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Reactions to Antituberculous Drugs1
REACTIONS TO ANTITUBERCULOUS DRUGS* EUGENE S. BERESTON, M.D., D.Sc. (Med.)
This paper represents a six year study in the evaluation of drug toxicity and sensitization reactions to the commonly used anti-tubereulous ehemo-therapeutie agents such as streptomycin, isonieotinie hydrazide, and para-amino-salicylie acid. There were approximately 2600 patients seen in 6 years from 1953 through 1958 in the Veterans Administration Hospital, Baltimore, Md. and treated for tuberculosis with these drugs.
developed sensitization on either patch testing or
intradermal testing better than 99% never developed any known drug sensitization reactions. Therefore, this showed hardly any correlation be-
tween sensitization testing and actual clinical sensitivity reactions (1). However, in the remaining almost 1% of the individuals, sensitization to 1 or several of the drugs occurred in the form of
I. CUTANEOUS TESTS
some of the cutaneous reactions that are to be described. Positive skin tests in the presence of other signs of beginning sensitivity reactions should be considered to be a warning of a possible drug reaction (2).
Patch testing to the three drugs of 100 random selected patients utilizing 1—100 dilutions was made on patients with varying length of treatment. Reading at 48 hours disclosed that individuals who had no signs of any sensitization or drug reactions, and who were under treatment up to three months with one or more of these drugs, had only a .5% sensitization to streptomycin, .9% sensitization to PAS and 0.1% to INH. In
II. DRUG REACTIONS
Streptomycin reactions in order of frequency are as follows: (see table I)
Concomitant to streptomycin sensitivity re-
individuals under treatment for 6 months the
actions there were often observed conjunctivitis, malaise, headaches, leg pains. It was found that desensitization in these individuals was feasible
following percentages of sensitization reactions to
(3,4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16).
patch testing were obtained: .8% to streptomyem, 1% for PAS and 0.2% for INH. For individuals under treatment for a year or more with these drugs, the incidence of sensitization on patch testing read by same technic shows 3% had developed sensitization to streptomycin, 3.5% had developed sensitization to PAS, and .4% had developed sensitization to INH. Intradermal testing in a similar group of individuals discloses that at the end of three months of treatment, streptomyein sensitivity reached a level of .8% and at six months advanced to 1.5% and at
Sensitivity reactions to streptomycin are usually demonstrated in many instances after five days
of therapy. Waksman (2), has shown that the severity of streptomycin sensitivity reactions is
determined by the size and frequency of the dosage used. Five per cent of all streptomyein reactions have associated fever. In mild eases of streptomycin sensitization reactions, therapy is
continued, or a rest period is decreed and the drug started again in small dosage. In either ease good results were obtained. However, in exfolia-
a year to 3.2% on intradermal testing. PAS intradermal testing disclosed sensitization in three months of treatment in 1%, 2.5% at 6 1. months and 3.1% at a year. With INH sensitiza-
TABLE I erythematous maeular and papular reactions (either febrile or afebrile). (See Generalized
figure 1)
tion on intradermal testing after 3 months of treatment was at a level of .1%, at 6 months it advanced to .3% and at a year it advanced to .5%. In the vast majority of the individuals who
2. Exfoliative dermatitis. (See figure 2)
3. Eosinophilia (5% or more in 30% of patients receiving Streptomyein). 4. Urticaria or angio-neurotie edema. 5. Morbilliform Eruptions. 6. Searlatiniform Eruptions. *From the Veterans Administration Hospital, 7. Hemorrhagic Eruptions (non-fatal usually). Baltimore, Maryland. Presented at the Twentieth Annual Meeting of 8. Milians' Ninth Day Erythema. the Society for Investigative Dermatology, Inc., 9. Local reactions at the site of injection. Atlantic City, N. J., June 7, 1959. 427
tJa
____ FIG. 1. Generalized maeulo-papular reaction (Streptomyein)
i/
Fio. 2. Exfoliative dermatitis (Streptomyein) 428
REACTIONS TO ANTITUBERCULOUS DRUGS
tive dermatitis the drug has to be stopped until the exfoliative dermatitis can be controlled either with steroids or other measures, but after the exfoliative dermatitis has subsided, streptomycin
treatment may be instituted in small dosage satisfactorily. In dihydro-streptomycin there is less sensitivity and little eosinophilia and very
little fever and only occasional dermatitis. Dihydro-streptomycin can be used in individuals
with severe sensitivity to streptomycin. Fiftyfive per cent of streptomycin sensitivity reaction patients have positive patch tests while only 31% had positive intradermal tests (1). To desensitize
individuals to streptomycin or PAS, steroids either oral or in the form of ACTH-injectible can
429
TABLE hA PAS reactions
Mild reactions Coryza Headache Lacrimation Conjunctivitis Spasmodic coughing Wheezing
Fever
TABLE JIB PAS reactions Severe reactions
be used to prevent severe reactions during the
Hemorrhagic disease with purpura hemor-
course of the desensitization. PAS reactions: Reactions to PAS may be mild or severe (17). The mild ones usually consist of
rhagica Eosinophilia' Loeffler s syndrome Pneumonitisf Meningitis (Guillian Barr syndrome) Hepatitis (cholangitic with jaundice) Maculopapules generalized Scarlatiniform eruptions Exfoliative dermatitis Ijrticaria and angioneurotic edema Vesico-bullous erosive eruptions Blood dyscrasias (agranulocytosis)
coryza, headache, lacrimation, conjunctivitis, spasmodic coughing, wheezing and fever (18). (See table hA) In the severe ones, (See table JIB) one sees hemorrhagic disease with purpura, menorrhagia, eosinophilia and pneumonitis (Loefflers syndrome), meningitis, or hepatitis (19, 20, 21, 22, 23, 24). The eruptions from PAS may be either macular or papular generalized erythematous eruptions, or may be scarletiniform or in the
form of an exfoliative dermatitis. In some PAS sensitization reactions, if on the drug one year or reactions, the eruption may be urticarial, mor- longer (24). The most frequent cause of sensitizabilliform, vesico-bullous erosive lesions or hemor- tion reactions with antituberculous drugs was rhagic (fig. 3 and 4). Occasionally the hemorrhagic PAS, with streptomyciri a runner-up and INH cases may be fatal with internal hemorrhages. as a rare cause. Desensitization to streptomycin Some of these patients are febrile others are not, and to PAS and to INH has been successfully patch tests are often strongly positive in PAS carried out in many instances. PAS delays the sensitization, cholangitic hepatitis with jaundice emergence of resistant strains of tuberele bacilli. INH Reactions: In INH reactions miliary and in some instances acute yellow atrophy and death are seen (25, 26, 27, 28, 29, 30, 31, 32, 33).
pruritic eruptions have been seen as well as
Blood dyscrasias, such as agranulocytosis (21),
purpuric eruptions (Table III) and also capillary hemorrhages, bullous dermatitis, jaundice, erythroderma, pellagra and maculo-papular eruptions with fever. Patch tests are often positive in these individuals, but intradermal tests are rarely found positive (34, 35, 36, 37, 38, 39, 40, 41, 44, 45). Desensitization has been successfully carried out. INH can cause aggravation of nummular eczema (41). INH administered alone permits drug resistant tubercle bacilli to emerge according to the joint Army, Navy VA. conferences on therapy (42). Metabolic antagonism between INH and nicotinamide precipitates pellagra in individuals on inadequate diets (37, 39). Other drugs used at this Hospital included pyrazinamide, viomycin
are found and occasionally pneumonitis and eosinophilia or Loeffler's syndrome (19). In these
patients with PAS sensitivity reactions 20% of the intradermal tests are positive, and 30% of the patch tests are positive. Occasionally concomitant
sensitivity to streptomycin and INH are seen along with the PAS sensitization reaction (5). The Guillian Barre syndrome is sometimes seen, as is also alopecia.
Patients allergic to PAS and who are also on streptomycin, occasionally get non-specific flares
of dermatitis when streptomycin alone is insti-
tuted (Sulzberger) (1). