Excited Skin

Derk P.

Syndrome (Angry Back)

MD

Bruynzeel, MD, Howard I. Maibach,

\s=b\ The excited skin syndrome, a state of skin hyperirritability often induced by a concomitant dermatitis, is responsible for numerous nonreproducible test results in battery patch testing. We analyzed the mechanisms and circumstances involved in its induction, as well as its clinical importance and frequency. Finally, we provide suggestions about how to deal with patients suspected of having the syndrome. (Arch Dermatol 1986;122:323-328)

The routine patch-test tends to create a false sense of security in the mind of the dermatologist. Hjorth, 1963

concomitant positive reactions to diagnostic patch tests for allergic contact dermatitis, in whom a single repeated challenge reveals certain of them to be nonreproducible (Fig 1). The ESS may also be caused by even minimal dermatitis elsewhere; it is a major cause of falsepositive, nonrelevant patch-test reactions. Since Jadassohn introduced the diagnostic patch test in 1895, it has been recognized that patients with eczema may show cutaneous hyperirritability.17 An excellent review of this subject was prepared by Bjrnberg,8 in 1968; he elucidated many factors involved in skin reactivity to irritants. Until recently, knowledge in this investigative area has not surfaced at a clinical level and has rarely been considered as a day-to-day problem by dermatologists performing patch tests. In 1975, Mitchell9 emphasized that hyperirritability is a seri ous problem in patch testing. He also showed that in the presence of a strong positive patch-test reaction, other concomitant weak-positive reactions may be
Accepted for publication Nov 14, 1985. From the Departments of Dermatology, Free University, Academic Hospital, Amsterdam (Dr Bruynzeel), and the University of California, San Francisco (Dr Maibach). Reprint requests to the Department of Dermatology, University of California, San Francisco, CA 94143 (Dr Maibach).

syndrome (ESS) is phenomenon The excited skin patients presenting with multiple that in
a occurs

false-positive.10 This phenomenon, which he called angry back syndrome, is probably due to a state of skin hyperreactivity induced by a dermatitis, eg, an eczema elsewhere on the body or a strong positive skin-test reaction. To put it succinctly, "eczema creates eczema."' This hyperreactivity is not restricted to the back of the patient but involves the entire skin"12; therefore, Maibach12 and Mitchell and Maibach13 have proposed the name ESS. Table 1 lists other terms used to describe this hyperreactivity. As a consequence of the ESS, test results should be evaluated carefully in patients with multiple positive concomitant diagnostic patch-test results. To ascer tain which reactions are false-positive, retesting at a
later date is necessary.
FREQUENCY OF THE ESS

The International Contact Dermatitis Research Group studied 56 patients who had two or more positive patch-test reactions to a routine series of allergens.21 In each subject, the two that were clini cally most important were retested one at a time, after the skin showed no signs of the previous testing. In 16 cases, the patient reacted to only one, and in eight cases, the patient reacted to neither of the allergens. Thus, in 24 (42%) of 56 patients, positive reactions were lost. This means that of the 112 reactions that were retested individually, 32 reactions (29%) had been false-positive. Strong posi tive reactions were retested as well. Bruynzeel et al22 used a testing schedule compara ble to that described by Mitchell.10 In 61 patients who had several concomitant positive reactions, the aller gens that elicited weak positive reactions (+) were retested after three weeks. Seventy-nine such aller-

Recent studies emphasize the importance of the ESS, as they show that the nonreproducibility of patch-test reactions can be over 40%. Mitchell10 observed, in 35 patients who showed 30 two-plus (++) and 90 one-plus (+) patch-test reactions, that 38 (42% ) of one-plus reactions were negative (that is, "lost") on retesting the responsible allergens seven days later.

Downloaded from www.archdermatol.com on July 30, 2010

Individually Retesting
->

Concomitant Positive Reactions

Still Positive

Now

Negative

In cases of possible excited skin syndrome, it is necessary to retest concomitant positive patch-test reactions individually at later date. Some reactions may be negative ("lost") on

retesting.

