The Persistence of Allergic Eczematous Sensitivity and the Cross-Sensitivity Pattern to Paraphenylenediamine*

THE PERSISTENCE OF ALLERGIC ECZEMATOTJS SENSITIVITY AND THE CROSS-SENSITIVITY PATTERN TO PARAPHENYLENEDIAMINE * ALEXANDER A, FISHER, M.D., ALFRED PELZIG, M.D. AND NORMAN B. KANOF, M.D., MED. Sc.D.

Paraphenylenediamine (PPD) is a frequent esthetics, sun screens, and sulfa drugs. 46 of the and potent sensitizer producing many cases 50 patients still reacted to PPD. All the 4+ reof allergic eczematous contact-type dermatitis. actors and all but one of the 3 + reactors had A review of the patient material of our Al- retained their hypersensitivity to this chemlergy Section from 1949 through 1956 reveals that PPD is one of the most common causes of patch test reactions. Of 712 patients referred to the Allergy Section for patch testing during 1956 who were tested to PPD, 26 (3.6%) gave strongly positive (3 or 4+) reactions. PPD (H2N-C6H4-NH2) is used principally

in hair and fur dying. It may cross react, allergenically or immunologically, with other chemicals having an amino grouping in the para position on the benzene ring. These include certain dyes, local anesthetics, para-aminobenzoie

ical. In contrast 3 of the 6 2+ reactors no longer manifested any sensitivity to PPD. Table II shows the other positive patch test reactions of the 46 patients who retained their PPD hypersensitivity. 28 reacted only to PPD

and showed no cross-reactions to any of the other test substances. 11 patients reacted to both PPD and benzocaine. 4 patients reacted to PPD, procaine and benzoeaine. 3 patients reacted to PPD, PABA and benzoeaine. One of these reacted to procaine as well. One patient reacted to sulfanilamide and PPD. In addition,

acid and the sulfonamides. 25 patients with strong positive patch tests to This paper deals with the persistence of PPD PPD were patch tested with two recently insensitivity, some aspects of the cross sensitivity troduced cral anti-diabetic eompounds* which pattern of this substance, and the clinical signifi- are structurally related to sulfanilamide. There cance of these findings. were no reactions to these sulfa compounds in any of these PPD positive patients. METHODS AND REsULTS DISCUSSION

In 1956, 50 patients with positive patch test reactions to PPD during the period from 1946

43 of 44 persons who had shown 3+ or 4-F patch test reactions to PPD during the years

to 1953 returned to the Allergy Section for 1946—53 still manifested this sensitivity when further investigation. The group consisted of they were retested with PPD in 1956. 3 of 6 38 women and 12 men, ranging in age from 18 to 70. 18 had had 4+ reactions, 26 had had 3+

persons who had shown weaker (2+) reactions during the initial period were negative to PPD

reactions, 6 had had 2+ reactions. In 1956 patch tests in 1956. Table III compares the these patients were patch tested with 2% PPD in petrolatum, 5% benzocaine in petrolatum, 1% aqueous procaine hydrochloride, 5% para-aminobenzoic acid( PABA) in petrolatum, and 5% sulfanilimide in petrolatum. The patients were care-

persistence over a 3 to 10 year period of strong

PPD sensitivity with that of other allergens similarly studied. Once established, allergic hypersensitivity to many simple chemicals is maintained for long periods of time (1—3). fully questioned concerning exposures and However "spontaneous" loss of sensitivity to reactions to nylon stockings, hair dyes, local ansome allergens has been observed (4). The * From The Department of Dermatology and Syphilology of the New York University Post Graduate Medical School (Dr. Marion B. Sulz-

persistence of allergic eezematous contact-type sensitization varies from substance to substance. berger, chairman) and The Skin and Cancer Unit PPD appears to belong with benzocaine, nickel, of the New York University Hospital. With the technical assistance of Mrs. Elaine *5% Carbutamide (1 butyl-3-p-aminobenzesulfonurea) in petrolatum and 5% tolbutamide. Caligiuri, R.N., and Miss Alice Ross, MT. Presented at the Eighteenth Annual Meeting (1 -butyl-3-p-tolysulfonurea) in petrolatum. These of The Society for Investigative Dermatology, tests were suggested by Dr. R. L. Baer, who supplied the materials for patch testing. Inc., New York, N. Y., June 2, 1957. 9

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TABLE I The persistence of PPD sensitivity in 50 patients During the Period 1946—1953

50 PPD Positive Patients Showed These Reactions

When Re-tested in 1956 The Same Patients Showed These Reactions

specific allergen might increase the level of sensitivity to that substance. Several of the PPD posi-

tive women in this study repeatedly exposed themselves to PPD (in hair dyes) without any increase in their PPD sensitivity as measured by

patch tests. Repeated patch testing with PPD also appeared to have no effect on the level of

4+

18

4+ 3+

13 5

3+

26

3+ 2+

17

Nag

1

1—2+

3 3

the primary allergen. These findings agree

Number of cross reactions in 46 individuals with PPD hypersensitivity

esthetics. On the other hand, these investigators

2+

6

8

TABLE II

.

