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Experimental Miliaria in Man
EXPERIMENTAL MILIARIA IN MAN III. Pnonuc'rio OF MILIARIA RUBRA (PRICKLY HEAT) * WALTER B. SHELLEY, M.D., PH.D. AND PETER N. HORVATH, M.D.
The experimental production of miliaria crystallina and sweat retention anidrosis has been reported in the first two papers of this series (1, 2). The present
report deals with the experimental production of miliaria rubra (prickly heat)
in iian. Numerous theories have been proposed to explain the etiology of miliaria rubra. Some investigators have attributed the process to an allergic reaction (3), an eczematous process, or a mycotic infection (4). However, the fundamental finding of Pollitzer (5), which was brilliantly confirmed and extended by Sulzberger and Zimmerman (6) as well as O'Brien (7) gives supportive evidence for the most attractive hypothesis describing the pathogenesis of miliaria rubra. These investigators found that the sweat duct was plugged in miliaria
rubra with a consequent retention of sweat. O'Brien felt that lipoid deficiency was the fundamental defect. Sulzberger and Zimmerman stressed the probability of faulty keratinization with plugs being the result of maceration of the skin by sweat. Experimental production of miliaria rubra was first achieved in 1927 by Smith (8) in s study conducted in Nigeria. His method consisted of the application to normal human skin of cultures of a yeast-like fungus he had isolated from the scales of patients who had miliaria rubra. A thick emulsion of the organism was applied under adhesive tape and cloth. After an incubation period of four days, minute sudaminal vesicles and small red papules appeared on an erythematous plaque corresponding exactly to the area treated. Control areas treated with saline apparently showed no change. A fungus, identical with that used for inoculation, was demonstrated in the scales of the experimentally produced lesion. Both clinically and histopathologically the experimental lesions duplicated miliaria rubra. Smith felt that a mechanical and a toxic factor were responsible for the changes noted. He stated that this led to edema of the cells with subsequent vesicle formation. He did not relate the process to the sweat gland, stating rather that prickly heat was a manifestation of a fungous infection of the skin. Twenty years later O'Brien briefly alluded to his studies on experimental miliaria rubra (7, 9). He applied kerosene daily, for short periods, to the abdomen of twenty subjects. In fifteen of these men a dermatitis similar to miliaria rubra was produced. Biopsy was made on one subject and sections showed many plugged sweat ducts. No note is made of vesicle formation and details of technic are not given. Since the kerosene removed lipoid from the skin, O'Brien felt that his work supported the thesis that miliaia rubra stemmed from a lipoid deficiency. EXPERIMENTAL
Method
Thirty-two normal healthy white males served as subjects. Only subjects with
normal sweating rates and patterns were used. The majority of observations These studies were supported by grants from the United States Public Health Service (RG330) and the Rockefeller Foundation. * From the Department of Dermatology and Syphilology, School of Medicine (Dr. Donald M. Pillsbury, Director), University of Pennsylvania. Read before The Tenth Annual Meeting of the Society for Investigative Dermatology, Atlantic City, N.J., June 12, 1949. 193
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were made in the winter so that appreciable sweating occurred only under experimental design. This sweating was induced by placing the men in an infra-red heat cabinet, previously described (1), or in a constant temperature hot room (dry bulb temperature 96°F., relative humidity 90%). Under these conditions, profuse sweating was induced within 30 minutes. Four measures, as described before (2), were employed to produce the desired
degree of epidermal injury: (a) iontophoresis, (b) maceration, (c) aluminum chloride, and (d) adhesive tape. Standard sites on the back and the abdomen were used. lontophoretic injury was produced by a 45 volt, 5 channel circuit apparatus,
using variably sized steel electrode plates (400 grams) with interposed filter paper moistened with tap water. Current densities under the anode of from 0.5 to 2.5 MA/cm.2 were applied for from 1 to 15 minutes. The higher current densities were always used in association with the shorter time interval. Under the cathode, current densities of from 0.05 MA to 0.25 MA/cm.2 were applied from 10 to 60 minutes. Maceration was achieved by placing a folded square of wet gauze on the skin under adhesive tape. The gauze was rewetted with tap water three times daily. These squares were removed at 24, 48, 72, 96 or 120 hours. A 25% aqueous solution of aluminum chloride was applied on filter paper under adhesive tape for 1 to 4 days. Finally, studies were made on the effect of application of commercial adhesive tape itself for from one to four days. The
subjects were cautioned not to wash these areas with soap. No other special measures were taken.
At various intervals (2 to 20 days) after a single injury to the skin by one of the above 4 measures, profuse sweating was induced. Clinical observations, including qualitative evaluation of sweating by the Guttmann technic (2), were made. Biopsies were taken on ten subjects after 30 minutes to 8 hours of sweating. The tissues were routinely fixed in formaldehyde and embedded in paraffin. Each of these was serially sectioned (6 micra) through the entire block and stained with hematoxylin and eosin. Results
In the non-sweating subject, the local areas treated with iontophoresis showed either no change or brownish puncta associated with the sweat duct orifices. The
areas in contact with the wet gauze (maceration) or the aluminum chloride showed no change. The tape areas used were normal at the time of study. Areas in which inflammatory responses were present in the non-sweating subject were not used in this work. In the sweating subject, a marked difference appeared between the treated and untreated areas. As soon as generalized sweating was induced, partial to complete anidrosis was found limited precisely to the areas treated. As sweating continued, one of three conditions occurred: either the anidrotic area remained unchanged,
or miliaria crystallina appeared, or, in susceptible subjects, miliaria rubra developed. The miliaria crystallina, described in the preceding papers (1, 2), was charac-
terized by the appearance of small superficial clear vesicles without any in-
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flammatory changes. It appeared most commonly in the areas injured by iontophoresis.
The miliaria rubra appeared in two forms. The first consisted of discrete to confluent erythematous macules associated with small papules (Fig. 1). In the second form, discrete clear superficial vesicles appeared, just as in miliaria crystallina, but in this case associated with erythematous halos. Often the first and second forms co-existed (Fig. 2). Symptoms of pruritus, burning, or pricking were present, but in variable intensity.
FIG. 1. EXPERIMENTAL MILIARIA RIJBRA
Wet gauze was kept over central area for a period of 3 days. Two days later, after three hours of sweating in hot room (D.B. 96°F—RH. 90%), this picture was taken showing typical miliaria rubra with papules and erythcma All of these changes developed only after entering the heat. Surrounding skin is normal.