Table 1.Various Expressions Used to Describe Hyperreactivity of the Skin*

Expression
Reflektorisches Ekzem Crazy back Metallergic and parallergic reactions Status eczematicus Skin fatigue

Source,
Von

Zumbusch,14 Jessner,15 1979

yr 1921

Shelmire,16 1939 Rostenberg,17 1959 Fisher,18 1967 ICDRG,19

Kligman
1970

Multiple nonspecific
reactions Conditioned hyperirritability and para-allergy

Angry back syndrome

Spillover
Rogue positive reactions Excited skin syndrome
*

Mitchell,9 1975 Mitchell,10 1977 Fisher,20 1980 Maibach,12 1981

Contact

and

Epstein,11

1975

ICDRG

indicates

International

Dermatitis

Research

Group.

gens were

Bruynzeel

retrospective study that irrelevant reactions occurred frequently in a population of patients with strong positive reactions and concomitant weak positive reactions (43%) and in patients with only concomitant weak positive reactions (29%). However, Bandmann and Agathos24 found far fewer false-positive reactions in their series of patients (13 of 151 reactions in 40 patients; 8.6%). Differences in retest protocols might explain their low figures, as Bandmann and Agathos retested both strong and weak positive reactions, sometimes retesting more than one allergen at a time.2526 They studied hospitalized patients with mainly stasis dermatitis, probably a group with many clinically relevant reactions.
a

retested; 35 (44% ) did not evoke a reaction.

et al23 observed in

an adhesive-tape dermatitis, or a strong positive patch-test reaction, may induce skin hyper irritability. Therefore, patch-test results in patients with even a minor dermatitis should be interpreted carefully.

irritants. These results showed that a limited derma titis could enhance skin reactivity. Magnusson and Hellgren27 studied patients with adhesive-tape der matitis. They recorded diagnostic patch-test positivity in male and female subjects and correlated the results to the severity of the localized dermatitis due to the adhesive-tape reactivity. The number of posi tive patch-test reactions to turpentine, potassium dichromate, p-phenylenediamine, and formaldehyde solution was increased in patients compared with those without a tape dermatitis. The difference was statistically significant. They observed similar dif ferences with irritants (detergents). Thus, a small localized dermatitis, eg, a hand

eczema,

LOCALIZATION

CIRCUMSTANCES

Bjrnberg8 demonstrated in experiments with dif ferent irritant materials that the skin reactivity of patients with hand eczema was enhanced for some

the skin on the back but also elsewhere, ie, the arms, will be hyperreactive. The ESS is not restricted to the original test area.13 A strong reaction on the right arm can produce a nonspecific response on the left arm. This indicates that the responsible mechanism has a systemic effect. But there are local aspects and mechanisms involved as well. This is supported by the hyperirritability due to adhesive-tape dermatitis and the observation of false-positive test reactions frequently noticed in the direct neighborhood of strong positive reactions.22 This suggested that a "runover" ("spillover") effect from one test site to another is also involved.1017 Spillover can be demonstrated experimentally by a strong positive (allergic) skin-test reaction and by eliciting, by means of a marginal irritant (eg, sodium

When a battery of patch tests is applied to a patient's back, false-positive reactions may occur due to the ESS scattered all over the test area; not only

Downloaded from www.archdermatol.com on July 30, 2010

lauryl sulfate), weak positive reactions at varying distances from the strong positive reaction. The irritant reaction adjacent to the strong positive skin reaction will be enhanced compared with the reac tions observed further away.28 Thus, the ESS is not a strict local phenomenon; it occurs anywhere on the bodyan excited skin not just an "angry back" or spillover.
SERIAL DILUTIONS

were tested with an open method (H.I.M., unpublished data, 1965). Most of the sensitive subjects reacted at 1.0% and 0.1% but not at 0.01% concentrations. Additional challenges were performed one at a time; the subjects continued to exhibit reactions at 1% concentrations. Several, however, no longer reacted at the 0.1% level. It appears that the spillover phenomenon will occur even with open testing and with several dilutions of the same material. Thus, when generating such data, an incorrect threshold level for challenging may be selected when the influence of spillover is not consid ered. Another form of enhanced skin reactivity of apparently normal skin is seen in recently inflamed sites. Many inflammatory cells remain in the dermis due to the recent dermatitis. Enhanced skin reactiv ity can be expected as long as an increased amount of such cells is present. Antigen-specific and, to a lesser extent, nonspecific reactivity will be enhanced, as shown by Scheper et al29 in flare-up experiments on guinea pigs. The increased nonspecific and specific reactivity in former skin-test reaction sites persisted for at least five weeks. Biopsy specimens of clinically healed patch-test reactions for nickel in humans were studied by Christensen et al.30 They showed that the number of Langerhans' cells in the epidermis is, in the case of nickel patch-test reactions, significant ly increased compared with normal skin six to eight weeks after testing. Patch tests should be applied only, when possible, on skin that has not been inflamed for the last two months to avoid the risk of false-positive reactions.