PPD and benzocaine PPD procaine and benzocaine... PPD, PABA and benzocaine.... Sulfanilamide

28 11 4*

3t 1

* Procaine reactors all reacted to benzocaine.

I One of these reacted to procaine as well. Comparison of persistence of strong PPD sensitivity over a period of 3 to 10 years with that of benzo-

caine, nickel sulphate, ragweed oleoresin and potassium dichromate

Benzocaine Nickel Ragweed oleoresin Potassium dichromate

generally with those of Tzanck, Sidi, and Dobkevitch-Morrill (6) who reported that a minority of their patients with a 'primary' sensitization to

PPD developed cross-reactions to local anreported that a majority of their patients with 'primary' sensitization to local anesthetics manifested cross-sensitization to PPD. We found in a separate study of 24 benzocaine positive patients in whom it appeared probable that benzocaine was the 'primary' allergen, that 10 showed hyper-

sensitivity to PPD as well. All three of our patients who reacted to both PPD and procaine also reacted to benzocaine.

Baer (7) reported that three of seven PPD

TABLE III

PPD

had been exposed to both allergens so it was not possible to determine which substance was

Nag

PPD alone—no cross reactions. .

sensitivity to the test substance. 11 of our 46 PPD positive patients were also sensitive to benzocaine. Many of these patients

No. of Cases

Persistant Positives

44

97% 96% 90%

25 100 18

100%

20

55%

and ragweed oleoreSin to that group of chemicals

in which allergic hypersensitivity may be repeatedly demonstrated years after the initial sensitization has taken place. Hypersensitivity to dichromate, on the other hand, is much less consistently maintained over a period of years. Any evaluation of desensitization procedures must be based on a knowledge of the natural

positive patients reacted to both procaine and benzocaine. Sidi and Dobkevitch-Morrill (8) also reported seven patients who reacted to PPD

and procaine and ointments containing local anesthetics (not benzocaine). The possibility that 'primary' sensitization to PPD or benzocaine may pave the way for severe reactions to

procaine administered at a later date will be dealt with more fully in another publication. It has been suggested that repeated exposure to a specific allergen might widen the spectrum

of sensitization (7). The patient-material reviewed in this paper includes 5 PPD positive women who repeatedly exposed themselves to this material over a period of several years. These

exposures always caused a severe dermatitis. These patients showed no widening of their spectmm of sensitivity. They maintained hypersensitivity to PPD and did not react to the other related compounds with which we tested them.

Nor did repeated patch testing of these PPD

persistence, or lack of persistence, of the hyper- positive patients with other compounds consensitivity to the substance in question. taining the para-amino benzyl grouping senBaer (5) suggested that repeated exposure to a sitize to the other compounds.

ALLERGIC ECZEMATOTJS SENSITIVITY TO PARAPHENYLENEDIAMINE

11

Our study indicates that PPD sensitivity, 3 to 10 years. In this series of 46 PPD reactors, once established, persists for years. The spectrum of cross sensitivity to PPD appears to be related

there were 11 who gave cross-reactions to benzo-

caine, 4 who gave cross-reactions to procaine to an individual "host" factor and to be estab- and benzocaine, 3 who reacted to PABA and lished early. The spectrum of cross sensitivity benzocaine, and 1 who reacted to sulfanilimide.

does not as a rule widen later even with reRepeated exposure to PPD did not affect peated exposure to the allergens in question. the level of PPD sensitivity of the patients in Only one of our patients showed a "spread", this series. or widening, of his PPD sensitivity to henzoRepeated exposure to PPD and/or related caine and procaine over a three year period. A broad pattern of cross sensitivity seems to be the exception rather than the rule. There was

allergens did not, as a rule, broaden the established spectrum of cross-sensitivity of the patients studied in this series.

