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Report of the Penicillin Study Group—American Academy of Allergy
Report of the Penicillin Study GroupAmerican Academy of Allergy George
dbinyton,
R. Green,
Pa., ad
M.D.,*
and
Arthur
Rosenblum,
M.D.,**
Chicago, Ill.
Many aspects of the problem of penicillin hypersensitivity remain unsolved. The Penicillin Study Group of the American Academy of Allergy was formed to investigate various aspects of this problem. A number of studies have attempted to evaluate the relationship of clinical penicillin hypersensitivity to reactions to skin tests with penicillin and its degradation products. These studies generally have shown positive correlations, but considerable variation has existed in their magnitude.= This variation may well relate to differences in protocol, techniques, patient populations, or investigators.2-n The present cooperative study was devised to investigate the relationship of skin reactivity to penicillin hypersensitivity. The reagents used were penicillin G (Pen G) and penicilloyl-polylysine (PPL), a conjugated form of a penicillin degradation product (penicilloyl) , which prior studies have shown to be associated with the majority of penicillin hypersensitivity reactions.g The patient population was drawn from the clinical and private practices of practicing allergists who are members of the Penicillin Study Group of the American Academy of Allergy. MATERIALS
AND
METHODS
Twenty-six clinical investigators contributed a total of 1,160 cases to the study. Patients were tested according to the following protocol: Patients being subjected to allergy investigation as well as selected patients being evaluated for a history of penicillin hypersensitivity were interviewed and skin tested for penicillin hypersensitivity. Two preparations were used for skin testing: (1) penicilloyl-polylysine (PPL),t a sterile solution of benzylpenicilloyl-polylysine in a concentration of 6.0 x lo-aM (penicilloyl) in O.OlM phosphate buffer and 0.15 sodium chloride at pH 7.6 (PPL is a derivative of poly-L-lysine in which at least 65 per cent of the epsilon amino groups are substituted forming benzylpenicilloyl alpha amide). The PPL was supplied in sealed glass single-dose ampules containing 0.25 ml. which were refrigerated until used; (2) benzylpenicillin (penicillin G) freshly diluted to a concentration of 10,000 units per milliliter. For maximum safety it was recommended that the tests first be done by the scratch technique. Intradermal tests lvere then to bc done on those showing negative scratch tests. In cases From the Department of Allergy and Immunology, Abington Memorial Hospital, the Hospital of the University, Philadelphia, and the Department of Pediatrics, Michael Reese Hospital. Received for publication March 23, 1971. Reprint requests to: Dr. Green, 1355 York Road, Abington, Pa. 19001. *Chairman, Penicillin Study Group, American Academy of Allergy. **Immediate Past Chairman, Penicillin Study Group, American Academy of Allergy. _. tSupplied by the Kremers-Urban Co., Milwaukee, Wm., as Pre-Pen under IND No. 2135.
332
Green
and
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Rosenblum
TABLE I. Distribution
of skin reactions
to penicilloyl-polylysine
(PPL) and penicillin
G (PG)
A. Distribution PPL (+I PG I+)
PPL (+I PG l-1
PPL I-1 PG I-1
PPL l-1 PG I+)
NO.
%
No.
%
NO.
79
6.9
(9.1)
34 (80)
3.0 (6.9)
38 (49)
%
No.
%
N@.
%
No.
151 (1;:)
13.1 (20.3)
1,153
$81,
(105)
%
I) .j .>.< (4.3 )
NO.
%
1,002 (919)
86.9 ( 79.7)
6. Totals PPL I+) No.
113 (135) Skin reactions theses show positive skin
PG
Total
(+I
(lh)
(234)
(+I
Total
tested %
1’00
recorded as “erythema only” were classified as ambiguous. Figures in parendistribution of skin reactions when ambiguous responses were counted as reactions.
in which the penicillin sensitivity was suspected to be of a violent c~haracter, more dilute reagents were recommended at the discretion of the individual investigator. A uniform technique was recommended for the performance of the intradermal tests. Only a minimal amount (about 0.01 to 0.03 ml.) of testing reagent was to be injected so as to make a barely discernible intradermal bleb. It was recognized that the interpretation of the test results was a critical matter. The reactions were recorded in terms of: (1) the time required for the appearance of a reaction, (2) the size of erythema, and (3) the size of whealing. These were recorded as actual measurements. Some objective measurement of dermographism was also recorded by noting response of the skin to scratching. It was also contemplated that all patients who were to be treated with penicillin be tested as recommended above, even though they had previously received penicillin with impunity. A comprehensive clinical history was taken on each patient with particular regard to previous penicillin therapy and reaction. In order to properly analyze the data on such a large number of patients, a data processing system was utilized. All data were recorded by the investigators on the form shown in Fig. 1. Data processing was accomplished in collaboration with Eleanor V. Price of the Public Health Service and Dr. Gordon Stewart of Tulane University.
RESULTS Table I summarizes the skin test results on all patients, without regard to other specific factors. It will be noted that the over-all positivity rate was higher for PPL (9.8 per cent) than for Pen G (6.2 per cent) (p = < 0.003). It will also be noted that a significantly greater number of patients reacted only to PPL (79) than to Pen G only (38) (p = < 0.001). A technical problem was classification of the ambiguous or borderline reactors, particularly those showing only erythema. Attempts to correlate the appearance of the erythematous flare without wheal formation with a history of penicillin hypersensitivity were unsuccessful. In some instances, however, erythema without wheal did appear to be associated with hypersensitivity to the antibiotic. Recent reports by Fellner and associates1o suggest a correlation of the flare reaction with hypersensitivity. The time of development of erythema without wheal varied widely from a few minutes to more than 7 days, which also made its importance questionable as a diagnostic sign. For these reasons erythema alone
VOLUME NUMBER
48 6
Report
of the Penicillin
Study
Group
333
responses were generally counted with the negatives. In some instances, however, data will be presented in which erythema without wheal are counted as positive responses (figures appearing in parentheses). Only 2 of the positive skin test reactions were delayed in onset. Tn Tahlc 11 the results of skin t,ests 011 patients who had given a hist,ory of hypcrsensitirity react,ions are compared w&h those from persons who had no such reactions. Also inrludcd in this t,ahle are analysts of those who had receivetl no previous penicillin or on whom no therapeutic history could be obtained. Table III presents a statistical analysis of Table II. Patients who have had previous penicillin reactions (Group II) show a significantly higher positivity rate for both reagents than those who hare had no such reactions following therapy (p = < 0.001 for both reagents). Table IV shows the distribution of skin test responses by history of time of reaction after the administration of therapeutic penicillin. These data indicate a higher incidence of skin reactivity in patients with histories of reactions to pencillin within 30 minutes than in patients developing reactions after 24 hours. Of those reacting within 30 minutes, 26 of 56 (46.5 per cent) exhibited positive skin test,s to PPL, while 17 of 56 (30.4 per cent) were positive to Pen G. A total of 31 of 56 (55.5 per cent) were positive to one or the other or both rea.gents. Of those reacting after 24 hours, 24 of 144 (16.7 per cent) were positive to PPL, while 17 of 144 (11.8 per cent) were positive to Pen G. A total of 33 of 144 (22.9 per cent) were positive to one or both reagents in this group. This difference between the fast- and slow-reacting groups is significant (p = < 0.001). These data also suggest a greater reliability of the skin-testing procedure in patients with history of reaction to penicillin within 30 minutes as opposed to patients whose rraction to penicillin occurred after 24 hours. The percentage of positivity for the group who had fast reactions was over twice that of the group who developed delayed reactions (55.4 per cent versus 22.9 per cent). No ready explanation of why certain patients in both groups failed to develop positive responses to eit,her of the reagents is apparent. Table V shows the distribution of positive tests in skin-reactive, penicillinhypersensitive patients. Note in the group of patients with a history of reaction to penicillin within 30 minutes that up to 83.9 per cent responded to PPL, while 51.8 per cent responded to penicillin G skin tests. This difference is significant (p = < 0.03). In like manner, among patients who had developed reactions to penicillin after 24 hours, 72.7 per cent responded to PPL and 51.5 per cent to penicillin G. This difference, however, is not significant (p = < 0.20). However, if ambiguous responses are counted with positive tests, the difference between the reagents becomes significant (p = < 0.03). Since penicillin reactions occurring within 30 minutes almost invariably represent anaphylaxis, the correlation with positive skin tests in this group is of great significance. Although the number of positive reactions to PPL is significantly higher than that to penicillin G, the maximum number of reactors will be picked up only when both reagents are used. Only 3 of the 100 patients challenged after testing were reported to have a reaction (Table VI). The first patient was a 30-year-old woman who had an urticarial reaction occurring after receiving parenteral penicillin G. Skin test,ing
SURVEY NUMBER (Leave blank)
’
:
v H
s
Rh r N
c
r
O(1)
izlw
REACTION (If no, check No Yes
O(X)
TO PENICILLIN and skip to #36) No data
38
36
35
min.
PATIENT
<15
DO
YOU
HAVE
OTHER ALLERGY n(l) None (J(2) Rhinitir
DID
n(2)
<30 <24 <4S
parenteral
Proc.
Pen. G
IN
min. hours hours ANY
ABOUT
THE
,
0
testing
testing
o(5) o(6)
-,..
-___
FIG. 1.
O(1)
No
VERIFIED
SKIN
37 FAMILY HISTORY O(1) None o(2) Father
A REACTION?