The spillover effect is important when dermatotoxicologic assays for contact sensitization or irritancy are performed. In such circumstances, the skin of the test subject or animal is challenged with decreasing concentrations to determine the lowest point at which it reacts. For convenience, it is the generally accepted procedure to challenge with sev eral dilutions at one time. In this way, a complete answer could theoretically be obtained in one visit.12 To verify the appropriateness of this technique by subsequently challenging with one dilution at a time,
two related lacrimants

various sites in 35 patients. Marked differences in response occurred from one site to another. These data can be tabulated as either a positive or negative response and a mean response. The most dramatic differences are in positivity. This concentration pro duced dermatitis on the upper back in 32 subjects and on the lower back in only 16 subjects. There was a difference of two in terms of mean reaction. How does this relate to the ESS? These regional differences combined with skin hyperirritability (or lowered threshold for irritants) can be responsible for the induction of a false-positive reaction when a marginal irritant is tested in the more-sensitive

Magnusson and Hersle31 performed experiments con cerning regional reactivity. They simultaneously patch tested with 5% benzalkonium chloride on

regions.

CHEMICALS

materials 2. The number of positive reactions observed 3. The severity of the concomitant reactions 4. The proximity of the reaction site 5. The existence of a dermatitis elsewhere
MECHANISM

quently produce nonreproducible positive responses. Often involved are formaldehyde solution, fragrance mixture, metal salts, rubber chemicals, "parasubstances," paraben mixture, and wool wax alcohol.1222 This does not mean that compounds of low irritance will never induce false-positive responses. It is clear that the reactions to relatively unknown compounds should be interpreted prudently. In conclusion, the circumstances related to the eliciting of nonreproducible tests are as follows: 1. The degree of irritancy of the various

Compounds that are patch tested in a marginal irritant concentration are likely to give nonspecific patch-test responses when the threshold for irrita tion is lowered, as in the case of an ESS. It is not completely established which compounds most fre

Enhancement of skin reactivity in animals has been observed for skin tests with irritants as well as

allergens.

REGIONAL SKIN VARIATION

Patch testing is performed with materials in a concentration that is nonirritating in nearly all patients but still high enough to elicit an allergic reaction. When different areas are used for patch testing, it is important to know if the entire skin surface reacts to the same degree to an irritant.

the height of the induced dermatitis compared with the reactions in animals without dermatitis. Magnusson and Kligman33 studied the influence of a crotn oil-induced dermatitis on skin tests for allergic reactions in guinea pigs. In the presence of a dermatitis, the reaction to a challenge with an allergen was enhanced in number and severity in sensitized animals. Van der Lugt and Veninga,34 experimenting with albino hairless mice, observed an enhancing effect on skin-test reactions for phenol in animals with a concomitant irritant dermatitis caused by the same irritant several days earlier. Andersen and Maibach35 induced hyperirritability

crotn oil and chrysarobin-induced irritant dermati tis on skin tests with the same irritant in guinea pigs. The crotn oil test reactions were enhanced at

Haeberlin and Fox32 studied the influence of

Downloaded from www.archdermatol.com on July 30, 2010

Table 2.Battery Testing: Strategy for Dealing With the Excited Skin Syndrome
.

When more than one positive reaction is noted, retake the clinical history It may not be necessary to retest positive reactions individually if (a) The material is readily avoided (eg, ammoniated

(b) History strongly negates the positive patch-test results It is important to retest positive reactions individually if the material is ubiquitous: (a) Preservatives (paraben mixture) (b) Vehicle (wool wax alcohol) (c) Medicament (neomycin) (d) Fragrance (fragrance mixture) (e) Rubber chemical (f ) Formaldehyde solution (g) Possible job change (h) Medicolegal situation (i ) Regulatory situation

mercury)