These clinical changes developed on normal appearing skin and only on the areas treated, in a period of from 30 minutes to 4 hours of profuse sweating, and
on cooling were seen to involute completely in a similar period of time. The miliaria crystallina vesicles appeared after a shorter period of sweating than the miliaria rubra lesions. The changes could he made to reappear as often as desired by simply having the subject resume sweating. After 2 to 3 weeks desquamation occurred, with an associated return to normal sweating in these areas following this. At this time neither miliaria crystallina nor rubra could be made to appear. No sequelae were seen. In the summer-time the sweating which occurred normally
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was sufficient to produce miliaria rubra in the treated areas. It is important to note that in the summer the lesions did not fade but remained constant in appearance since sweating was sustained. They were not under the control of the investigator. For this reason, studies in the winter were more useful for the study of the pathogenesis of miliaria rubra. Only as a result of the winter studies could one separate the two independent factors of plugging and sweating.
Fin. 2. EXPERIMENTAL MILIARIA RUBRA
Subject had been treated five days previously with iontophoresis, using distilled water and a current density at the anode of 2.5 MA/em.2 for 2 minutes. Picture taken after three hours of sweating in the heat (D.B. 96°F.—Tt.H. 90%) shows superficial clear vesieles with associated erythematous areolae. This is a second type of miliaria rubra which is less common clinically than the type seen in Figure 1.
The production of these miliarial changes was associated with the production and maintenance of a sweat retention anidrosis. Accordingly, a variable latent period of from hours to several days (1, 2) was required before the changes could be accomplished. Miliarial changes were not seen in any area in which treatment had failed to produce anidrosis. The specific role of the sweat gland was further demonstrated by studying the effect of atropine. It was found that when atropine sulfate (0.5 mgm.) was injected intradermally to produce local inhibition of sweating, neither miliaria crystallina nor miliaria rubra could be made to appear. Control injections of saline solution were without effect.
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Ilisto pathology
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Biopsies were performed on 10 of 42 areas which had developed experimental miliaria rubra. All were taken after the subject had been in the heat and sweating for at least 2 hours; four were taken after 8 hours. Hence the very earliest stages of miliaria rubra were studied. Control observations, made on normal skin which was included in the biopsy specimens, showed no abnormal changes. Additional
FIG. 3. PLUGGING OF SWEAT DUCT AND AccoIpANYINc, DILATATION DUE TO SWEAT RETENTION (200X)
Biopsy taken on area shown in Fig. 1. Here is seen fundamental change, viz., keratinous plugging of sweat duct orifice. Biopsy was taken while subject was sweating so that re. tention of sweat has caused dilatation of duct.
control biopsies taken in the treated areas before heating showed only keratinous plugging of sweat duct. In the areas of skin in which experimental miliaria rubra had developed, histo-
pathologic examination revealed similar changes regardless of method; i.e., whether by iontophoresis, aluminum chloride, adhesive tape or maceration. Hyper- and parakeratotic plugs and plaques of stratum corneum developed at the sweat duct orifices (Fig. 3). The earliest abnormality consisted in a dilatation
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of the sweat duct in its terminal, intraepidermal portion (Fig. 4). Thereafter, edema and a lymphocytic infiltration appeared immediately underneath in the corium (Fig. 5). Subsequently, the morphology of spongiosis and intracellular edema was developed at the site of a disorganized duct; whether this is due to sweat or serum remains to be established. This "spongiosis" could extend well laterally, and in extreme cases (as in the "maceration" sections), progressed as
FIG. 4. PLUGGED SWEAT DUcT WITH PERIDUCTAL VESICLES (80X) from area over which wet gauze had been kept for 3 days. The biopsy was taken Biopsy 1 day later after 1 hour of sweating. During heating miliaria rubra developed in area which previously was normal in appearance. Section shows plugging and dilation of sweat duct with periductal vesicles. No evidence of rupture of duct in serial sections.
far as the development of large intraepidermal vesicles (Fig. 6). By "disorganiza-
tion" it is meant that the wall of the duct disappeared, as though by autolysis, and became continuous with the spongiotic tissue. It was not possible to recognize an actual rupture in the sense of a break such as occurs in hemorrhage by rhexis. Eventually, a striking lymphocytic infiltration and edema developed in the corium around the upper portion of the sweat duct. By and large, the sweat ducts in the corium and the glandular acini were normal in appearance, although at times they appeared dilated. Otherwise, no abnormal changes were detected.
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4' Fie. 5. SWEAT RETENTION VESICLE AND PERIDUCTAI, INFLAMMATORY INFII,TEATE (200X)
Biopsy, from area in contact with wet gauze for 3 days, taken two days later after S
hours of sweating. During sweating miliaria ruhra had appeared in this area. Section shows
hugely dilated terminal sweat duet. Below, eorium shows inflammatory response with edema.
FIG. 6. INTEAEI'IDERMAL VESICLE (352x) Same biopsy as for Fig. 4. Large intraepidermal vesiele With appearance of sponginsis. Sweat duet is not seen. 199
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The histopathologic findings duplicated those of clinically occurring miliaria ruhra (6, 7). DISCUSSION
The first two papers of this series (1, 2) presented data which demonstrated that many types of superficial epidermal injury may interfere with normal keratinization. The prime result of this abnormal keratinization is an invisible plugging of the sweat duet orifice without any effect on the aeinar glandular epithelium. Accordingly, it has been found that any sweat formed is entrapped in the sweat duct. As it cannot escape on the surface, a partial to complete localized anidrosis results. This often is asymptomatic. Study of the profusely sweating subject reveals that the anidrotic area may develop either miliaria crystallina er miliaria rubra. The pathogenesis of the anidrosis and concomitant miliaria crystallina has been discussed formerly. Here the problem of miliaria rubra only will be reviewed. On the basis of physiologic and histologic study, it appeared that a single superficial epidermal injury induced hyper- and or para-keratotic plugging of the sweat duct with consequent sweat retention anidrosis. At this point, no visible change was present in the non-sweating subject. However, in susceptible subjects thus prepared a single heat exposure of several hours led to disorganization of the intraepidermal segment of the sweat duct due to the pressure of entrapped sweat. This manifested itself as miliaria rubra whenever sweating occurred, apparently by directing the flow of sweat into, instead of on-to, the skin. The question of subjects is an important one. The production of sweat retention anidrosis and miliaria erystallina could be accomplished routinely in every subject studied. However, the production of miliaria rubra posed a greater problem. Miliaria rubra could be produced only infrequently in the volunteer subjects who presented themselves for study. Analysis of the situation revealed that this might result from the fact that the volunteer group, far from being a random sample of young male adults, was a specific group of individuals who had never had prickly heat clinically. The knowledge that this project was concerned with sweating was apparently enough to dissuade men who had suffered with dermatologic problems during hot weather. Accordingly, in the latter part of this work subjects were selected who had had some form of prickly heat. Using this method of selection, it was possible to induce experimental miliaria in each of ten men, whereas it had been produced in only one in ten of the regular volunteer group who had never had prickly heat. The basis for the factor of susceptibility is not known, but it may be related to the structure and permeability of the sweat duct wall.
Thus, it has been possible to distinguish three separate factors in the pathogenesis of experimental miliaria rubra, viz. (1) non-specific minor epidermal injury, (2) intensive sweating for several hours, and (3) individual susceptibility. Alone, none of the factors was sufficient. In the present study, miliaria rubra was produced in areas in which epidermal injury had been produced in four different ways. This points to the non-speei-
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ficity of the injury in causing plugging. Moreover, the production of miliaria by both Smith and O'Brien can be readily explained on the basis of a non-spccific injury, although each method taken alone was construed as indicating a specific pathogenesis. To reiterate, we do not feel that either lipoid deficiency or a fungous infection is the specific derangement leading to prickly heat. We feel, rather, that the common denominator is non-specific injury to the epidermis, clinically most often resulting from maceration due to sweat itself. This experimental study therefore supports the hypothesis of Sulzberger and Zimmerman (6). The experiments with atropine point up the essential role of the sweat itself in the pathogenesis of miliaria rubra. In the absence of sweating no changes could he produced by placing the men in the heat. Since the selective elimination of sweating completely prevented any development of miliaria, this corresponds to the clinical finding that in the anidrotic plaques seen in leprosy prickly heat never devclops since the glands do not form sweat in these areas (10). The clinical induction of miliaria rubra in subjects requires at least 3 days of
continuous exposure to heat (11). It would seem that this latent period presumably is required for the formation of plugs in the sweat duct orifices since similar latent periods were encountered experimentally.
In the first paper of this series, no effect on sweating was found under the cathode. Further study has shown that the iontophoretic injury under the cathode will lead to anidrosis. Anidrosis is more easily produced under the anode, hut does occur under both electrodes. Furthermore, miliaria rubra has been made to appear in both positive and negative electrode areas. This finding stresses the non-specificity of the cause of sweat duet plugging since dissimilar electrolytic changes occur at the two poles. The experimental finding of asymptomatically plugged sweat glands confirms
Sulzberger's (12) suggestion that many people in hot environments may have some plugged duets without any visible evidence of their presence. Perhaps, either the ducts resist rupture or sweating is stopped by the back pressure of entrapped sweat. Just as subclinical infections or diseases are common, so also may one suppose that commonly in the summer the maceration of the epidermis by sweat leads to an asymptomatic miliarial type of plugging in many individuals. These experimental studies suggest broadening the clinical concept of when and where miliaria rubra may he seen. It is interesting to note that in susceptible
individuals miliaria rubra was produced under aluminum chloride patch tests. This indicates that some of the inflammatory dermatoses seen in the axillae following the use of antiperspirants is miliaria rubra and not contact dermatitis per se. This occurs both winter and summer. Likewise, adhesive tape reactions seen in patients who are sweating freely, summer or winter, may be simply examples of miliaria rubra with sweat retention. Finally, this work suggests that maceration in the diaper area leads to sweat duct plugging with a resultant inflammatory dermatitis when sweating occurs. Hence, certain examples of diaper rash are probably manifestations of miliaria rubra. Care must be taken to recognize the production of miliaria rubra by therapeutic measures such as compresses or mildly irritant topical agents in patients who are sweating vigorously. Con-
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tinuance of such therapy can only lead to aggravation of the preexisting dermatosis. The discussion already presented leads to a final note concerning what these experimental observations suggest in regard to therapy of miliaria rubra itself. The striking and rapid disappearance of the experimental miliaria rubra in a cool
environment demands that the cornerstone of therapy be a reduction in the need for sweating or at least a reduction of the macerative effects of sweat. Sweating can be decreased by placing the patient in a cooler environment, reducing his work load, increasing the efficiency of evaporation of sweat, and increasing heat loss by other routes. The second need is t.he avoidance of all irritative therapy. Soap should not be used. The conflicting results on ultra-violet light therapy (10) can be resolved by noting that smaller doses cause epidermal injury with more plugging, whereas larger doses aid by causing desquamation of the plugs. There is often no great need for vigorous keratolytics since body so readily returns to normal if sweating can be controlled. Finally, Vitamin A in high doses may be indicated to aid in restoration of normal keratinization. Studies on this aspect of the problem are in progress. SUMMARY
A condition which is clinically and histopathologically identical with miliaria rubra has been experimentally produced in man. It has been possible to distinguish three separate factors in the pathogenesis of this experimental miliaria rubra, viz., (1) minor epidermal injury (maceration, iontophoresis, aluminum chloride, adhesive tape), (2) intensive sweating for several hours, and (3) individual susceptibility. Alone, none of these factors was sufficient.
On the basis of physiologic and histologic study, it appeared that a single superficial epidermal injury induced hyperkeratotic plugging of the sweat duct with consequent sweat retention anidrosis. In susceptible subjects thus prepared, a single heat exposure of several hours led to disorganization of upper end of the sweat duct due to pressure of entrapped sweat. This manifested itself clinically as miliaria rubra each time that sweating occurred, apparently by permitting the flow of sweat into the epidermis. ACKNOWLEDGMENTS
We are indebted to Dr. H. C. Bazett, of the Department of Physiology, University of Pennsylvania, for the use of the constant temperature room. Mr. E. R. Deats, Philadelphia, took the photographs included in this article. We wish to express our special gratitude to Dr. Fred D. Weidman for aid in the histopatho-
logical studies and to Dr. D. M. Pillsbury for continued interest, advice and encouragement. REFERENCES 1. SHELLEY, W. B., HORVATH, P. N., WEIDMAN, F. D. AND PILLSBLItY, D. M.: Experi-
mental miliaria in man: I. Production of sweat retention anidrosis and vesicles by means of iontophoresis. J. Invest. Dermat., 11: 275, 1948. 2. SHELLEY, W. B. AND HORVATH, P. N.: Experimental miliaria in man: II. Production
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of sweat retention anidrosis and miliaria crystallina by various kinds of injury.