WAS REACTION BY PHYSICIAN?
31
OF
No
o(2)
D(2)
Yes-Incomplete
Allergy
number
Group
of
REPORT
Injection
Yes
O(3)
O(X)
Other More than No data
Yes-Complete
o(5) n(6) O(X)
______
More than None
More than None
More than No data
No data
No data cl(X)
n(5) O(X)
site only O(6) O(X)
n(7) 0(X1
one
one
one
one
AMOUNT RECEIVED o(1) One dose O(X) No data D(2) one covrre n(3) More then one course
case
dermatitis
n(1)
cv collapse Purpura
Rosh Contact
ALLERGY O(3) Mother O(4) Sibling
O(1)
rJ(3) D(4)
O(4) o(5)
_______-
22
Your
Study
Academy
HYPERSENSITIVITY
Penicillin
American
PENICILLIN
~,
Benzathine penicillin G New Penicillin (specify)
VISCERAL (1 ) Wheeze c](2) Tightness in throat or chest
q
HAD
34
32
HISTORY?
derm.
lnitiol Repeclt
0
Address
and
.._I
Name
” -_,.
Physician’s
“,,..m.
ROUTE OF ADMINISTRATION n(i) od U(4) More than one O(2) Porentercll O(3) Topical O(X) No data
.,-...
TYPE OF REACTION: O(2) Pruritur O(3) Urticaria
Aqueous Depot
HAVING
ABOVE
Contact Urticaria No data
AFTER
<7 daw Longer Uncertain
06) o(6) O(X)
FORM
O(6) l-J(7) O(X)
O(4)
O(3)
,
sub.
21
v....
Student Pre-school child Other or N.D.
-..,I
- Allergy to: o(3) Pen. L other f-J(4) Irrelevant
n(X)
o(7) o(S)
RACE
,,.ersrr
ESTIMATED LAST DOSE , “7’ , ,Yey
10
25-30 ESTIMATED DATE LAST REACTlON , Mq”“, / Da? i”r”r;
1 S-20 DATE rMqn,h/
EVIDENCE
PATIENT o(3) Asthma C](4) Eczema
PENICILLIN
DOCUMENTARY
OF
TOLERATE
13(3) O(4) o(5)
PENICILLIN O(l) Oral o(2) Aqueous,
33D;7fmo,~d!;~CT’oN
24
Food-handler Office worker Factory worker Housewife
9 SEX Male Female
13 REASON FOR TESTING n(l) Penicillin O(2) Other substances
n(3) m(4) n(5) (-J(6)
7.8 AGE (Years)
PREVIOUS PENICILLIN THERAPY (If no, check and skip to #36) No Data O(X)
000
HANDLER No Dota
: P 23 FORM OF Y Pen. G or v Penicillin G
A E
14
PENICILLIN
3
5:
IR
H
12
11 OCCUPATION O(1) Medical or paramedical n(2) Animal-handler
1-6
“,a,yI8,
-
’
s 1 s
ffi
<4B hours <7 days Longer Uncertain
OF REACTION: O(1) Immediate O(l) Immediate n(l) Immediate
O(5) O(6) lJ(7) [3(X)
DOSAGE pen. G pen.
Month
test] O(4) O(S) O(6) O(X)
Edema (I+ 5 min. Edema at 30 min. Later Not done
Present-Normal
fi
52
FOR
O(3)
or4
60
FURTHER
o(1) D(5)
SHOCK
MILD SEVERE BRONCHOSPASM PRURITUS
Interrogation? Not ovailqble
72 73 74 75
Purpurcl
O(3) D(4)
Wheal Wheol Wheal Wheal
Wheal Wheel Wheel Wheel
O(l)
D(X)
42
--
follow-through?
Immediate Immediate ‘J(l) Immed. Remote
O(2) n(2) O(2) O(2)
-~--~.-______
Delayed Delayed Delayed Generalized
76
Urticaria
Uncertain
clw
G
COMPETENT
PSYCHOLOGICAL? U(1) No Yes fJ(X) Doubtful
D(3)
IJCX)
BY
Benzothine penicillin Other (specify) More thon one
done
SPEED OF REACTION [7(l) One minute o(2) Five minutes D(3) Thirty minutes O(4) Later
SPEED OF REACTION o(l) One minute o(2) Five minutes o(3) Thirty minutes lJ(4) toter
OBSERVED
U(5) @(6) O(7)
Not
45
O(2) Yes
WAS REACTION WITNESS? U(1) No
65
Pen. G Aqueous Depot
Both Neither
20 mm
20 mm
~.
site only O(2) Pruritus U(6) Mare than one D(X) None Tightness in throat or chest 00) More than one O(X) None
Clinical
Ini.
O(1) O(1)
o(2)
O(2)
O(l) dematitis
FIG. 1. Continued.
-
67 SKIN J(SJ Contact O(l) Wheeze (J(4)
q
O(4) O(5) O(6) 3(7)
O(4) U(5) O(6) j(7)
onlyl
FORM OF PENICILLIN o(l) Pen. G or V Proc. tablets O(3) lJ(2) Pen. G - Aq: O(4)
Eorinophilia Thrombocytopenio
one rquore
DID PATIENT EXPERIENCE REACTION TO PEN.? If “a, check and skip lo 577. D(X) N.D. Yes O(l) No
O(1) O(2)
INTRADERMAL TEST n(l) Negative U(2) Erythema only D(3) Erythemc with wheal in bleb
ROUTE OF ADMIN. O(1) Oral O(3) I.V. O(2) I.M. O(4) Other
64
(Check
INTRADERMAL TEST O(1) Negative O(2) Erythema only O(3) Erythema with wheal in bleb
TESTS:
44
41
TYPE OF REACTION: O(4) Rash 68 VISCERAL O(3) C.V. collapse
59
OBSERVATIONS Present-Exoggeroted
LABORATORY
HYPOTENSIVE O(2) Delayed O(2) Delayed U(2) Delayed
I
I.D. test) U(4) Edema at 5 min O(S) Edema at 30 min. D(6) later D(X) Not done
I.D.
O(2)
LIKELY TO BE AVAILABLE o(4) Therapeutic challenge?
YOUR CLASSIFICATION 69 INJ. SITE ONLY 70 URTICARIA 71 ANGIO-EDEMA
77 IS THIS PATIENT O(3) Skin tests?
; E
to #77
PENI-
62.63 TOTAL Million units Grams other
OF
skip
NUMBER OF DOSES
and
;;;;‘;heyyJo”ep
DATE
at
omit
omit
~~~~
SCRATCH TEST (If +, Cl(l) Negative O(2) Erythema only lJ(3) Edemo 1 min.
66 TIME OF OCCURRENCE o(l) Immediate o(2)
n R L 61
1 E-
43
53.58
p P
c
00)
p 40 SCRATCH TEST (If + E o(1) Negative N O(2) Erythema only O(3) Edema at 1 min.
DER~IOGRAPHIA:
T E
YG N
S
39
CURRENT
336
Green
and
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Rosenblum
TABLE II. Distribution
of skin reactions
PPL (+I
Group II Pen. I$, sensitive (352 patients) Group III No Pen. fi (,70 pat,ients)
Group 1.v No data (56 patientsj Totals (1,153 patients)
TABLE III. Academy
(PPL) and
PG(+l
PPL 1-l %
NO.
NO.
I
%
1.3
15
(44)
(6.5)
(34)
(5.0)
(22)
(3.3 /
49
13.9
24
ti.8
23
ti.3
(57)
(16.2)
(40)
(11.4)
(25)
(7.1)
1
1.4
0
(2)
(2.9)
(4)
(5.7)
(1)
2
3.6
1
1.8
0
(“1
(3.6)
(2)
0
(X(i)
6.9 34 (9.1) (80) both positive and ambiguous skin reactions:
Statistical
2.n (6.9)
Group
No.
(1)
i 1.X)
(“,“,I
:I.,3 (4.2)
analysis PG (+I
%
36
5.3
(78)
(11.5)
73
20.7
(97)
(27.6)
109 (175)
10.6 (17.0)
(A)
((3
(1.4’1
reactors.
PPL I+)
Totals (1,027)
PG (+I
9
of Allergy
Group II Penicillin I$, sensitive (352 patients)
G (PG)
4.0
include
Group I Penicillin I$, not sensitive (675 patients)
Penicillin
I, ., -.-
79 (105)
in parentheses
PPL (+I
%
27
Group I Pen. I$, not sensitive (675 patients)
Figures
PG l-1
NO.
Group
:o peniciiloyl-polylysine
No.