In humans, the spillover experiment28 demon strated that there was no increase in the number of inflammatory cells in the dermis of the uninvolved skin directly adjacent to the area exhibiting a strong positive patch-test reaction. Therefore, the hyperir ritability near such an area is likely to be caused not by cellular elements but by humoral factors. Howev er, the observations of Christensen et al30, the increased number of Langerhans' cells in six- to eight-week-old patch-test sites, and results of the experiments by Scheper et al29 showing the impor tance of T lymphocytes in flare-up reactions support the possibility that these cellular elements are involved in hyperirritability of recently inflamed skin. A practical consequence of the observations in the animal experiments is that results of guinea pig maximization tests should be evaluated carefully; an ESS may exist in FCA-treated animals.5253
RETESTING

cumulative irritancy assay in guinea pigs by repeated application of low-grade irritant dermato logie vehicles. Nonspecific increases in skin reactivi ty were noted in animals pretreated with an intra
in
a

dermal

crotn oil-induced dermatitis. In contrast to the

injection of Freund complete adjuvant (FCA). Bruynzeel et al36 demonstrated the induction of skin hyperirritability in guinea pigs for skin tests to both an irritant and an allergen by pretreating the animals with FCA. Similar but less marked hyper reactivity was induced by evoking a localized chronic

sion of intracutaneous skin reactions. In summarizing these experiments, we see that the reactivity of the skin is influenced by a concomitant dermatitis or an inflammation process as caused, for example, by FCA. The influence on the skin can run a biphasic course: depression of reactivity in the early phase of a severe acute inflammation and enhance ment of the reactivity when the inflammation becomes more chronic. This biphasic course is seen in humans with an acute dermatitis.42-4318 The skin hyporeactivity may be explained by a temporary shortage of circulating lymphocytes owing to the attraction of these cells to a site of acute inflammation.44 Enhancement can be explained by the stimulating effect on the bone marrow and the immune system by a chronic inflammatory process as induced, for example, by FCA45 47; these cells might contribute to the inflammatory reaction of otherwise weak irritant and allergic reactions. The histologie features of both types of reactions are similar and thus do not enable us to distinguish between them.28'30'48'49 Which of the two situations will occur probably depends on the balance of released inflam mation-inhibiting or -promoting mediators.5051

findings of Haeberlin and Fox32 and Magnusson and Kligman,33 this hyperirritability was preceded by a short period (one to four days) of depressed skin reactivity. Depression of skin reactivity was also described by Frey37 in dinitrochlorobenzene-sensitized guinea pigs. Additional reports concerning depressed skin reactivity3841 are mainly about depres

In cases of possible ESS, it is necessary that patients with multiple concomitant positive patchtest reactions and volunteers in toxicologie assays for allergic contact dermatitis be retested. For con firmation of sensitization, each test that yielded a positive reaction, one at a time, should be retested after a suitable rest period. The length of this period has not been defined. As a practical matter, six weeks should elapse after the skin in the test area is clinically healed before the same region is used again for testing. A dermatitis in any other region should preferably be healed or at least be in a quiet phase. Remember that the conversion of a patch-test reac tion from positive to negative on sequential testing is not absolute proof that the first reaction was falsepositive; it could be false-negative the second time due to fluctuations in skin reactivity owing to other
causes

than the ESS.

one

PRACTICAL DIRECTIONS

deal with patients who have multi ple positive patch-test reactions in battery testing? To save time and trouble for both patient and physician, we have developed a strategy that does not avoid but minimizes the work (Table 2).
Step
1
we note more than one positive patch-test reaction, we immediately retake the clinical history. This procedure alone is often enough to solve the problem.

How does

When

Step
areas

It may not be necessary to individually retest the that yielded positive reactions. For instance, if the material is a chemical that is relatively easily avoided by a given patient (such as ammoniated mercury, which is rarely used in the United States), it is easier to inform the patient about this, question him about previous reactions, and then cease testing. If there is nothing in the patient's history to back

Downloaded from www.archdermatol.com on July 30, 2010

this further, the diminished.

impetus for delving into it deeply is

Equally important, if the subject has a history strongly negating the relevance of the positive patch-test reaction, the patient may not be inter ested in working through the physician's academic curiosity. Clinically, it is not as important to repeat that test, because it will presumably make little difference to the patient, even though it might make significant inroads into the diagnosis.
Step 3 It is important to retest the individual if a positive patch-test reaction is related to an ubiquitous sub stance. The physician can lose credibility when the patient is told that he is allergic to something that he knows does not cause the difficulty. When the chem ical is something like a preservative (the parabens), a vehicle (wool wax alcohol or lanolin), or from a medicament (neomycin), a fragrance, rubber chemi cals, or formaldehyde solution, this fact is of great importance. To avoid these materials involves con siderable effort on the part of the patient. If it is, in fact, a false-positive response, it is a needless waste of time and causes loss of confidence in the physi

troublesome if the data turn out to be nonreproduci ble. A time will come when perspicacious and knowl edgeable compensation boards will ask the pertinent questions: Was the patch testing concomitant or sequential, and was the positive result reproducible? Were allergic reactions enhanced, or were irritant reactions evoked? In this respect, the informed patch tester is forewarned.
VALUE OF THE PROVOCATIVE TEST (USE TEST)