J. Invest. Dermat., in press. 3. RIBBLE, G. B., LiIEDEMANN, W. S. AND PEABODY, S. M.: Epidemic of prickly heat on aircraft carrier. U. S. Nay. Med. Bull., 47: 77, 1947.
4. MATE, J. K.: Die Erkrankungen der Schweissdrusen, in Jadassohn J. Handbuch der Haut-TJnd Geschlestskrankheiten Berlin, Julius Springer, 1932, Vol. 13 pt. 1. 5. POLLITZER, S.: Prickly heat lichen tropicus, miliaria papulosa, M. rubra, etc. J. Cutan. Genito-Urinary Diseases, 11: 50, 1893. 6. SULZBERGER, MARION B. AND ZIMMERMAN, H. M.: Studies on prickly heat: II. Experi-
mental and histologic findings. J. Invest. Dermat., 7: 61, 1946. 7. O'BRIEN, J. P.: A study of miliaria rubra tropical anhidrosis and anhidrotic asthenia. Brit. J. Dermat., 59: 125, 1947. 8. SMITH, E. C.: Prickly heat: Its etiology and pathology. Trans. Roy. Soc. Trop. Med. and Hyg., 20: 344, 1927. 9. O'BRIEN, J. P.: Personal communication. 10. SIMONS, R. D. G. PH.: Studies on prickly heat. Dermatologica, 93: 172, 1946. 11. DUFFNEB, G. J.: Heat rash as a problem in the naval service. Am. J. Trop. Med., 26: 539, 1946. 12. SULZBERGER, MARION B., ZIMMERMAN, H. M. AND EMERSON, K.: Tropical anidrotic
asthenia (thermogenic anhidrosis) and its relationship to prickly heat. J. Invest. Dermat., 7: 153, 1946.
DISCUSSION DR. SIJLZBERGER: I believe I can say for all of us that we admire this beautiful
work and the simple, crystal-clear presentation and fine photographs. The work done by Shelley, Horvath and collaborators at the University of Pennsylvania is undoubtedly of fundamental importance. Every manifestation clinically and histo-pathologically described by O'Brien and his co-workers in Australia, and
by H. Zimmerman and me at Commodore Thomas Rivers Naval Research Unit ,' 2 on Guam, has now been reproduced experimentally and the mechanisms completely verified by these experimental pictures presented today. This is of course tremendously important, for it gives an opportunity for further experimental study. A good deal of the credit for this work goes to those silent men who cut the sections and examine them under the microscope. For unless true serial sections are cut and each carefully examined, one cannot demonstrate either the plugs or the relation of the fluid accumulations to the sweat ducts. And just as I am indebted for this to Dr. Harry Zimmerman on Guam and to Dr. Zak in New York, just so, I am sure, the Philadelphia group realize their debt to Dr. Fred Weidman for taking on that tedious duty. DR. LEON GOLDMAN: I wonder if these experiments could not be visualized dynamically with surface microscopy, either with special dye technic, or with a technic which as yet we do not use but certainly ought to use in dermatology, namely microsurgery, or some type of similar micro-manipulation technic. DR. RtJDOLF L. BARR: I would like to ask Dr. Shelley whether the zones of much more intense blue staining surrounding the anidrotic zones—in the kodachrome of the volunteer on whom anidrosis had been produced by 8 different measures—are evidence of a compensatory increase in sweat secretion surrounding the anidrotic area; or whether these are due to the photographic or experimental technic?
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DR. FRED D. WEIDMAN: I have been sweating through this matter at the microscope. I was particularly struck by a spongiotic appearance, somewhere along the course of the duct as it passed through the epidermis. In the many serial sections that I looked through to find actual connection between these spongiotic appearing cells and the actual lumen of the duct, I failed. I approached
this subject under the wrong impression. In O'Brien's work he used the word "rupture"; this to me means an actual break, as in a blood vessel when hemorrhage takes place by rhexis. I could not see anything of that kind in our sections;
and in case anybody is disposed to follow this subject and starts out with O'Brien's work, I would warn him about the manner in which the word "rupture" should be interpreted. As I see it, the integrity of the duct has been compromised as a result of imbibition of fluid on the part of the epidermal cells surrounding it. I recall that Dr. Sulzberger's printed illustration showed very much the same sort of circumstances and which are shown here on the screen. We have doubts as to whether the fluid in these spongiotic appearing areas is sweat or serum. That, I think, is the next problems to attack. This situation is similar to that for pompholyx, namely whether a sweat duct actually enters the vesicle or simply lies alongside. The literature disagrees on this point. DR. STEPHEN ROTHMAN: The point of Dr. Weidman concerning pompholyx is
well taken. However, if pompholyx were a sweat retention phenomenon, the urea concentration in the blister fluid should be higher than in the blood serum. In my analyses this has not been the case. Still, the last word has not been said on this subject. DR. PETER N. HORVATH: (Closing discussion) I want to thank all the discussors
for their remarks. In answer to Dr. Baer, we were equally worried about the appearance of our subject's back on our kodachrome, and were at a loss to account for this until we consulted with the photographer, who felt that this was an error in photographical technic and not our experimental finding. This study has tended to broaden the concept of just when and where miiaria can occur. It is very interesting to note that miliaria rubra occurred after the application of the aluminum chloride patch test. Many dermatoses that occur in the axilla can be related to the production of miliaria rubra on the basis of the use of anidrotic agents. Such an eruption can occur both in summer and winter. Furthermore, adhesive tape reactions occurring in warm weather are also in part due to miliaria rubra. Lastly, the diaper rashes occurring in infants due partly to irritation and partly to maceration can have plugged up sweat glands and sweat retention anidrosis and thus be related to the syndrome of miliaria rubra. As far as therapy of miliaria rubra is concerned, our findings suggest a few points.
The rapid disappearance of the lesions when the individual was put in cool, dry environment suggests that the cornerstone of such therapy should depend on a minimum of sweating for the individual, so that the macerative effects of sweating can be avoided. Strong keratolytics are not necessary and the use of soap and water should be minimized.
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The experimental production of miliaria crystallina and sweat retention anidrosis has been reported in the first two papers of this series (1, 2). The present
report deals with the experimental production of miliaria rubra (prickly heat)
in iian. Numerous theories have been proposed to explain the etiology of miliaria rubra. Some investigators have attributed the process to an allergic reaction (3), an eczematous process, or a mycotic infection (4). However, the fundamental finding of Pollitzer (5), which was brilliantly confirmed and extended by Sulzberger and Zimmerman (6) as well as O'Brien (7) gives supportive evidence for the most attractive hypothesis describing the pathogenesis of miliaria rubra. These investigators found that the sweat duct was plugged in miliaria
rubra with a consequent retention of sweat. O'Brien felt that lipoid deficiency was the fundamental defect. Sulzberger and Zimmerman stressed the probability of faulty keratinization with plugs being the result of maceration of the skin by sweat. Experimental production of miliaria rubra was first achieved in 1927 by Smith (8) in s study conducted in Nigeria. His method consisted of the application to normal human skin of cultures of a yeast-like fungus he had isolated from the scales of patients who had miliaria rubra. A thick emulsion of the organism was applied under adhesive tape and cloth. After an incubation period of four days, minute sudaminal vesicles and small red papules appeared on an erythematous plaque corresponding exactly to the area treated. Control areas treated with saline apparently showed no change. A fungus, identical with that used for inoculation, was demonstrated in the scales of the experimentally produced lesion. Both clinically and histopathologically the experimental lesions duplicated miliaria rubra. Smith felt that a mechanical and a toxic factor were responsible for the changes noted. He stated that this led to edema of the cells with subsequent vesicle formation. He did not relate the process to the sweat gland, stating rather that prickly heat was a manifestation of a fungous infection of the skin. Twenty years later O'Brien briefly alluded to his studies on experimental miliaria rubra (7, 9). He applied kerosene daily, for short periods, to the abdomen of twenty subjects. In fifteen of these men a dermatitis similar to miliaria rubra was produced. Biopsy was made on one subject and sections showed many plugged sweat ducts. No note is made of vesicle formation and details of technic are not given. Since the kerosene removed lipoid from the skin, O'Brien felt that his work supported the thesis that miliaia rubra stemmed from a lipoid deficiency. EXPERIMENTAL
Method
Thirty-two normal healthy white males served as subjects. Only subjects with
normal sweating rates and patterns were used. The majority of observations These studies were supported by grants from the United States Public Health Service (RG330) and the Rockefeller Foundation. * From the Department of Dermatology and Syphilology, School of Medicine (Dr. Donald M. Pillsbury, Director), University of Pennsylvania. Read before The Tenth Annual Meeting of the Society for Investigative Dermatology, Atlantic City, N.J., June 12, 1949. 193
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were made in the winter so that appreciable sweating occurred only under experimental design. This sweating was induced by placing the men in an infra-red heat cabinet, previously described (1), or in a constant temperature hot room (dry bulb temperature 96°F., relative humidity 90%). Under these conditions, profuse sweating was induced within 30 minutes. Four measures, as described before (2), were employed to produce the desired
degree of epidermal injury: (a) iontophoresis, (b) maceration, (c) aluminum chloride, and (d) adhesive tape. Standard sites on the back and the abdomen were used. lontophoretic injury was produced by a 45 volt, 5 channel circuit apparatus,
using variably sized steel electrode plates (400 grams) with interposed filter paper moistened with tap water. Current densities under the anode of from 0.5 to 2.5 MA/cm.2 were applied for from 1 to 15 minutes. The higher current densities were always used in association with the shorter time interval. Under the cathode, current densities of from 0.05 MA to 0.25 MA/cm.2 were applied from 10 to 60 minutes. Maceration was achieved by placing a folded square of wet gauze on the skin under adhesive tape. The gauze was rewetted with tap water three times daily. These squares were removed at 24, 48, 72, 96 or 120 hours. A 25% aqueous solution of aluminum chloride was applied on filter paper under adhesive tape for 1 to 4 days. Finally, studies were made on the effect of application of commercial adhesive tape itself for from one to four days. The
subjects were cautioned not to wash these areas with soap. No other special measures were taken.
At various intervals (2 to 20 days) after a single injury to the skin by one of the above 4 measures, profuse sweating was induced. Clinical observations, including qualitative evaluation of sweating by the Guttmann technic (2), were made. Biopsies were taken on ten subjects after 30 minutes to 8 hours of sweating. The tissues were routinely fixed in formaldehyde and embedded in paraffin. Each of these was serially sectioned (6 micra) through the entire block and stained with hematoxylin and eosin. Results
In the non-sweating subject, the local areas treated with iontophoresis showed either no change or brownish puncta associated with the sweat duct orifices. The
areas in contact with the wet gauze (maceration) or the aluminum chloride showed no change. The tape areas used were normal at the time of study. Areas in which inflammatory responses were present in the non-sweating subject were not used in this work. In the sweating subject, a marked difference appeared between the treated and untreated areas. As soon as generalized sweating was induced, partial to complete anidrosis was found limited precisely to the areas treated. As sweating continued, one of three conditions occurred: either the anidrotic area remained unchanged,
or miliaria crystallina appeared, or, in susceptible subjects, miliaria rubra developed. The miliaria crystallina, described in the preceding papers (1, 2), was charac-
terized by the appearance of small superficial clear vesicles without any in-
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flammatory changes. It appeared most commonly in the areas injured by iontophoresis.
The miliaria rubra appeared in two forms. The first consisted of discrete to confluent erythematous macules associated with small papules (Fig. 1). In the second form, discrete clear superficial vesicles appeared, just as in miliaria crystallina, but in this case associated with erythematous halos. Often the first and second forms co-existed (Fig. 2). Symptoms of pruritus, burning, or pricking were present, but in variable intensity.
FIG. 1. EXPERIMENTAL MILIARIA RIJBRA
Wet gauze was kept over central area for a period of 3 days. Two days later, after three hours of sweating in hot room (D.B. 96°F—RH. 90%), this picture was taken showing typical miliaria rubra with papules and erythcma All of these changes developed only after entering the heat. Surrounding skin is normal.
These clinical changes developed on normal appearing skin and only on the areas treated, in a period of from 30 minutes to 4 hours of profuse sweating, and
on cooling were seen to involute completely in a similar period of time. The miliaria crystallina vesicles appeared after a shorter period of sweating than the miliaria rubra lesions. The changes could he made to reappear as often as desired by simply having the subject resume sweating. After 2 to 3 weeks desquamation occurred, with an associated return to normal sweating in these areas following this. At this time neither miliaria crystallina nor rubra could be made to appear. No sequelae were seen. In the summer-time the sweating which occurred normally
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was sufficient to produce miliaria rubra in the treated areas. It is important to note that in the summer the lesions did not fade but remained constant in appearance since sweating was sustained. They were not under the control of the investigator. For this reason, studies in the winter were more useful for the study of the pathogenesis of miliaria rubra. Only as a result of the winter studies could one separate the two independent factors of plugging and sweating.
Fin. 2. EXPERIMENTAL MILIARIA RUBRA
Subject had been treated five days previously with iontophoresis, using distilled water and a current density at the anode of 2.5 MA/em.2 for 2 minutes. Picture taken after three hours of sweating in the heat (D.B. 96°F.—Tt.H. 90%) shows superficial clear vesieles with associated erythematous areolae. This is a second type of miliaria rubra which is less common clinically than the type seen in Figure 1.
The production of these miliarial changes was associated with the production and maintenance of a sweat retention anidrosis. Accordingly, a variable latent period of from hours to several days (1, 2) was required before the changes could be accomplished. Miliarial changes were not seen in any area in which treatment had failed to produce anidrosis. The specific role of the sweat gland was further demonstrated by studying the effect of atropine. It was found that when atropine sulfate (0.5 mgm.) was injected intradermally to produce local inhibition of sweating, neither miliaria crystallina nor miliaria rubra could be made to appear. Control injections of saline solution were without effect.
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EXPERIMENTAL MILIARIA IN MAN. III
Ilisto pathology
4 7
.
I
F:
Biopsies were performed on 10 of 42 areas which had developed experimental miliaria rubra. All were taken after the subject had been in the heat and sweating for at least 2 hours; four were taken after 8 hours. Hence the very earliest stages of miliaria rubra were studied. Control observations, made on normal skin which was included in the biopsy specimens, showed no abnormal changes. Additional
FIG. 3. PLUGGING OF SWEAT DUCT AND AccoIpANYINc, DILATATION DUE TO SWEAT RETENTION (200X)
Biopsy taken on area shown in Fig. 1. Here is seen fundamental change, viz., keratinous plugging of sweat duct orifice. Biopsy was taken while subject was sweating so that re. tention of sweat has caused dilatation of duct.
control biopsies taken in the treated areas before heating showed only keratinous plugging of sweat duct. In the areas of skin in which experimental miliaria rubra had developed, histo-
pathologic examination revealed similar changes regardless of method; i.e., whether by iontophoresis, aluminum chloride, adhesive tape or maceration. Hyper- and parakeratotic plugs and plaques of stratum corneum developed at the sweat duct orifices (Fig. 3). The earliest abnormality consisted in a dilatation
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of the sweat duct in its terminal, intraepidermal portion (Fig. 4). Thereafter, edema and a lymphocytic infiltration appeared immediately underneath in the corium (Fig. 5). Subsequently, the morphology of spongiosis and intracellular edema was developed at the site of a disorganized duct; whether this is due to sweat or serum remains to be established. This "spongiosis" could extend well laterally, and in extreme cases (as in the "maceration" sections), progressed as
FIG. 4. PLUGGED SWEAT DUcT WITH PERIDUCTAL VESICLES (80X) from area over which wet gauze had been kept for 3 days. The biopsy was taken Biopsy 1 day later after 1 hour of sweating. During heating miliaria rubra developed in area which previously was normal in appearance. Section shows plugging and dilation of sweat duct with periductal vesicles. No evidence of rupture of duct in serial sections.
far as the development of large intraepidermal vesicles (Fig. 6). By "disorganiza-
tion" it is meant that the wall of the duct disappeared, as though by autolysis, and became continuous with the spongiotic tissue. It was not possible to recognize an actual rupture in the sense of a break such as occurs in hemorrhage by rhexis. Eventually, a striking lymphocytic infiltration and edema developed in the corium around the upper portion of the sweat duct. By and large, the sweat ducts in the corium and the glandular acini were normal in appearance, although at times they appeared dilated. Otherwise, no abnormal changes were detected.
if44
jr
4' Fie. 5. SWEAT RETENTION VESICLE AND PERIDUCTAI, INFLAMMATORY INFII,TEATE (200X)
Biopsy, from area in contact with wet gauze for 3 days, taken two days later after S
hours of sweating. During sweating miliaria ruhra had appeared in this area. Section shows
hugely dilated terminal sweat duet. Below, eorium shows inflammatory response with edema.
FIG. 6. INTEAEI'IDERMAL VESICLE (352x) Same biopsy as for Fig. 4. Large intraepidermal vesiele With appearance of sponginsis. Sweat duet is not seen. 199
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The histopathologic findings duplicated those of clinically occurring miliaria ruhra (6, 7). DISCUSSION
The first two papers of this series (1, 2) presented data which demonstrated that many types of superficial epidermal injury may interfere with normal keratinization. The prime result of this abnormal keratinization is an invisible plugging of the sweat duet orifice without any effect on the aeinar glandular epithelium. Accordingly, it has been found that any sweat formed is entrapped in the sweat duct. As it cannot escape on the surface, a partial to complete localized anidrosis results. This often is asymptomatic. Study of the profusely sweating subject reveals that the anidrotic area may develop either miliaria crystallina er miliaria rubra. The pathogenesis of the anidrosis and concomitant miliaria crystallina has been discussed formerly. Here the problem of miliaria rubra only will be reviewed. On the basis of physiologic and histologic study, it appeared that a single superficial epidermal injury induced hyper- and or para-keratotic plugging of the sweat duct with consequent sweat retention anidrosis. At this point, no visible change was present in the non-sweating subject. However, in susceptible subjects thus prepared a single heat exposure of several hours led to disorganization of the intraepidermal segment of the sweat duct due to the pressure of entrapped sweat. This manifested itself as miliaria rubra whenever sweating occurred, apparently by directing the flow of sweat into, instead of on-to, the skin. The question of subjects is an important one. The production of sweat retention anidrosis and miliaria erystallina could be accomplished routinely in every subject studied. However, the production of miliaria rubra posed a greater problem. Miliaria rubra could be produced only infrequently in the volunteer subjects who presented themselves for study. Analysis of the situation revealed that this might result from the fact that the volunteer group, far from being a random sample of young male adults, was a specific group of individuals who had never had prickly heat clinically. The knowledge that this project was concerned with sweating was apparently enough to dissuade men who had suffered with dermatologic problems during hot weather. Accordingly, in the latter part of this work subjects were selected who had had some form of prickly heat. Using this method of selection, it was possible to induce experimental miliaria in each of ten men, whereas it had been produced in only one in ten of the regular volunteer group who had never had prickly heat. The basis for the factor of susceptibility is not known, but it may be related to the structure and permeability of the sweat duct wall.