%
24
3.6
(RI
P)
(56)
(8.31
47
13.3
(65)
(1X.5)
71
(121)
6.9
(11.8’l
Analysis X’ (A) vs. (R) 2.196 (2.110) < 0.20 p (< 0.20) 3.579 (6.278) < 0.06 (< 0.02) (Cj vs. CD) 54.091 (A) vs. (C) (40.780) < 0.001 36.040 (22.053) < 0.001 (RI vs. (Dj Figures in parentheses include both positives and ambiguous reactors. rSumma_r;y: 1. Of 675 patients previously treated with penicillin but not previously sensitive, 36 (0.3 per cent) were PPL positive while 24 (3.6 per cent) were PG positive. (If ambiguous reactions are counted as positives, the percentages increase to 11.5 per cent for PPL and 8.3 per cent for PG.) 2. Of 352 patients with histories of sensitivity to peni(dillin, 73 (20.7 per cent) were positive to PPL while 47 (13.3 per cent) were positive to PG. (If ambiguous reactions are counted as positives, the percentages become 27.6 per cent for PPL and 18.5 per cent for PG and the difference is significant, p = <0.02). 3. Difference in positive skin tests to both reagents in patients who tolerated previous penicillin and those who did not is highly significant, (p =
6 months later resulted in an 8 x 12 mm. wheal to Pl?l~. Carbcnacillin, 30 (inr. daily, was administered for 2 days, and 20 days later a rash occurred. A sccontl patient was a 50-year-old man who had a local reaction to a nasal aerosol of penicillin in 1955. When tested in 1967 he had delayed erythema without wheal
JOLUME 48 NUMBER 6
Report
of the
Study
Penicillin
Group
337
Total
---~ PPL
_~
I+1
PG
I
I+)
Total
I
I+)
No.
%
NO.
%
(is)
(11.5)
(5(i)
(8.3)
i3
20.7
47
13.4
96
27.3
(97)
(27.6)
(65)
(18.5)
(123)
(34.i)
I
1.4
0
1
1.4
(61
(X.6)
(5)
(7.1)
(il
(10.0)
3
5.4
1
1.x
3
5.4
(4)
(i.1)
i 3)
(5.4)
113
(1::;)
TABLE IV. Distribution of therapeutic
(1291
of skin
responses
(11.2)
by history
(14.8 I
of time
of
(5)
(X.9)
151 (“34)
13.1 (20.3)
reaction
after
administration
penicillin Skin PPL
Time reaction
%
(loo)
6.3
72
(1X5)
NO.
of penicillin ofter therapy
Within 30 minutes (56 patients) Between 30 minutes and 24 hours (87 patients)
(+I
PG
No.
l-1
%
PPL
(+I
PG
NO.
(+I
%
responses PPL
l-1
NO.
($C,
(ii)
(i&
(1:)
(&
(if,
($T)
More than 24 hours (144 patients)
(22,
TABLE V. Distribution
of positive
PPL
(+)
C-1
f-1
44.6 135.7 I
x.9 (X.9) 5.7 (X.0)
i;,
PG
%
NO.
%
r (it)
PG
70.0 (63.4)
(&
77.1 111 (69.4) (100) Skin reactions recortled as “ergthema only” were classifie(l as ambiguous. Figures in parentheses show distribution of skin reactions ahen ambiguous responses were counteIl as positive skin reactions.
skin-reactive
Time reaction
IPithin tk:t\vern
11.1 (15.3)
skin
(1:)
tests
($)
in penicillin
(1:)
6.2 (7.6)
allergy
patients
having
antibodies
I
of penicillin afier therapy
Total PPL (+)
30 Inillutw tll:aL
24 I1our.s
and
Total PG (+I %
NO.
X3.9
li
(Z )
( Sti. I )
(17)
54.8 (47.” i
“1 (24)
30.X (i7.4 1
!i (“I 1
((ii.7
24 (33)
(i5.0)
(&
(50.0)
NO.
30 minutes
24 hours Mow
If
72.;
I
%
I
31 (36) “6
65.4 51.3
Total positive . (No.1
)
(31) 33
(441 Skin reactions recordecl as “er$hema only” were classifircl as ambiguous. Figures in parentheses show distribution of skin reactions when ambiguous responses were counteci as positive skin reactions.
338
Green
and
Rosenblum
TABLE VI. Patients penicilloyi-polylysine
challenged
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
(PPL) and
with penicillin subsequent penicillin (PG)
PPL I+) PG I+) PPL I+) PG (-I
Number
eldlengtd
Number reacting challenge
1
to skin testing
with
PPL (-1 PG (+) PPL (4 PG (-1
Total challenged
4
3
92
100
1
1
1
3
1
1
1
3
to
Observed by competent witness
TABLE VII. Distribution
of skin test responses
by type of hypersensitive
reaction
(i.e., skin versus visceral) Skin test response Type hypersensitivity
Skin reactions
PPL+
of reaction
only
I
No.
11
PG+ %
I
No.
I
%
Total tested (No.)
66
21.4
39
12.6
309
Visceral (with or without skin reaction)
IO
23.3
14
32.6
13
No reactions
36
5.3
2‘i
3.6
675
-formation to intradcrmal penicillin. Hc received intramuscular penicillin 5 da?s later and tle~clopctl generalized prnritus and a rash within 21 hours. The thirtl patient reacting to challenge was a 59-year-old physician who reported an untoward reaction to the administration of penicillin in beeswax in 1948. skin tests in 1967 mere negative, and penicillin was cautiously begun at a dose of 20,000,OOO units daily. He had transient urticaria one week later, but penicillin was continued without further difficulty. Since he had no reaction until after one week of penicillin, this may represent sensitization to the current course of t,herapy and hence does not necessarily represent a false negative skin test. Table VII shows an analysis of the skin test responses by history of the type of hypersensitivity reaction experienced, i.e., visceral (with or without skin reactions) or skin reactions only, It will be noted that the posit,ivity rate is significantly higher in both categories than in patients who had tolerated penicillin therapy Jvithout any reaction. PPL appeared to give a significantly higher positivity rate than Pen G with regard to skin reactions (p = < 0.006). The positivity rate for Pen G was higher for visceral than for skin reactions (p = < 0.02). The difference, however, in skin test reactivity between PPL and Pen G in patients who had experienced visceral reactions is not significant. Patients were analyzed (Table VIII) with regard t,o the reason for testing. One group was specifically tested because of suspected allergy to penicillin, and this was compared with the group that was tested for suspected allergy to other substances. The group being specifically tested for penicillin hypersensitivity showed a more highly significantly increased incidence of positive skin tests than the patients tested for hypersensitivity to other substances (p =
Report
VOLUME 48 NUMBER 6
TABLE VIII.
Distribution
Reason
for testing
“penicillin”
Suspected allergy t.0 other substances TABLE IX. Distribution
Study
Group
339
of skin tests by reason for testing PPl.+
Suspected allergy
of the Penicillin
No.
%
Total tested (No.1
10.11
34
IX.8
240
1.9
27
5.8
463
Total
PG+
No.
%
No.
31
12.9
24
21
4.5
9
of skin responses
%
by history of penicillin
in patients
+
therapy
Skin reactions
No.
%
No.
%
No.
%
Total tested (No.1
One course Multiple courses
24 14 14
15.8 5.6 7.9
17 8 10
11.2 3.2 5.6
23 19 22
22.4 7.6 12.4
152 249 177
Totals
52
9.0
35
6.1
75
13.0
578
PPL+ History One
of therapy
dose
TABLE X. Time lapse between Time
penicillin
reaction
with
three
+
and skin testing
Positive tests/total
lapse
3 MO. or less 4-12 MO. 13-60 MO. More than 60 mo. p = <0.05
Total
PG+
skin tested
X3/ 61 17/ 47 29/ 86 26/134
%
29.5 36.2 33.7 19.4
degrees of freedom.
significant, but the difference in response to the two reagents in the “other substances” group is significant (p = <0.05). The analysis of data on penicillin handlers indicates a significant correlation with positive skin responses to both reagents (p = <0.05). Twenty-six per cent (7 of 26) of the penicillin handlers had a positive skin test, whereas 11.8 per cent (Xl of 685) of the individuals with no such history had positive responses. Of possible importance is the high incidence of positive skin reactions in those patients having had only one dose of penicillin (Table IX). The differences in skin reactivity to both reagents in patients receiving one dose as compared with one course or multiple courses of penicillin is significant (p =
340
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Green and Rosenblum
TABLE Xl. Intensity
of skin reactions
versus history
of penicillin Skin
History penicillin
of allergy
Reagent
Weak
I<
8
mm.1
1%
20/148 S/140
PI’1 ‘ PG
*31/153 (20%) S/134 (16%)
PPJ,
(14%) (65%)
allergy reactions I
Strong
r>
8
mm.)
M/148 8/140
(9%) (6% )
‘7/153 i/134
(18% 1 (5%j
the intensity of the intradermal skin reaction and a history of penicillin allerg! (Table XI). The data show a significant excess (p <0.04) of skin reactions of greater than 8 mm. to PPL in patients with a history of penicillin intolerance. IIowevcr, the reverse was seen with Pen G in that a significant excess of reactions of less than 8 mm. developed in patients with a history of penicillin allergy. The percentage of strong reactions to Pen G, on the other hand, was essentially equal among patients with and without a history of penicillin allergy. The possibility that age of the patients could play a role in the large number of patients with a hist,ory of penicillin intolerance but negative skin tests was considered. Among patients with a positive history of penicillin allergy, 72 per cent of those 15 years old or less had negative skin tests, whereas 62 per cent, of those over 15 years had negative skin reactions. DISCUSSION The above data and analysis demonstrate that positive skin tests with penicillin G and PPL were correlated with: (1) clinical history of a penicillin reaction ; (2) time of occurrence of reactions following administration of penicillin ; (3) type of hypersensitivity reaction (visceral or skin) ; (4) reason for testing, i.e., to penicillin or to other substances; (5) patients having received only one dose of penicillin as compared with patients having histories of multiple COL~SCS of therapy ; (6) patients reporting non-therapeutic contact with penicillin. No significant correlation was found regarding : (1) route of administration ; (2) family history of allergy; (3) personal history of allergy. There are certain inherent sources of error in a study of this sort due to: (1) the number of investigators, (2) deviation from adherence to the protocol, (3) large dependence on the accuracy of previous medical records, and (4) histories as given by the patient. The most likely source of inaccuracy lies in the history of a previous penicillin reaction as stated by the patient and recorded by the investigator. Direct examination of the patient records revealed instances in which the history was inadequate or difficult to interpret. The patient is given penicillin because of an illness, and any unt.oward reaction that occurs after penicillin administration is likely to be attributed to the penicillin, whereas it is quite probable that many of these untoward “reactions” are, in fact,, a symptom or complication of the illness. This is particularly true of rashes of various sorts. IJrticarial rashes, erythema multiforme, and other toxic rashes commonly occur in the course of various viral or st,reptococcal infections. Similar problems may occur in the tliffcrentiation of gastrointestinal and pulmonary complaints. Welltlrti~~etl anat)hylactic reactions are not likely to be misdiagnosed.
VOLUME 48 NUMBER 6
Report of the Penicillin Study Group
341
Another problem is the interpretation of skin tests. The significance of minimal reactions, particularly erythema without edema, has not been established. (iruerally, significant positive skin tests are well defined and show a large central wheal. The equivocal test, as cxcmplific(l by rr!-tht>ma wlonc, clevclops so c1rrat.C ~~11~ t,hat, its significance is not clear. Ko conclusions are. drawn regarding the signific*anct: of positive skin tests brcausc of the minimal number of posit,ivc skin reactors challenged. This series would bc cxpectetl to be small because of the potential hazards of giving penicillin to paticnt.s having known positive skin tests. The occurrence of reactions in two of the skin test-positive subjects is suggestive of the danger of administering penicillin to such patients. The lack of a strong correlation between the results of skin testing and the interval of time since the prior penicillin reaction was unexpected. However, it, should be noted that a similar lack of correlation between the interval of time since the prior reaction and the incidence of reactions to challenge with penicillin has been reported previous1y.l’ Penicillin hppersrnsitirity, once induced, may be less evanescent than some would believe. No clear correlation was found between the intensity of the intradermal skin reaction and a history of penicillin allergy when penicillin CGwas used for testing, although a significant correlation appeared with PPL. These data could be affected, however, by the fact that most patients with a positive scratch test were never tested by the intradermal route. Some strong reactions may thercforc have) been excluded. The finding of more negative skin reactions in patients with a history of peilicillin allergy who were less than 15 years old is not surprising. Hoover, the difference is relatively small (and statistically insignificant,, p = 0.3). Even allowing for the problems and inherent inaccuracy of the study, the results permit the following conclusions: (1) Skin testing to PPL and Pen (: was shown to be safe and of value in this study. (2) Results of skin tests show a significant correlation with history of clinical penicillin hypersensitivity. (3) The skin test reaction rate is particularly high in patients who experienced penicillin reactions of the immediate type within 30 minutes (Table IV). In these patie&, 26 of 56 (46.5 per cent) exhibited positive skin tests to PPL, while 17 of 56 (30.4 per cent) were positive to penicillin G. A total of 31 of 56 (55.5 per cent) were positive to one or the other or both reagents. (a) In the immediate reactor group, analysis of those patients having positive skin t,ests (Table V) indicates that 84 per cent were positive to PPL, while 55 per cent, were positive t,o Pen (: This would indicate that in this group 16 per cent would be missed if only PPII were used as a skin test antigen, while 45 per cent would be missed if only Pen (: were used. The necessity of using both reagents for testing, therefore, seems obvious, and the ilata suggest that these tests are most valuable in detecting immediate hypersensitivity reactions. Since these are the most dangerous types of penicillin reactions, often including anaphylaxis, it would be anticipated that such skin-testing procedures performed before the administration of therapeutic penicillin would be valuable in preventing and avoiding such reactions. (5) Lack of a 100 per vent correlation of skin tests with clinical history point’s up the importance of nufhenficnti~q the clinical history of penicillin reactions. The
342
Green
and
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Rosenblum
number of patients challenged was insufficient to draw any conclusions as to which is the more predictive-clinical history or skin testing. Moreover, the possible evanescent nature of penicillin hypersensitivity should not be overlooked. (6) Patients who have had authenticated penicillin reactions are known to be likely candidates for subsequent reactions, and such patients are not likely to receive more penicillin except under carefully controlled conditions. Further studies are planned by the Penicillin Study Group and others to provide more information regarding the importance of skin tests in the historynegative patients who are to receive therapeutic penicillin. The role of other minor determinants of penicillin hypersensitivity, such as benzylpenicilloate, and their relation to the broad problem of immediate penicillin reactions is being evaluated. The cross-reactivity of the various semisynthetic penicillins and cephalosporins needs further study.12 The major importance of this study was the fact that these standardized skin testing reagents could be safely used by a large number of practicing physicians to show that such testing is a valuable procedure in assessing a history of clinical sensitivity to penicillin. Hence, the Study Group feels that the reagent PPL should be made generally available and that the Food and Drug Administration should be so informed. ADDENDUM The contributions and cooperation of the following Group are herewith gratefully acknowledged: Alan G. Cazort, M.D., Little Rock, Ark. Monroe Coleman, M.D., Stamford, Conn. Lloyd V. Crawford, M.D., Memphis, Term. Bernard R. Feldman, M.D., New York, N. Y. Stanley R. Finke, M.D., Flushing, N. Y. Harold J. Friedman, M.D., Cleveland Heights, Ohio Kenneth L. Gerson, M.D., Lexington, Ky. Michael H. Grieco, M.D., New York, N. Y. J. Desmond Horan, M.D., Vancouver, British Columbia, Canada William B. Hunt, Jr., M.D., Charlottesville, Va. Manuel Ingall, M.D., Newton Lower Falls, Mass. Joseph E. Johnson III, M.D., Gainesville, Fla.
invest,igators
of the Penicillin
Study
Martin J. Kaplan, M.D., Highland Park, 111. Martin P. Kaplan, M.D., Lexington, Ky. Bernard B. Levine, M.D., New York, N. Y. Abe Matheson, M.D., Chicago, Ill. (Deceased) Charles W. Parker, M.D., St. Louis, MO. H. Rowland Pearsall, M.D., Seattle, Wash. Mrs. Eleanor Price, Atlanta, Ga. Bernard B. Siegal, M.D., Far Rockaway, N. Y. Cheyney C. Sigman, Jr., M.D., Atlanta, Ga. William B. Steen, M.D., Tucson, Ariz. Gordon T. Stewart, M.D., New Orleans, La. Lawrence C. Sweet, M.D., Detroit, Mich. Paul P. Van Arsdel, Jr., M.D., Seattle, Wash. Howard E. Voss, M.D., Stamford, Conn. Stanley I. Wolf, M.D., Silver Spring, Md. Bernard M. Zussman, M.D., Memphis, Tenn.
REFERENCES 1 Idsoe, O., Guthe, T., Willcox, R. R., and deWeck, A. L.: Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactie shock, Bull. W. H. 0. 38: 159, 1968. 2 Parker, C. W., Shapiro, J., Kern, M., and Eisen, H. N.: Hypersensitivity to penicillenic acid derivatives in human beings with penicillin allergy, J. Exp. Med. 115: 821, 1962. 3 Levine, B. B., and Zolov, D. M.: Prediction of penicillin allergy by immunological tests, J. ALLERGY 43: 231, 1969. 4 deWeck, A. L., and Blum, G.: Recent clinical and immunological aspects of penicillin allergy, Int. Arch. Allergy 27: 221, 1965.
VOLUME 48 NUMBER 6
Report
of the Penicillin
Study
Group
343
5 Brown, B. C., Price, E. V., and Moore, M. B., Jr.: Penicilloyl-polylysine as an intradermal test of penicillin sensitivity, J. A. M. A. 189: 599, 1964. 6 Rytel, M. W., Klion, F. M., Arlancler, T. R., and Miller, L. F.: Detection of penicillin hypersensitivity with penicilloyl-polylysine, J. A. M. A. 186: 894, 1963. 7 Voss, H. E., Redmond, A. P., and Levine, B. B.: Clinical detection of the potential allergic reactor to penicillin by immunologic tests, J. A. M. A. 196: 679, 1966. 8 Bierman, C. W., and Van Arsdel, P. P., Jr.: Penicillin allergy in children: The role of immunological tests in its diagnosis, J. ALLERGY 43: 267, 1969. 9 Schneider, C. H., and Parker, C. W.: In Stewart, G. T., and McGovern, J. P., editors: Penicillin allergy, Clinical and Immunologic Aspects, Springfield, Tll., 19780, Charles (‘ Thomas, Publisher, chaps. 2 aud 4. 10 Fellner, M. J., Ball, E. H., Allyn, B., and Baer, R. L.: Delayed hypersensitivity to penicillin, J. A. M. A. 21: 2061, 1969. 11 Green, G. R., Peters, G. A., and Geraci, J. E.: Treatment of bacterial endocarditis in patients with penicillin hypersensitivity, Ann. Intern. Med. 67: 235, 1967. 12 Van Dellen, R. G., Walsh, W. E., Peters, G. A., and Gleich, G. J.: Differing patterns of J. ALLERGY 47: wheal and flare skin reactivity in patients allergic to the penicillins, 230, 1971.
dbinyton,
R. Green,
Pa., ad
M.D.,*
and
Arthur
Rosenblum,
M.D.,**
Chicago, Ill.
Many aspects of the problem of penicillin hypersensitivity remain unsolved. The Penicillin Study Group of the American Academy of Allergy was formed to investigate various aspects of this problem. A number of studies have attempted to evaluate the relationship of clinical penicillin hypersensitivity to reactions to skin tests with penicillin and its degradation products. These studies generally have shown positive correlations, but considerable variation has existed in their magnitude.= This variation may well relate to differences in protocol, techniques, patient populations, or investigators.2-n The present cooperative study was devised to investigate the relationship of skin reactivity to penicillin hypersensitivity. The reagents used were penicillin G (Pen G) and penicilloyl-polylysine (PPL), a conjugated form of a penicillin degradation product (penicilloyl) , which prior studies have shown to be associated with the majority of penicillin hypersensitivity reactions.g The patient population was drawn from the clinical and private practices of practicing allergists who are members of the Penicillin Study Group of the American Academy of Allergy. MATERIALS
AND
METHODS
Twenty-six clinical investigators contributed a total of 1,160 cases to the study. Patients were tested according to the following protocol: Patients being subjected to allergy investigation as well as selected patients being evaluated for a history of penicillin hypersensitivity were interviewed and skin tested for penicillin hypersensitivity. Two preparations were used for skin testing: (1) penicilloyl-polylysine (PPL),t a sterile solution of benzylpenicilloyl-polylysine in a concentration of 6.0 x lo-aM (penicilloyl) in O.OlM phosphate buffer and 0.15 sodium chloride at pH 7.6 (PPL is a derivative of poly-L-lysine in which at least 65 per cent of the epsilon amino groups are substituted forming benzylpenicilloyl alpha amide). The PPL was supplied in sealed glass single-dose ampules containing 0.25 ml. which were refrigerated until used; (2) benzylpenicillin (penicillin G) freshly diluted to a concentration of 10,000 units per milliliter. For maximum safety it was recommended that the tests first be done by the scratch technique. Intradermal tests lvere then to bc done on those showing negative scratch tests. In cases From the Department of Allergy and Immunology, Abington Memorial Hospital, the Hospital of the University, Philadelphia, and the Department of Pediatrics, Michael Reese Hospital. Received for publication March 23, 1971. Reprint requests to: Dr. Green, 1355 York Road, Abington, Pa. 19001. *Chairman, Penicillin Study Group, American Academy of Allergy. **Immediate Past Chairman, Penicillin Study Group, American Academy of Allergy. _. tSupplied by the Kremers-Urban Co., Milwaukee, Wm., as Pre-Pen under IND No. 2135.
332
Green
and
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Rosenblum
TABLE I. Distribution
of skin reactions
to penicilloyl-polylysine
(PPL) and penicillin
G (PG)
A. Distribution PPL (+I PG I+)
PPL (+I PG l-1
PPL I-1 PG I-1
PPL l-1 PG I+)
NO.
%
No.
%
NO.
79
6.9
(9.1)
34 (80)
3.0 (6.9)
38 (49)
%
No.
%
N@.
%
No.
151 (1;:)
13.1 (20.3)
1,153
$81,
(105)
%
I) .j .>.< (4.3 )
NO.
%
1,002 (919)
86.9 ( 79.7)
6. Totals PPL I+) No.
113 (135) Skin reactions theses show positive skin
PG
Total
(+I
(lh)
(234)
(+I
Total
tested %
1’00
recorded as “erythema only” were classified as ambiguous. Figures in parendistribution of skin reactions when ambiguous responses were counted as reactions.
in which the penicillin sensitivity was suspected to be of a violent c~haracter, more dilute reagents were recommended at the discretion of the individual investigator. A uniform technique was recommended for the performance of the intradermal tests. Only a minimal amount (about 0.01 to 0.03 ml.) of testing reagent was to be injected so as to make a barely discernible intradermal bleb. It was recognized that the interpretation of the test results was a critical matter. The reactions were recorded in terms of: (1) the time required for the appearance of a reaction, (2) the size of erythema, and (3) the size of whealing. These were recorded as actual measurements. Some objective measurement of dermographism was also recorded by noting response of the skin to scratching. It was also contemplated that all patients who were to be treated with penicillin be tested as recommended above, even though they had previously received penicillin with impunity. A comprehensive clinical history was taken on each patient with particular regard to previous penicillin therapy and reaction. In order to properly analyze the data on such a large number of patients, a data processing system was utilized. All data were recorded by the investigators on the form shown in Fig. 1. Data processing was accomplished in collaboration with Eleanor V. Price of the Public Health Service and Dr. Gordon Stewart of Tulane University.
RESULTS Table I summarizes the skin test results on all patients, without regard to other specific factors. It will be noted that the over-all positivity rate was higher for PPL (9.8 per cent) than for Pen G (6.2 per cent) (p = < 0.003). It will also be noted that a significantly greater number of patients reacted only to PPL (79) than to Pen G only (38) (p = < 0.001). A technical problem was classification of the ambiguous or borderline reactors, particularly those showing only erythema. Attempts to correlate the appearance of the erythematous flare without wheal formation with a history of penicillin hypersensitivity were unsuccessful. In some instances, however, erythema without wheal did appear to be associated with hypersensitivity to the antibiotic. Recent reports by Fellner and associates1o suggest a correlation of the flare reaction with hypersensitivity. The time of development of erythema without wheal varied widely from a few minutes to more than 7 days, which also made its importance questionable as a diagnostic sign. For these reasons erythema alone
VOLUME NUMBER
48 6
Report
of the Penicillin
Study
Group
333
responses were generally counted with the negatives. In some instances, however, data will be presented in which erythema without wheal are counted as positive responses (figures appearing in parentheses). Only 2 of the positive skin test reactions were delayed in onset. Tn Tahlc 11 the results of skin t,ests 011 patients who had given a hist,ory of hypcrsensitirity react,ions are compared w&h those from persons who had no such reactions. Also inrludcd in this t,ahle are analysts of those who had receivetl no previous penicillin or on whom no therapeutic history could be obtained. Table III presents a statistical analysis of Table II. Patients who have had previous penicillin reactions (Group II) show a significantly higher positivity rate for both reagents than those who hare had no such reactions following therapy (p = < 0.001 for both reagents). Table IV shows the distribution of skin test responses by history of time of reaction after the administration of therapeutic penicillin. These data indicate a higher incidence of skin reactivity in patients with histories of reactions to pencillin within 30 minutes than in patients developing reactions after 24 hours. Of those reacting within 30 minutes, 26 of 56 (46.5 per cent) exhibited positive skin test,s to PPL, while 17 of 56 (30.4 per cent) were positive to Pen G. A total of 31 of 56 (55.5 per cent) were positive to one or the other or both rea.gents. Of those reacting after 24 hours, 24 of 144 (16.7 per cent) were positive to PPL, while 17 of 144 (11.8 per cent) were positive to Pen G. A total of 33 of 144 (22.9 per cent) were positive to one or both reagents in this group. This difference between the fast- and slow-reacting groups is significant (p = < 0.001). These data also suggest a greater reliability of the skin-testing procedure in patients with history of reaction to penicillin within 30 minutes as opposed to patients whose rraction to penicillin occurred after 24 hours. The percentage of positivity for the group who had fast reactions was over twice that of the group who developed delayed reactions (55.4 per cent versus 22.9 per cent). No ready explanation of why certain patients in both groups failed to develop positive responses to eit,her of the reagents is apparent. Table V shows the distribution of positive tests in skin-reactive, penicillinhypersensitive patients. Note in the group of patients with a history of reaction to penicillin within 30 minutes that up to 83.9 per cent responded to PPL, while 51.8 per cent responded to penicillin G skin tests. This difference is significant (p = < 0.03). In like manner, among patients who had developed reactions to penicillin after 24 hours, 72.7 per cent responded to PPL and 51.5 per cent to penicillin G. This difference, however, is not significant (p = < 0.20). However, if ambiguous responses are counted with positive tests, the difference between the reagents becomes significant (p = < 0.03). Since penicillin reactions occurring within 30 minutes almost invariably represent anaphylaxis, the correlation with positive skin tests in this group is of great significance. Although the number of positive reactions to PPL is significantly higher than that to penicillin G, the maximum number of reactors will be picked up only when both reagents are used. Only 3 of the 100 patients challenged after testing were reported to have a reaction (Table VI). The first patient was a 30-year-old woman who had an urticarial reaction occurring after receiving parenteral penicillin G. Skin test,ing
SURVEY NUMBER (Leave blank)
’
:
v H
s
Rh r N
c
r
O(1)
izlw
REACTION (If no, check No Yes
O(X)
TO PENICILLIN and skip to #36) No data
38
36
35
min.
PATIENT
<15
DO
YOU
HAVE
OTHER ALLERGY n(l) None (J(2) Rhinitir
DID
n(2)
<30 <24 <4S
parenteral
Proc.
Pen. G
IN
min. hours hours ANY
ABOUT
THE
,
0
testing
testing
o(5) o(6)
-,..
-___
FIG. 1.
O(1)
No
VERIFIED
SKIN
37 FAMILY HISTORY O(1) None o(2) Father
A REACTION?
WAS REACTION BY PHYSICIAN?