Our definition of allergic contact dermatitis is operational. A positive patch-test reaction alone does not indicate contact allergy. The bioassay is still too primitive a technique to utilize by itself. It assumes many other aspects, such as appropriate controls, pertinent patch-testing techniques, and lack of irri tation. It is beyond the province of our article to review all aspects of false-negative and false-positive

cian.

JOB CHANGE AND MEDICOLEGAL CONSIDERATIONS

Whenever a job change is considered as a way of solving a clinical problem of allergic contact derma titis, it is critical that the reliability of the patch-test reaction be established. Sometime, physicians too lightly advise the patient to change job positions. This can be difficult for the patient, for it often involves not only a change in work but also in socioeconomic life style. Nevertheless, when this recommendation is made, it should be done so on the basis of a verified patch-test response once the significant possibility of a false-positive response due to the ESS has been negated. For instance, potassium dichromate is one of the routine battery chemicals tested near its irritancy threshold. We have observed many instances of positive reactions to chromate in association with strong positive reactions to other chemicals, notably nickel sulfate. On retesting, some of the positive chromate reactions were not reproducible. Until this misinformation was corrected, the patient, usually a construction worker, was given incorrect advice regarding his industrial future, sometimes with dev astating consequences. In some cases, despite all of its complexity, judgment of a legal claim rests almost solely on the patch-test result; it is not unreasonable to perform the patch test more than
once.

reactions.5456 A final arbiter of great practical value in such a situation is the provocative test. The basic strategy behind this test is that open testing is far less likely to give an irritant response than closed testing. Unfortunately, a single open application is likely to have a high incidence of false-negative response. The provocative test has not been adequately standardized. We coined the term provocative test, which comes from the similar term used in respira tory testing for allergy. The principle is basically

concentrations to the skin. We ordinarily apply the material twice daily for approximately seven days. If a strong positive reaction is noted before that time, it is not necessary to complete the seven-day period. We have performed such applications to the forearm, the cubital fossa, and the cheek. Certain sites, such as the soles and palms, are only rarely suitable for such testing.57 It is important that appropriate controls be obtained because irritation can occur even with open application. However, the artifacts from this are far fewer than from occlusive patch testing. It is essen tial that there be repetitive applications to avoid the false-negative responses from open application.
THE FUTURE

straightforward:

open

application

at

appropriate

This also holds for

cases

in which there is

possibility of a medicolegal claim or involvement of a government regulatory stance. The individual, the industry, and the courts are entitled to the most reliable information possible. Changing regulations on the basis of several patients with allergic contact
dermatitis is
a

Until we understand all of the factors involved in the ESS, we cannot design experiments that might give a generic answer as to its frequency and cannot rationally circumvent misinformation that can arise from its occurrence. In the meantime, the patch tester is urged to take the ESS into account when evaluating multiple concomitant patch-test reac tions and to perform sequential retesting as required in the interests of good patient care.
References

difficult matter, and it is

even more

Jaeger H: De la nature de l'ecz\l=e'\ma:Recherches exp\l=e'\rimentales: Hypersensibilit\l=e'\,idiosyncrasie et anaphylaxie cutan\l=e'\eschez les ecz\l=e'\mateux.Ann Dermatol 1923;6:109-129. 2. Geiger R: Unspezifische Desensibilisierungsversuche an Ekzematikern mit Terpentin\l=o"\lauf percutanem Wege. Arch Der1.