Thus, it has been possible to distinguish three separate factors in the pathogenesis of experimental miliaria rubra, viz. (1) non-specific minor epidermal injury, (2) intensive sweating for several hours, and (3) individual susceptibility. Alone, none of the factors was sufficient. In the present study, miliaria rubra was produced in areas in which epidermal injury had been produced in four different ways. This points to the non-speei-
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ficity of the injury in causing plugging. Moreover, the production of miliaria by both Smith and O'Brien can be readily explained on the basis of a non-spccific injury, although each method taken alone was construed as indicating a specific pathogenesis. To reiterate, we do not feel that either lipoid deficiency or a fungous infection is the specific derangement leading to prickly heat. We feel, rather, that the common denominator is non-specific injury to the epidermis, clinically most often resulting from maceration due to sweat itself. This experimental study therefore supports the hypothesis of Sulzberger and Zimmerman (6). The experiments with atropine point up the essential role of the sweat itself in the pathogenesis of miliaria rubra. In the absence of sweating no changes could he produced by placing the men in the heat. Since the selective elimination of sweating completely prevented any development of miliaria, this corresponds to the clinical finding that in the anidrotic plaques seen in leprosy prickly heat never devclops since the glands do not form sweat in these areas (10). The clinical induction of miliaria rubra in subjects requires at least 3 days of
continuous exposure to heat (11). It would seem that this latent period presumably is required for the formation of plugs in the sweat duct orifices since similar latent periods were encountered experimentally.
In the first paper of this series, no effect on sweating was found under the cathode. Further study has shown that the iontophoretic injury under the cathode will lead to anidrosis. Anidrosis is more easily produced under the anode, hut does occur under both electrodes. Furthermore, miliaria rubra has been made to appear in both positive and negative electrode areas. This finding stresses the non-specificity of the cause of sweat duet plugging since dissimilar electrolytic changes occur at the two poles. The experimental finding of asymptomatically plugged sweat glands confirms
Sulzberger's (12) suggestion that many people in hot environments may have some plugged duets without any visible evidence of their presence. Perhaps, either the ducts resist rupture or sweating is stopped by the back pressure of entrapped sweat. Just as subclinical infections or diseases are common, so also may one suppose that commonly in the summer the maceration of the epidermis by sweat leads to an asymptomatic miliarial type of plugging in many individuals. These experimental studies suggest broadening the clinical concept of when and where miliaria rubra may he seen. It is interesting to note that in susceptible
individuals miliaria rubra was produced under aluminum chloride patch tests. This indicates that some of the inflammatory dermatoses seen in the axillae following the use of antiperspirants is miliaria rubra and not contact dermatitis per se. This occurs both winter and summer. Likewise, adhesive tape reactions seen in patients who are sweating freely, summer or winter, may be simply examples of miliaria rubra with sweat retention. Finally, this work suggests that maceration in the diaper area leads to sweat duct plugging with a resultant inflammatory dermatitis when sweating occurs. Hence, certain examples of diaper rash are probably manifestations of miliaria rubra. Care must be taken to recognize the production of miliaria rubra by therapeutic measures such as compresses or mildly irritant topical agents in patients who are sweating vigorously. Con-
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tinuance of such therapy can only lead to aggravation of the preexisting dermatosis. The discussion already presented leads to a final note concerning what these experimental observations suggest in regard to therapy of miliaria rubra itself. The striking and rapid disappearance of the experimental miliaria rubra in a cool
environment demands that the cornerstone of therapy be a reduction in the need for sweating or at least a reduction of the macerative effects of sweat. Sweating can be decreased by placing the patient in a cooler environment, reducing his work load, increasing the efficiency of evaporation of sweat, and increasing heat loss by other routes. The second need is t.he avoidance of all irritative therapy. Soap should not be used. The conflicting results on ultra-violet light therapy (10) can be resolved by noting that smaller doses cause epidermal injury with more plugging, whereas larger doses aid by causing desquamation of the plugs. There is often no great need for vigorous keratolytics since body so readily returns to normal if sweating can be controlled. Finally, Vitamin A in high doses may be indicated to aid in restoration of normal keratinization. Studies on this aspect of the problem are in progress. SUMMARY
A condition which is clinically and histopathologically identical with miliaria rubra has been experimentally produced in man. It has been possible to distinguish three separate factors in the pathogenesis of this experimental miliaria rubra, viz., (1) minor epidermal injury (maceration, iontophoresis, aluminum chloride, adhesive tape), (2) intensive sweating for several hours, and (3) individual susceptibility. Alone, none of these factors was sufficient.
On the basis of physiologic and histologic study, it appeared that a single superficial epidermal injury induced hyperkeratotic plugging of the sweat duct with consequent sweat retention anidrosis. In susceptible subjects thus prepared, a single heat exposure of several hours led to disorganization of upper end of the sweat duct due to pressure of entrapped sweat. This manifested itself clinically as miliaria rubra each time that sweating occurred, apparently by permitting the flow of sweat into the epidermis. ACKNOWLEDGMENTS
We are indebted to Dr. H. C. Bazett, of the Department of Physiology, University of Pennsylvania, for the use of the constant temperature room. Mr. E. R. Deats, Philadelphia, took the photographs included in this article. We wish to express our special gratitude to Dr. Fred D. Weidman for aid in the histopatho-
logical studies and to Dr. D. M. Pillsbury for continued interest, advice and encouragement. REFERENCES 1. SHELLEY, W. B., HORVATH, P. N., WEIDMAN, F. D. AND PILLSBLItY, D. M.: Experi-
mental miliaria in man: I. Production of sweat retention anidrosis and vesicles by means of iontophoresis. J. Invest. Dermat., 11: 275, 1948. 2. SHELLEY, W. B. AND HORVATH, P. N.: Experimental miliaria in man: II. Production
EXPERIMENTAL MILIARIA IN MAN. Xli
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of sweat retention anidrosis and miliaria crystallina by various kinds of injury.