31
OF
No
o(2)
D(2)
Yes-Incomplete
Allergy
number
Group
of
REPORT
Injection
Yes
O(3)
O(X)
Other More than No data
Yes-Complete
o(5) n(6) O(X)
______
More than None
More than None
More than No data
No data
No data cl(X)
n(5) O(X)
site only O(6) O(X)
n(7) 0(X1
one
one
one
one
AMOUNT RECEIVED o(1) One dose O(X) No data D(2) one covrre n(3) More then one course
case
dermatitis
n(1)
cv collapse Purpura
Rosh Contact
ALLERGY O(3) Mother O(4) Sibling
O(1)
rJ(3) D(4)
O(4) o(5)
_______-
22
Your
Study
Academy
HYPERSENSITIVITY
Penicillin
American
PENICILLIN
~,
Benzathine penicillin G New Penicillin (specify)
VISCERAL (1 ) Wheeze c](2) Tightness in throat or chest
q
HAD
34
32
HISTORY?
derm.
lnitiol Repeclt
0
Address
and
.._I
Name
” -_,.
Physician’s
“,,..m.
ROUTE OF ADMINISTRATION n(i) od U(4) More than one O(2) Porentercll O(3) Topical O(X) No data
.,-...
TYPE OF REACTION: O(2) Pruritur O(3) Urticaria
Aqueous Depot
HAVING
ABOVE
Contact Urticaria No data
AFTER
<7 daw Longer Uncertain
06) o(6) O(X)
FORM
O(6) l-J(7) O(X)
O(4)
O(3)
,
sub.
21
v....
Student Pre-school child Other or N.D.
-..,I
- Allergy to: o(3) Pen. L other f-J(4) Irrelevant
n(X)
o(7) o(S)
RACE
,,.ersrr
ESTIMATED LAST DOSE , “7’ , ,Yey
10
25-30 ESTIMATED DATE LAST REACTlON , Mq”“, / Da? i”r”r;
1 S-20 DATE rMqn,h/
EVIDENCE
PATIENT o(3) Asthma C](4) Eczema
PENICILLIN
DOCUMENTARY
OF
TOLERATE
13(3) O(4) o(5)
PENICILLIN O(l) Oral o(2) Aqueous,
33D;7fmo,~d!;~CT’oN
24
Food-handler Office worker Factory worker Housewife
9 SEX Male Female
13 REASON FOR TESTING n(l) Penicillin O(2) Other substances
n(3) m(4) n(5) (-J(6)
7.8 AGE (Years)
PREVIOUS PENICILLIN THERAPY (If no, check and skip to #36) No Data O(X)
000
HANDLER No Dota
: P 23 FORM OF Y Pen. G or v Penicillin G
A E
14
PENICILLIN
3
5:
IR
H
12
11 OCCUPATION O(1) Medical or paramedical n(2) Animal-handler
1-6
“,a,yI8,
-
’
s 1 s
ffi
<4B hours <7 days Longer Uncertain
OF REACTION: O(1) Immediate O(l) Immediate n(l) Immediate
O(5) O(6) lJ(7) [3(X)
DOSAGE pen. G pen.
Month
test] O(4) O(S) O(6) O(X)
Edema (I+ 5 min. Edema at 30 min. Later Not done
Present-Normal
fi
52
FOR
O(3)
or4
60
FURTHER
o(1) D(5)
SHOCK
MILD SEVERE BRONCHOSPASM PRURITUS
Interrogation? Not ovailqble
72 73 74 75
Purpurcl
O(3) D(4)
Wheal Wheol Wheal Wheal
Wheal Wheel Wheel Wheel
O(l)
D(X)
42
--
follow-through?
Immediate Immediate ‘J(l) Immed. Remote
O(2) n(2) O(2) O(2)
-~--~.-______
Delayed Delayed Delayed Generalized
76
Urticaria
Uncertain
clw
G
COMPETENT
PSYCHOLOGICAL? U(1) No Yes fJ(X) Doubtful
D(3)
IJCX)
BY
Benzothine penicillin Other (specify) More thon one
done
SPEED OF REACTION [7(l) One minute o(2) Five minutes D(3) Thirty minutes O(4) Later
SPEED OF REACTION o(l) One minute o(2) Five minutes o(3) Thirty minutes lJ(4) toter
OBSERVED
U(5) @(6) O(7)
Not
45
O(2) Yes
WAS REACTION WITNESS? U(1) No
65
Pen. G Aqueous Depot
Both Neither
20 mm
20 mm
~.
site only O(2) Pruritus U(6) Mare than one D(X) None Tightness in throat or chest 00) More than one O(X) None
Clinical
Ini.
O(1) O(1)
o(2)
O(2)
O(l) dematitis
FIG. 1. Continued.
-
67 SKIN J(SJ Contact O(l) Wheeze (J(4)
q
O(4) O(5) O(6) 3(7)
O(4) U(5) O(6) j(7)
onlyl
FORM OF PENICILLIN o(l) Pen. G or V Proc. tablets O(3) lJ(2) Pen. G - Aq: O(4)
Eorinophilia Thrombocytopenio
one rquore
DID PATIENT EXPERIENCE REACTION TO PEN.? If “a, check and skip lo 577. D(X) N.D. Yes O(l) No
O(1) O(2)
INTRADERMAL TEST n(l) Negative U(2) Erythema only D(3) Erythemc with wheal in bleb
ROUTE OF ADMIN. O(1) Oral O(3) I.V. O(2) I.M. O(4) Other
64
(Check
INTRADERMAL TEST O(1) Negative O(2) Erythema only O(3) Erythema with wheal in bleb
TESTS:
44
41
TYPE OF REACTION: O(4) Rash 68 VISCERAL O(3) C.V. collapse
59
OBSERVATIONS Present-Exoggeroted
LABORATORY
HYPOTENSIVE O(2) Delayed O(2) Delayed U(2) Delayed
I
I.D. test) U(4) Edema at 5 min O(S) Edema at 30 min. D(6) later D(X) Not done
I.D.
O(2)
LIKELY TO BE AVAILABLE o(4) Therapeutic challenge?
YOUR CLASSIFICATION 69 INJ. SITE ONLY 70 URTICARIA 71 ANGIO-EDEMA
77 IS THIS PATIENT O(3) Skin tests?
; E
to #77
PENI-
62.63 TOTAL Million units Grams other
OF
skip
NUMBER OF DOSES
and
;;;;‘;heyyJo”ep
DATE
at
omit
omit
~~~~
SCRATCH TEST (If +, Cl(l) Negative O(2) Erythema only lJ(3) Edemo 1 min.
66 TIME OF OCCURRENCE o(l) Immediate o(2)
n R L 61
1 E-
43
53.58
p P
c
00)
p 40 SCRATCH TEST (If + E o(1) Negative N O(2) Erythema only O(3) Edema at 1 min.
DER~IOGRAPHIA:
T E
YG N
S
39
CURRENT
336
Green
and
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Rosenblum
TABLE II. Distribution
of skin reactions
PPL (+I
Group II Pen. I$, sensitive (352 patients) Group III No Pen. fi (,70 pat,ients)
Group 1.v No data (56 patientsj Totals (1,153 patients)
TABLE III. Academy
(PPL) and
PG(+l
PPL 1-l %
NO.
NO.
I
%
1.3
15
(44)
(6.5)
(34)
(5.0)
(22)
(3.3 /
49
13.9
24
ti.8
23
ti.3
(57)
(16.2)
(40)
(11.4)
(25)
(7.1)
1
1.4
0
(2)
(2.9)
(4)
(5.7)
(1)
2
3.6
1
1.8
0
(“1
(3.6)
(2)
0
(X(i)
6.9 34 (9.1) (80) both positive and ambiguous skin reactions:
Statistical
2.n (6.9)
Group
No.
(1)
i 1.X)
(“,“,I
:I.,3 (4.2)
analysis PG (+I
%
36
5.3
(78)
(11.5)
73
20.7
(97)
(27.6)
109 (175)
10.6 (17.0)
(A)
((3
(1.4’1
reactors.
PPL I+)
Totals (1,027)
PG (+I
9
of Allergy
Group II Penicillin I$, sensitive (352 patients)
G (PG)
4.0
include
Group I Penicillin I$, not sensitive (675 patients)
Penicillin
I, ., -.-
79 (105)
in parentheses
PPL (+I
%
27
Group I Pen. I$, not sensitive (675 patients)
Figures
PG l-1
NO.
Group
:o peniciiloyl-polylysine
No.
%
24
3.6
(RI
P)
(56)
(8.31
47
13.3
(65)
(1X.5)
71
(121)
6.9
(11.8’l
Analysis X’ (A) vs. (R) 2.196 (2.110) < 0.20 p (< 0.20) 3.579 (6.278) < 0.06 (< 0.02) (Cj vs. CD) 54.091 (A) vs. (C) (40.780) < 0.001 36.040 (22.053) < 0.001 (RI vs. (Dj Figures in parentheses include both positives and ambiguous reactors. rSumma_r;y: 1. Of 675 patients previously treated with penicillin but not previously sensitive, 36 (0.3 per cent) were PPL positive while 24 (3.6 per cent) were PG positive. (If ambiguous reactions are counted as positives, the percentages increase to 11.5 per cent for PPL and 8.3 per cent for PG.) 2. Of 352 patients with histories of sensitivity to peni(dillin, 73 (20.7 per cent) were positive to PPL while 47 (13.3 per cent) were positive to PG. (If ambiguous reactions are counted as positives, the percentages become 27.6 per cent for PPL and 18.5 per cent for PG and the difference is significant, p = <0.02). 3. Difference in positive skin tests to both reagents in patients who tolerated previous penicillin and those who did not is highly significant, (p =
6 months later resulted in an 8 x 12 mm. wheal to Pl?l~. Carbcnacillin, 30 (inr. daily, was administered for 2 days, and 20 days later a rash occurred. A sccontl patient was a 50-year-old man who had a local reaction to a nasal aerosol of penicillin in 1955. When tested in 1967 he had delayed erythema without wheal
JOLUME 48 NUMBER 6
Report
of the
Study
Penicillin
Group
337
Total
---~ PPL
_~
I+1
PG
I
I+)
Total
I
I+)
No.
