulation
and insomnia, increased urinary frequency,
moon facies, voracious appetite and
exces-sive weight gain. None of these side reac-tions were considered serious enough to
necessitate discontinuation of therapy.
Blood pressure was measured in all of the
patients, and no changes were demon-strated. Supplemental potassium was not
provided, nor was sodium restricted in the
diet of any of the subjects. Chemical an-alyses of the blood and roentgenograms were obtained as indicated by the clinical status of the patient. These studies revealed
no abnormalities.
Many of the subjects treated with a
schedule of intermittent prednisolone
ther-U)
(‘J
..-..
0’
E
z 0 F-U a:: 0 x U z
U 0
I
0
2.5 to 30mg. Prednisolone/day
apy developed infections such as are
corn-rnonly observed in children of a comparable
age group. Most of these infections did not
affect the patient adversely as related to the
hormone therapy, nor pose a therapeutic
problem. However, special precautions
were taken whenever an illness was present
by administering supplementary hormone
during periods when prednisolone
ordinar-ily would have been withheld. Because
chickenpox may become malignant in
pa-tients receiving steroids,16 therapy was
temporarily discontinued in all patients
known to be exposed to this disease.
How-ever, three children, not known to have
been exposed, developed chickenpox dur-ing the course of treatment, without
corn-plications.
DAYS
DISCUSSION
In any discussion of the treatment of
atopic hypersensitivities with
adrenocor-ticotropin or steroids it should be
empha-sized that this therapy is symptomatic and
should not supplant the ordinary orthodox
methods of treatment. The authors’
indica-tions for the use of these agents in the
treatment of allergic children are as
fol-lows : First, there is general agreement that
these drugs should be administered
promptly in acute, severe allergic reactions
(
status asthmaticus, exfoliative dermatitis,anaphylaxis, etc.). Secondly, in the
self-limiting allergic entities
(
seasonal pollenasthma, contact dermatitis, serum sickness,
etc.), where the hormones need be
adminis-tered for only relatively short periods of
time, their use often will reduce
appreci-ably the morbidity and the duration of the
allergic reaction. Finally, these agents can
be utilized in the treatment of severe,
chronically allergic patients. However, it is
in this latter group that the indications for
hormone therapy are the most controversial
and the least discernible. The objections to
hormone therapy in these patients have
stemmed primarily from the necessity of
administering hormones for prolonged
periods of time and thereby greatly
increas-ing the probability of untoward reactions.17
In the present study only those patients
whose allergic symptoms were resistant to
conventional means of allergic therapy
were selected for treatment with a
sched-ule of intermittent prednisolone therapy.
Thus, the subjects treated by this technique
were a highly select group of patients with
either severe intractable asthma or severe
generalized atopic dermatitis.
Although the intermittent steroid
regi-men was helpful in the management of the
majority of these severely allergic children,
some of the beneficial effects observed
could conceivably have been due to
remis-sions which occasionally occur
spontane-ously during the natural course of allergic
diseases.182#{176} The periodic weekly
exacerba-tions of symptoms occurring during the
lat-ten part of each rest period, when steroids
were being withheld, suggest that the
amelioration of allergic symptoms mainly
resulted from the administration of the
hor-mones.
The plan of scheduled intermittent
ther-apy was originally introduced in an attempt to reduce the incidence of complications
from steroid therapy. Despite rather exten-sive experience with intermittent hormone
therapy, especially in treatment of the
nephrotic syndrome,29 relatively little
in-formation has been published regarding the
complications arising from this type of
ther-apy. In the present study no serious
corn-plications were observed in the 42 patients
treated from 13 to 20 months. The absence
of serious complications may have been
related to the intermittent method of
ad-ministering steroids, but other factors, such as the special precautions taken to maintain
the dosage of hormones at the lowest
pos-sible level
(
lower than those recommendedfor the nephrotic syndrome), the period of
time that the patients have been observed
and the number of subjects studied, may
also have contributed to this finding. It is
possible, since 19 patients were studied less
than 6 months, that serious complications
might have occurred with more prolonged
periods of therapy. Many of the patients in
this series are still under therapy and
ad-ditional information with regard to possible
complications may be forthcoming.