J. Invest. Dermat., in press. 3. RIBBLE, G. B., LiIEDEMANN, W. S. AND PEABODY, S. M.: Epidemic of prickly heat on aircraft carrier. U. S. Nay. Med. Bull., 47: 77, 1947.
4. MATE, J. K.: Die Erkrankungen der Schweissdrusen, in Jadassohn J. Handbuch der Haut-TJnd Geschlestskrankheiten Berlin, Julius Springer, 1932, Vol. 13 pt. 1. 5. POLLITZER, S.: Prickly heat lichen tropicus, miliaria papulosa, M. rubra, etc. J. Cutan. Genito-Urinary Diseases, 11: 50, 1893. 6. SULZBERGER, MARION B. AND ZIMMERMAN, H. M.: Studies on prickly heat: II. Experi-
mental and histologic findings. J. Invest. Dermat., 7: 61, 1946. 7. O'BRIEN, J. P.: A study of miliaria rubra tropical anhidrosis and anhidrotic asthenia. Brit. J. Dermat., 59: 125, 1947. 8. SMITH, E. C.: Prickly heat: Its etiology and pathology. Trans. Roy. Soc. Trop. Med. and Hyg., 20: 344, 1927. 9. O'BRIEN, J. P.: Personal communication. 10. SIMONS, R. D. G. PH.: Studies on prickly heat. Dermatologica, 93: 172, 1946. 11. DUFFNEB, G. J.: Heat rash as a problem in the naval service. Am. J. Trop. Med., 26: 539, 1946. 12. SULZBERGER, MARION B., ZIMMERMAN, H. M. AND EMERSON, K.: Tropical anidrotic
asthenia (thermogenic anhidrosis) and its relationship to prickly heat. J. Invest. Dermat., 7: 153, 1946.
DISCUSSION DR. SIJLZBERGER: I believe I can say for all of us that we admire this beautiful
work and the simple, crystal-clear presentation and fine photographs. The work done by Shelley, Horvath and collaborators at the University of Pennsylvania is undoubtedly of fundamental importance. Every manifestation clinically and histo-pathologically described by O'Brien and his co-workers in Australia, and
by H. Zimmerman and me at Commodore Thomas Rivers Naval Research Unit ,' 2 on Guam, has now been reproduced experimentally and the mechanisms completely verified by these experimental pictures presented today. This is of course tremendously important, for it gives an opportunity for further experimental study. A good deal of the credit for this work goes to those silent men who cut the sections and examine them under the microscope. For unless true serial sections are cut and each carefully examined, one cannot demonstrate either the plugs or the relation of the fluid accumulations to the sweat ducts. And just as I am indebted for this to Dr. Harry Zimmerman on Guam and to Dr. Zak in New York, just so, I am sure, the Philadelphia group realize their debt to Dr. Fred Weidman for taking on that tedious duty. DR. LEON GOLDMAN: I wonder if these experiments could not be visualized dynamically with surface microscopy, either with special dye technic, or with a technic which as yet we do not use but certainly ought to use in dermatology, namely microsurgery, or some type of similar micro-manipulation technic. DR. RtJDOLF L. BARR: I would like to ask Dr. Shelley whether the zones of much more intense blue staining surrounding the anidrotic zones—in the kodachrome of the volunteer on whom anidrosis had been produced by 8 different measures—are evidence of a compensatory increase in sweat secretion surrounding the anidrotic area; or whether these are due to the photographic or experimental technic?
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DR. FRED D. WEIDMAN: I have been sweating through this matter at the microscope. I was particularly struck by a spongiotic appearance, somewhere along the course of the duct as it passed through the epidermis. In the many serial sections that I looked through to find actual connection between these spongiotic appearing cells and the actual lumen of the duct, I failed. I approached
this subject under the wrong impression. In O'Brien's work he used the word "rupture"; this to me means an actual break, as in a blood vessel when hemorrhage takes place by rhexis. I could not see anything of that kind in our sections;
and in case anybody is disposed to follow this subject and starts out with O'Brien's work, I would warn him about the manner in which the word "rupture" should be interpreted. As I see it, the integrity of the duct has been compromised as a result of imbibition of fluid on the part of the epidermal cells surrounding it. I recall that Dr. Sulzberger's printed illustration showed very much the same sort of circumstances and which are shown here on the screen. We have doubts as to whether the fluid in these spongiotic appearing areas is sweat or serum. That, I think, is the next problems to attack. This situation is similar to that for pompholyx, namely whether a sweat duct actually enters the vesicle or simply lies alongside. The literature disagrees on this point. DR. STEPHEN ROTHMAN: The point of Dr. Weidman concerning pompholyx is
well taken. However, if pompholyx were a sweat retention phenomenon, the urea concentration in the blister fluid should be higher than in the blood serum. In my analyses this has not been the case. Still, the last word has not been said on this subject. DR. PETER N. HORVATH: (Closing discussion) I want to thank all the discussors
for their remarks. In answer to Dr. Baer, we were equally worried about the appearance of our subject's back on our kodachrome, and were at a loss to account for this until we consulted with the photographer, who felt that this was an error in photographical technic and not our experimental finding. This study has tended to broaden the concept of just when and where miiaria can occur. It is very interesting to note that miliaria rubra occurred after the application of the aluminum chloride patch test. Many dermatoses that occur in the axilla can be related to the production of miliaria rubra on the basis of the use of anidrotic agents. Such an eruption can occur both in summer and winter. Furthermore, adhesive tape reactions occurring in warm weather are also in part due to miliaria rubra. Lastly, the diaper rashes occurring in infants due partly to irritation and partly to maceration can have plugged up sweat glands and sweat retention anidrosis and thus be related to the syndrome of miliaria rubra. As far as therapy of miliaria rubra is concerned, our findings suggest a few points.
The rapid disappearance of the lesions when the individual was put in cool, dry environment suggests that the cornerstone of such therapy should depend on a minimum of sweating for the individual, so that the macerative effects of sweating can be avoided. Strong keratolytics are not necessary and the use of soap and water should be minimized.
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94
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