no difference in the findings between the younger

REFERENCES

and the older age groups in our material. Baer (7) has pointed out the unpredictability of an individual's pattern of sensitization. No

1. SULzEERGER, M. B. AND RO5TENBERG, A.:

two of his 9 PPD positive patients showed identical patterns when tested to 20 related

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tions on the persistence of sensitivity of the eczematous type after prolonged periods of removal from contact with the allergen. J. Invest. Dermat., 4: 175, 1941.

whether a hypersensitive individual will react 3. SEQURRA, J. II, INGRAM, J. T. AND BRAIN, R. T.: Diseases of the skin. 5th Ed. London, to one or more or all of a group of related comJ. & A. Churchill, 1947. pounds. Furthermore in cases of multiple reac- 4. NJRL5ON, J. P. AND BANG, K.: On the persistions of cross sensitivity, it may be very difficult or impossible to determine the 'primary' allergen

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if there has been exposure to several of the related substances.

Aeta dermat. venereol., 34: 110, 1954. 5. BARR, R. L.: Example of cross sensitization in

SUMMARY

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in MacKenna, Modern Trends in Dermacer Unit and patch tested with 2 per cent PPD tology, Second Series 232—257. N. Y. Paul B. in petrolatum showed strongly positive (3—4+) iloeber, Inc., 1954. S. Srm, E. AND DOBRRvITCII-MORRILL, S.: The reactions to this allergen. injection and injestion test in cross sensitiza46 of 50 patients with strong hypersensitivity tion to the para group. J. Invest. Dermat. to PPD retained this sensitivity over a period of 16: 299, 1951.

DISCUSSION DR. FRRDRRIcK REIS5 (New York, N. Y.): one reacted to both dyes. This illustrates the Dr. Sulzberger pointed out before, studies on high specificity of sensitized patients. An interesting factor in this series is that none sensitivity are an endless task of research and Dr. Fisher demonstrated in his work how chal- of these patients had previously used hair dye, lenging this problem is. We recently have published our investigation

which indicates some sort of cross-sensitization

28: 134, 1957). We used the paraphenylenediamine and the paratoluylenediamine. Among 1,028 patients, only S patients showed a positive reaction. Four reacted positively to paraphenyldia-

used procaine. Amongst the 8 positive reactors only 2 showed positive reaction to procaine. On retesting 301 patients at intervals of from three to four weeks, once on 301 persons and twice on 67 persons, no change developed in the speci-

to certain substances we have not elicited. It on patch testing with oxidation hair dyes on also has been our interest to investigate crossover 1,000 hospitalized patients. (J. of Allergy sensitizing phenomenon. For that purpose we

mine and three to paratoluylenediamine, and

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ficity of the reaction. In only one patient who case of p-phenylenediamine, a variety of such was found sensitive to the dye, early repetition quinones may arise in the body, such as quinone gave weaker reactions and the repetition on diimine, imino quinone, benzo quinone, oxythree occasions a year later gave negative results. imino quinone, etc. Many factors determine the nature of this intermediate, among them pH, DR. R. L. MAYER (Summit, N. J.): Sensitiza- intensity of metabolism, type of exposure, etc. tion patterns of various compounds belonging to These variations explain, in my opinion, the the same antigenic group are most variable; various patterns of cross sensitivity. It would be this is one of the most curious aspects of the quite interesting to determine in each case of sensitization problem. It is a priori quite difficult sensitization the real chemical nature of the to understand why patients primarily sensitized intermediate responsible for the sensitization, to p-phenylenediamine are more often sensitive but this is, of course, a quite difficult problem. to procaine than vice versa. The reasons for the existence of various patterns within a specific DR. ALEXANDER A. FISHER (in closing): Dr. type of cross-sensitization is probably due to Reiss mentioned the incidence of PPD sensithe fact that the sensitization is not caused by tivity. In our series there were 1712 patients the original substance, but by metabolites. It is who were tested to PPD. 3.6 per cent reacted to established that different metabolites are formed this substance. We interviewed some of the within the same group; they all constitute direct

sensitizers of different potency. In the case of beauty parlors in New York City to see how p-phenylenediamine, for instance, and of com- many patients they rejected because of a posi-

pounds related to it, the antigenic active metabo- tive patch test. The "better" beauty parlors lites are all compounds of quinone structure, rejected 1 per cent.

I wish to thank Dr. Mayer for his discussion and I have for this reason called this sensitizaon the role that intermediate products may tion the "Group Sensitivity to Compounds of Quinone Structure". But even in the special play in this sensitivity.

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