%
NO.
%
(is)
(11.5)
(5(i)
(8.3)
i3
20.7
47
13.4
96
27.3
(97)
(27.6)
(65)
(18.5)
(123)
(34.i)
I
1.4
0
1
1.4
(61
(X.6)
(5)
(7.1)
(il
(10.0)
3
5.4
1
1.x
3
5.4
(4)
(i.1)
i 3)
(5.4)
113
(1::;)
TABLE IV. Distribution of therapeutic
(1291
of skin
responses
(11.2)
by history
(14.8 I
of time
of
(5)
(X.9)
151 (“34)
13.1 (20.3)
reaction
after
administration
penicillin Skin PPL
Time reaction
%
(loo)
6.3
72
(1X5)
NO.
of penicillin ofter therapy
Within 30 minutes (56 patients) Between 30 minutes and 24 hours (87 patients)
(+I
PG
No.
l-1
%
PPL
(+I
PG
NO.
(+I
%
responses PPL
l-1
NO.
($C,
(ii)
(i&
(1:)
(&
(if,
($T)
More than 24 hours (144 patients)
(22,
TABLE V. Distribution
of positive
PPL
(+)
C-1
f-1
44.6 135.7 I
x.9 (X.9) 5.7 (X.0)
i;,
PG
%
NO.
%
r (it)
PG
70.0 (63.4)
(&
77.1 111 (69.4) (100) Skin reactions recortled as “ergthema only” were classifie(l as ambiguous. Figures in parentheses show distribution of skin reactions ahen ambiguous responses were counteIl as positive skin reactions.
skin-reactive
Time reaction
IPithin tk:t\vern
11.1 (15.3)
skin
(1:)
tests
($)
in penicillin
(1:)
6.2 (7.6)
allergy
patients
having
antibodies
I
of penicillin afier therapy
Total PPL (+)
30 Inillutw tll:aL
24 I1our.s
and
Total PG (+I %
NO.
X3.9
li
(Z )
( Sti. I )
(17)
54.8 (47.” i
“1 (24)
30.X (i7.4 1
!i (“I 1
((ii.7
24 (33)
(i5.0)
(&
(50.0)
NO.
30 minutes
24 hours Mow
If
72.;
I
%
I
31 (36) “6
65.4 51.3
Total positive . (No.1
)
(31) 33
(441 Skin reactions recordecl as “er$hema only” were classifircl as ambiguous. Figures in parentheses show distribution of skin reactions when ambiguous responses were counteci as positive skin reactions.
338
Green
and
Rosenblum
TABLE VI. Patients penicilloyi-polylysine
challenged
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
(PPL) and
with penicillin subsequent penicillin (PG)
PPL I+) PG I+) PPL I+) PG (-I
Number
eldlengtd
Number reacting challenge
1
to skin testing
with
PPL (-1 PG (+) PPL (4 PG (-1
Total challenged
4
3
92
100
1
1
1
3
1
1
1
3
to
Observed by competent witness
TABLE VII. Distribution
of skin test responses
by type of hypersensitive
reaction
(i.e., skin versus visceral) Skin test response Type hypersensitivity
Skin reactions
PPL+
of reaction
only
I
No.
11
PG+ %
I
No.
I
%
Total tested (No.)
66
21.4
39
12.6
309
Visceral (with or without skin reaction)
IO
23.3
14
32.6
13
No reactions
36
5.3
2‘i
3.6
675
-formation to intradcrmal penicillin. Hc received intramuscular penicillin 5 da?s later and tle~clopctl generalized prnritus and a rash within 21 hours. The thirtl patient reacting to challenge was a 59-year-old physician who reported an untoward reaction to the administration of penicillin in beeswax in 1948. skin tests in 1967 mere negative, and penicillin was cautiously begun at a dose of 20,000,OOO units daily. He had transient urticaria one week later, but penicillin was continued without further difficulty. Since he had no reaction until after one week of penicillin, this may represent sensitization to the current course of t,herapy and hence does not necessarily represent a false negative skin test. Table VII shows an analysis of the skin test responses by history of the type of hypersensitivity reaction experienced, i.e., visceral (with or without skin reactions) or skin reactions only, It will be noted that the posit,ivity rate is significantly higher in both categories than in patients who had tolerated penicillin therapy Jvithout any reaction. PPL appeared to give a significantly higher positivity rate than Pen G with regard to skin reactions (p = < 0.006). The positivity rate for Pen G was higher for visceral than for skin reactions (p = < 0.02). The difference, however, in skin test reactivity between PPL and Pen G in patients who had experienced visceral reactions is not significant. Patients were analyzed (Table VIII) with regard t,o the reason for testing. One group was specifically tested because of suspected allergy to penicillin, and this was compared with the group that was tested for suspected allergy to other substances. The group being specifically tested for penicillin hypersensitivity showed a more highly significantly increased incidence of positive skin tests than the patients tested for hypersensitivity to other substances (p =
Report
VOLUME 48 NUMBER 6
TABLE VIII.
Distribution
Reason
for testing
“penicillin”
Suspected allergy t.0 other substances TABLE IX. Distribution
Study
Group
339
of skin tests by reason for testing PPl.+
Suspected allergy
of the Penicillin
No.
%
Total tested (No.1
10.11
34
IX.8
240
1.9
27
5.8
463
Total
PG+
No.
%
No.
31
12.9
24
21
4.5
9
of skin responses
%
by history of penicillin
in patients
+
therapy
Skin reactions
No.
%
No.
%
No.
%
Total tested (No.1
One course Multiple courses
24 14 14
15.8 5.6 7.9
17 8 10
11.2 3.2 5.6
23 19 22
22.4 7.6 12.4
152 249 177
Totals
52
9.0
35
6.1
75
13.0
578
PPL+ History One
of therapy
dose
TABLE X. Time lapse between Time
penicillin
reaction
with
three
+
and skin testing
Positive tests/total
lapse
3 MO. or less 4-12 MO. 13-60 MO. More than 60 mo. p = <0.05
Total
PG+
skin tested
X3/ 61 17/ 47 29/ 86 26/134
%
29.5 36.2 33.7 19.4
degrees of freedom.
significant, but the difference in response to the two reagents in the “other substances” group is significant (p = <0.05). The analysis of data on penicillin handlers indicates a significant correlation with positive skin responses to both reagents (p = <0.05). Twenty-six per cent (7 of 26) of the penicillin handlers had a positive skin test, whereas 11.8 per cent (Xl of 685) of the individuals with no such history had positive responses. Of possible importance is the high incidence of positive skin reactions in those patients having had only one dose of penicillin (Table IX). The differences in skin reactivity to both reagents in patients receiving one dose as compared with one course or multiple courses of penicillin is significant (p =
340
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Green and Rosenblum
TABLE Xl. Intensity
of skin reactions
versus history
of penicillin Skin
History penicillin
of allergy
Reagent
Weak
I<
8
mm.1
1%
20/148 S/140
PI’1 ‘ PG
*31/153 (20%) S/134 (16%)
PPJ,
(14%) (65%)
allergy reactions I
Strong
r>
8
mm.)
M/148 8/140
(9%) (6% )
‘7/153 i/134
(18% 1 (5%j
the intensity of the intradermal skin reaction and a history of penicillin allerg! (Table XI). The data show a significant excess (p <0.04) of skin reactions of greater than 8 mm. to PPL in patients with a history of penicillin intolerance. IIowevcr, the reverse was seen with Pen G in that a significant excess of reactions of less than 8 mm. developed in patients with a history of penicillin allergy. The percentage of strong reactions to Pen G, on the other hand, was essentially equal among patients with and without a history of penicillin allergy. The possibility that age of the patients could play a role in the large number of patients with a hist,ory of penicillin intolerance but negative skin tests was considered. Among patients with a positive history of penicillin allergy, 72 per cent of those 15 years old or less had negative skin tests, whereas 62 per cent, of those over 15 years had negative skin reactions. DISCUSSION The above data and analysis demonstrate that positive skin tests with penicillin G and PPL were correlated with: (1) clinical history of a penicillin reaction ; (2) time of occurrence of reactions following administration of penicillin ; (3) type of hypersensitivity reaction (visceral or skin) ; (4) reason for testing, i.e., to penicillin or to other substances; (5) patients having received only one dose of penicillin as compared with patients having histories of multiple COL~SCS of therapy ; (6) patients reporting non-therapeutic contact with penicillin. No significant correlation was found regarding : (1) route of administration ; (2) family history of allergy; (3) personal history of allergy. There are certain inherent sources of error in a study of this sort due to: (1) the number of investigators, (2) deviation from adherence to the protocol, (3) large dependence on the accuracy of previous medical records, and (4) histories as given by the patient. The most likely source of inaccuracy lies in the history of a previous penicillin reaction as stated by the patient and recorded by the investigator. Direct examination of the patient records revealed instances in which the history was inadequate or difficult to interpret. The patient is given penicillin because of an illness, and any unt.oward reaction that occurs after penicillin administration is likely to be attributed to the penicillin, whereas it is quite probable that many of these untoward “reactions” are, in fact,, a symptom or complication of the illness. This is particularly true of rashes of various sorts. IJrticarial rashes, erythema multiforme, and other toxic rashes commonly occur in the course of various viral or st,reptococcal infections. Similar problems may occur in the tliffcrentiation of gastrointestinal and pulmonary complaints. Welltlrti~~etl anat)hylactic reactions are not likely to be misdiagnosed.
VOLUME 48 NUMBER 6
Report of the Penicillin Study Group
341
Another problem is the interpretation of skin tests. The significance of minimal reactions, particularly erythema without edema, has not been established. (iruerally, significant positive skin tests are well defined and show a large central wheal. The equivocal test, as cxcmplific(l by rr!-tht>ma wlonc, clevclops so c1rrat.C ~~11~ t,hat, its significance is not clear. Ko conclusions are. drawn regarding the signific*anct: of positive skin tests brcausc of the minimal number of posit,ivc skin reactors challenged. This series would bc cxpectetl to be small because of the potential hazards of giving penicillin to paticnt.s having known positive skin tests. The occurrence of reactions in two of the skin test-positive subjects is suggestive of the danger of administering penicillin to such patients. The lack of a strong correlation between the results of skin testing and the interval of time since the prior penicillin reaction was unexpected. However, it, should be noted that a similar lack of correlation between the interval of time since the prior reaction and the incidence of reactions to challenge with penicillin has been reported previous1y.l’ Penicillin hppersrnsitirity, once induced, may be less evanescent than some would believe. No clear correlation was found between the intensity of the intradermal skin reaction and a history of penicillin allergy when penicillin CGwas used for testing, although a significant correlation appeared with PPL. These data could be affected, however, by the fact that most patients with a positive scratch test were never tested by the intradermal route. Some strong reactions may thercforc have) been excluded. The finding of more negative skin reactions in patients with a history of peilicillin allergy who were less than 15 years old is not surprising. Hoover, the difference is relatively small (and statistically insignificant,, p = 0.3). Even allowing for the problems and inherent inaccuracy of the study, the results permit the following conclusions: (1) Skin testing to PPL and Pen (: was shown to be safe and of value in this study. (2) Results of skin tests show a significant correlation with history of clinical penicillin hypersensitivity. (3) The skin test reaction rate is particularly high in patients who experienced penicillin reactions of the immediate type within 30 minutes (Table IV). In these patie&, 26 of 56 (46.5 per cent) exhibited positive skin tests to PPL, while 17 of 56 (30.4 per cent) were positive to penicillin G. A total of 31 of 56 (55.5 per cent) were positive to one or the other or both reagents. (a) In the immediate reactor group, analysis of those patients having positive skin t,ests (Table V) indicates that 84 per cent were positive to PPL, while 55 per cent, were positive t,o Pen (: This would indicate that in this group 16 per cent would be missed if only PPII were used as a skin test antigen, while 45 per cent would be missed if only Pen (: were used. The necessity of using both reagents for testing, therefore, seems obvious, and the ilata suggest that these tests are most valuable in detecting immediate hypersensitivity reactions. Since these are the most dangerous types of penicillin reactions, often including anaphylaxis, it would be anticipated that such skin-testing procedures performed before the administration of therapeutic penicillin would be valuable in preventing and avoiding such reactions. (5) Lack of a 100 per vent correlation of skin tests with clinical history point’s up the importance of nufhenficnti~q the clinical history of penicillin reactions. The
342
Green
and
J. ALLERGY CLIN. IMMUNOL. DECEMBER 1971
Rosenblum
number of patients challenged was insufficient to draw any conclusions as to which is the more predictive-clinical history or skin testing. Moreover, the possible evanescent nature of penicillin hypersensitivity should not be overlooked. (6) Patients who have had authenticated penicillin reactions are known to be likely candidates for subsequent reactions, and such patients are not likely to receive more penicillin except under carefully controlled conditions. Further studies are planned by the Penicillin Study Group and others to provide more information regarding the importance of skin tests in the historynegative patients who are to receive therapeutic penicillin. The role of other minor determinants of penicillin hypersensitivity, such as benzylpenicilloate, and their relation to the broad problem of immediate penicillin reactions is being evaluated. The cross-reactivity of the various semisynthetic penicillins and cephalosporins needs further study.12 The major importance of this study was the fact that these standardized skin testing reagents could be safely used by a large number of practicing physicians to show that such testing is a valuable procedure in assessing a history of clinical sensitivity to penicillin. Hence, the Study Group feels that the reagent PPL should be made generally available and that the Food and Drug Administration should be so informed. ADDENDUM The contributions and cooperation of the following Group are herewith gratefully acknowledged: Alan G. Cazort, M.D., Little Rock, Ark. Monroe Coleman, M.D., Stamford, Conn. Lloyd V. Crawford, M.D., Memphis, Term. Bernard R. Feldman, M.D., New York, N. Y. Stanley R. Finke, M.D., Flushing, N. Y. Harold J. Friedman, M.D., Cleveland Heights, Ohio Kenneth L. Gerson, M.D., Lexington, Ky. Michael H. Grieco, M.D., New York, N. Y. J. Desmond Horan, M.D., Vancouver, British Columbia, Canada William B. Hunt, Jr., M.D., Charlottesville, Va. Manuel Ingall, M.D., Newton Lower Falls, Mass. Joseph E. Johnson III, M.D., Gainesville, Fla.
invest,igators
of the Penicillin
Study
Martin J. Kaplan, M.D., Highland Park, 111. Martin P. Kaplan, M.D., Lexington, Ky. Bernard B. Levine, M.D., New York, N. Y. Abe Matheson, M.D., Chicago, Ill. (Deceased) Charles W. Parker, M.D., St. Louis, MO. H. Rowland Pearsall, M.D., Seattle, Wash. Mrs. Eleanor Price, Atlanta, Ga. Bernard B. Siegal, M.D., Far Rockaway, N. Y. Cheyney C. Sigman, Jr., M.D., Atlanta, Ga. William B. Steen, M.D., Tucson, Ariz. Gordon T. Stewart, M.D., New Orleans, La. Lawrence C. Sweet, M.D., Detroit, Mich. Paul P. Van Arsdel, Jr., M.D., Seattle, Wash. Howard E. Voss, M.D., Stamford, Conn. Stanley I. Wolf, M.D., Silver Spring, Md. Bernard M. Zussman, M.D., Memphis, Tenn.
REFERENCES 1 Idsoe, O., Guthe, T., Willcox, R. R., and deWeck, A. L.: Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactie shock, Bull. W. H. 0. 38: 159, 1968. 2 Parker, C. W., Shapiro, J., Kern, M., and Eisen, H. N.: Hypersensitivity to penicillenic acid derivatives in human beings with penicillin allergy, J. Exp. Med. 115: 821, 1962. 3 Levine, B. B., and Zolov, D. M.: Prediction of penicillin allergy by immunological tests, J. ALLERGY 43: 231, 1969. 4 deWeck, A. L., and Blum, G.: Recent clinical and immunological aspects of penicillin allergy, Int. Arch. Allergy 27: 221, 1965.
VOLUME 48 NUMBER 6
Report
of the Penicillin
Study
Group
343
5 Brown, B. C., Price, E. V., and Moore, M. B., Jr.: Penicilloyl-polylysine as an intradermal test of penicillin sensitivity, J. A. M. A. 189: 599, 1964. 6 Rytel, M. W., Klion, F. M., Arlancler, T. R., and Miller, L. F.: Detection of penicillin hypersensitivity with penicilloyl-polylysine, J. A. M. A. 186: 894, 1963. 7 Voss, H. E., Redmond, A. P., and Levine, B. B.: Clinical detection of the potential allergic reactor to penicillin by immunologic tests, J. A. M. A. 196: 679, 1966. 8 Bierman, C. W., and Van Arsdel, P. P., Jr.: Penicillin allergy in children: The role of immunological tests in its diagnosis, J. ALLERGY 43: 267, 1969. 9 Schneider, C. H., and Parker, C. W.: In Stewart, G. T., and McGovern, J. P., editors: Penicillin allergy, Clinical and Immunologic Aspects, Springfield, Tll., 19780, Charles (‘ Thomas, Publisher, chaps. 2 aud 4. 10 Fellner, M. J., Ball, E. H., Allyn, B., and Baer, R. L.: Delayed hypersensitivity to penicillin, J. A. M. A. 21: 2061, 1969. 11 Green, G. R., Peters, G. A., and Geraci, J. E.: Treatment of bacterial endocarditis in patients with penicillin hypersensitivity, Ann. Intern. Med. 67: 235, 1967. 12 Van Dellen, R. G., Walsh, W. E., Peters, G. A., and Gleich, G. J.: Differing patterns of J. ALLERGY 47: wheal and flare skin reactivity in patients allergic to the penicillins, 230, 1971.