One of the serious hazards of steroid
therapy is suppression of
pituitary-adreno-cortical function.17,2l39 Utilizing the same
method of assessing adrenocortical function
as in the present study (the
ACTH-17-OHCS response test), the authors
pre-viously demonstrated that the adrenals of
allergic children receiving even small doses
of prednisolone (5 mg), respond poorly to
the administration of ACTH.1#{176} Although
this abnormal response to ACTH was found
to be short-lived in the children studied,
other investigators have concluded that a
state of relative adrenal insufficiency may
persist for as long as 4% months after
this constitutes a real hazard has been
am-ply shown by the increasing number of case
reports of acute adrenal insufficiency and
death occurring during stressful situations
in individuals who previously had received
steroids.7’ 27-39
From the observations of Calkins et al.4#{176}
it seemed possible that with the
intermit-tent therapy regimen used in the present
study, 1) the period of administering
hor-mones (3 days) might be short enough to
obviate completely, or at least partially, the
suppression of pituitary-adrenocortical
ac-tivity which occurs in patients receiving
continuous daily steroid therapy, and that
2) whatever suppression did occur might
be compensated for during the 4-day
period of withholding hormones.
From the data presented, it is evident
that with intermittent therapy some
sup-pression of adrenocortical responsiveness
does occur and that, although there is
par-tial recovery of pituitary-adrenal function
during the 4-day rest periods, some residual
impaired activity of these glands is still
evi-dent on the fourth day after hormones have
been discontinued. In view of these
find-ings, it would seem advisable, during
pen-ods of stress, to administer supplemental
steroids to patients who are receiving this
type of steroid therapy and to revert
tern-poranily to continuous steroid maintenance
therapy at these times.
It should be re-emphasized that although
the regimen of intermittent prednisolone
therapy was found to be extremely helpful
in the management of severe cases of
in-tractable asthma and atropic dermatitis, it
was not demonstrated to be superior to
continuous maintenance therapy. Either
method should be used only to supplement
and not to supplant other conventional
methods of allergic treatment. Furthermore,
until further data are forthcoming and
pa-tients have been observed for longer
pen-ods of time to determine whether this
method of therapy does in reality obviate
the serious untoward effects of prolonged
hormone treatment, extreme caution should
be exercised in its use.
SUMMARY AND CONCLUSIONS
An evaluation of a schedule of
intermit-tent prednisolone therapy in the treatment
of 42 children with severe allergic
dis-orders, who had failed to respond to
ordi-nary allergic management, is presented. In
11 subjects the response was excellent; in
28, good; and in 3, poor. No serious
com-plications were observed as a consequence
of the method of treatment.
Appraisal of adrenal function, as
meas-ured by a standardized test of response to
adnenocorticotropin, was undertaken before
and after the institution of therapy in the
majority of the subjects. The mean urinary
excretion of 17-hydroxycorticostenoids in
the test observed after the introduction of
therapy was significantly less than that
prior to treatment. This suggests that the
regimen of therapy employed impairs the
adrenals’ response to exogenous ACTH. The
unresponsiveness of the adrenals was at
least partly dependent upon the dosage
of hormone administered.
The effect of intermittent steroid therapy
on the urinary excretion of adnenocortical
steroids in 16 subjects is also reported.
Some hypofunction of the adrenals, which
is overcome only partially during the days
hormones are withheld, is suggested by the
data on 17-OHCS. There was no discernible
effect on the urinary excretion of 17-KS.
The indications for use of steroid therapy
in allergic children and the implications of
the findings in this study are discussed.
Although a schedule of intermittent steroid
therapy was found to be useful as an
ad-junct in the treatment of intractable asthma
and atopic dermatitis, it should not be used
as a substitute for conventional methods of
treating allergic patients. The criteria for
selection of patients and the precautions
required in the administration of continuous
hormone therapy, should also be applied
in the use of intermittent hormone therapy.
Acknowledgment
The authors gratefully acknowledge the
as-sistance of Betty Reid, RN., Heidi Nakamuna,
in the collection and preparation of blood and urine specimens; the technical assistance of
Doris F. Tippit, Carolyn Cranny, Richard B.
Young and Alice Tustison in performing the
steroid determinations; and the assistance and
advice of Dr. Wilfrid J. Dixon, Professor of Biostatistics, University of California at Los Angeles, in the statistical analysis of the data.
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