Downloaded from www.archdermatol.com on July 30, 2010

3. Rostenberg A Jr, Sulzberger MB: Some results of patch tests. Arch Dermatol 1937;35:433-454. 4. Beek CH: The sensibility of the skin against soap among patients with eczema. Dermatologica 1946;93:167-172. 5. Grolnick M: Studies in contact dermatitis: The response of healed specific sites to stimulation with another contactant. J Allergy Clin Immunol 1948;19:298-303. 6. Wilson HTH: Standard patch tests in eczema and dermatitis. Br J Dermatol 1955;67:291-298. 7. Bettley FR: Non-specific irritant reactions in eczematous subjects. Br J Dermatol 1964;76:116-119. 8. Bj\l=o"\rnbergA: Skin Reactions to Primary Irritants in Patients With Hand Eczema. G\l=o"\teborg,Sweden, Oscar Isacsons Tryckeri AB, 1968. 9. Mitchell JC: The angry back syndrome: Eczema creates eczema. Contact Dermatitis 1975;1:193-194. 10. Mitchell JC: Multiple concomitant positive patch test reactions. Contact Dermatitis 1977;3:315-320. 11. Kligman AM, Epstein W: Updating the maximization test for identifying contact allergens. Contact Dermatitis 1975;1:231\x=req-\ 239. 12. Maibach HI: The ESS: Excited skin syndrome, in Ring J, Burg G (eds): New Trends in Allergy. New York, Springer-Verlag NY Inc, 1981, pp 208-221. 13. Mitchell JC, Maibach HI: The angry back syndrome: The excited skin syndrome. Semin Dermatol 1982;1:9-13. 14. Von Zumbusch L: Ueber die Behandlung des Ekzems. M\l=u"\nch Med Wochenschr 1921;68:401. 15. Jessner M, quoted by Fisher AA: Occupational, industrial and plant dermatology symposium, San Francisco. Cutis 1979; 24:143-154. 16. Shelmire B: Contact dermatitis from weeds: Patch testing with their oleoresins. JAMA 1939;113:1085-1090. 17. Rostenberg A: Predictive procedures for eczematous hypersensitivity. Arch Indust Health 1959;20:181-193. 18. Fisher AA: Contact Dermatitis. Philadelphia, Lea & Febiger, 1967, p 18. 19. Wilkinson DS, Fregert S, Magnusson B, et al: Terminology of contact dermatitis. Acta Derm Venereol 1970;50:287-292. 20. Fisher AA, quoted by Cronin E: Contact Dermatitis. New York, Churchill Livingstone Inc, 1980, p 12. 21. Maibach HI, Fregert S, Magnusson B, et al: Quantification of the excited skin syndrome (the `angry back'): Retesting one patch at a time. Contact Dermatitis 1982;8:78. 22. Bruynzeel DP, Van Ketel WG, Scheper RJ, et al: Angry back or the excited skin syndrome: A prospective study. J Am Acad Dermatol 1983;8:392-397. 23. Bruynzeel DP, Van Ketel WG, Scheper RJ, et al: The angry back syndrome: A retrospective study. Contact Dermatitis 1981; 7:293-297. 24. Bandmann H-J, Agathos M: New results and some remarks to the `angry back syndrome.' Contact Dermatitis 1981;7:23-26. 25. Mitchell JC: Angry back syndrome. Contact Dermatitis 1981; 7:359-360. 26. Bandmann H-J: Angry back syndrome. Contact Dermatitis

matol 1929;158:76-87.

the Guinea Pig.

Springfield, Ill, Charles C Thomas Publisher, 1970,

p 100. 34. Van der Lugt L, Veninga TS: Nonspecific hypersensitivity of the skin. Dermatologica 1981;162:438-443. 35. Andersen KE, Maibach HI: Cumulative irritancy in the guinea pig from low-grade irritant vehicles and the angry skin

syndrome. Contact Dermatitis 1980;6:430-434. 36. Bruynzeel DP, Von Blomberg-Van der Flier BME, Van Ketel WG, et al: Depression or enhancement of skin reactivity by inflammatory processes in the guinea pig. Int Arch Allergy Appl Immunol 1983;72:67-70. 37. Frey JR: Quantitative Untersuchungen bei epidermaler Sensibilisierung von Meerschweinchen mit Dinitrochlorobenzol. Dermatologica 1951;102:1-11. 38. Jokipii AMM, Jokipii L: Dose-response relationships and interference of simultaneous skin tests in delayed hypersensitivity. J Clin Pathol 1973;26:687-690.
39. Thestrup-Pedersen K: Suppression of tuberculin skin reactivity by prior tuberculin skin testing. Immunology 1975;28:343\x=req-\

348. 40. Von Blomberg M, Boerrigter GH, Scheper RJ: Interference of simultaneous skin tests in delayed hypersensitivity. Immunology 1978;35:361-367. 41. Uehara M, Ofuji S: Suppressed cell-mediated immunity associated with eczematous inflammation. Acta Derm Venereol

1977;57:137-139. 42. Hering H: Zur Beurteilung berufsbedingter Hauterkrankungen unter Ber\l=u"\cksichtigungvon Fehlerquellen bei epikutanen Testproben. Dermatol Monatsschr 1954;130:1129-1135. 43. Kligman AM: Poison ivy (Rhus) dermatitis. Arch Dermatol 1958;77:149-180. 44. McGuire R, Fox RA: Suppression of delayed hypersensitivity by the depletion of circulating monocytes. Immunology 1979;
38:157-161. 45. Meyer-Bloch JCH, Grundmann H-P, Weis H, et al: Skin test and lymphocyte stimulation in delayed hypersensitivity against Staphylococcus aureus antigens. Arch Dermatol Res 1980;267:291\x=req-\ 299. 46. Asherson GL, Allwood GG, Mayhew B: Contact sensitivity in the mouse: Movement of T blasts in the draining lymph nodes to sites of inflammation. Immunology 1973;25:485-494. 47. Van Dinther-Janssen ACHM, Van Maarsseveen ACMTh, De Groot J, et al: Comparative migration of T- and B-lymphocyte subpopulations into the skin inflammatory sites. Immunology

characteristics of

1981;7:360-361. 27. Magnusson B, Hellgren L: Skin-irritating and adhesive

some

different tapes. Acta Derm Venereol

1962;42:463-472. 28. Bruynzeel DP, Nieboer C, Boorsma DM, et al: Allergic reactions, `spillover' reactions and T-cell subsets. Arch Dermatol Res 1983;275:80-85. 29. Scheper RJ, Von Blomberg-Van der Flier BME, Boerrigter GH, et al: Induction of immunological memory in the skin: Role of local T cell retention. Clin Exp Immunol 1983;51:141-148. 30. Christensen OB, Daniels TE, Maibach HI: Langerhans' cells in allergic and non-allergic patch test reactions. Contact Dermatitis, in press. 31. Magnusson B, Hersle K: Patch test methods: II. Regional variation of patch test responses. Acta Derm Venereol 1965;45:257\x=req-\
261.
32. Haeberlin JB, Fox JM:

1983;48:519-527. 48. Ranki A, Kanerval L, F\l=o"\rstr\l=o"\mL, et al: T and B lymphocytes, macrophages and Langerhans' cells during the course of contact allergic and irritant skin reactions in man. Acta Derm Venereol 1983;63:376-383. 49. Scheynius A, Fischer T, Forsum U, et al: Phenotypic characterization in sites of inflammatory cells in allergic and irritant contact dermatitis in man. Clin Exp Immunol 1984;55:81-90. 50. Van Gool J, Schreuder J, Ladiges NCJJ: Inhibitory effect of foetal \g=a\2-globulin,an acute phase protein, on carrageenin oedema in the rat. J Pathol 1974;112:245-262. 51. Van Gool J: Acute-fase-eiwitten; betekenis voor de ontstekingsreactie. Ned Tijdschr Geneeskd 1980;124:869-876. 52. Klecak G: Identification of contact allergens: Predictive tests in animals, in Marzulli FN, Maibach HI (eds): Dermatotoxicology. Washington, DC, Hemisphere Publishing Corp, 1983,
pp 193-236. 53. Nethercot

JR, Lawrence M: The effect of the guinea pig maximization protocol on the irritant response to deodorized kerosene: The excited skin syndrome. Contact Dermatitis

1983;9:439-443. 54. Sulzberger MB: The patch test: Who should and should not use it and why. Contact Dermatitis 1975;1:117-119. 55. Adams RM: Patch testing: A recapitulation. J Am Acad
Dermatol 1981;5:629-643. 56. Grosshans E, Foussereau J: Complications et complexit\l=e'\sde lecture des tests \l=e'\picutan\l=e'\s.Ann Dermatol Venereol 1983;110:259\x=req-\
268.

Dermatol 1959;80:690-699.
33.

Primary irritation of the skin. Arch

Magnusson B, Kligman AM: Allergic Contact Dermatitis in

Allen A, Smiths R, et al: Contact sensitivity Relationship between age, sex, history of exposure and reactivity to standard patch tests. Clin Res 1978;26:301.

57.

to nickel:

Prystowsky S,

Downloaded from www.archdermatol.com on July 30, 2010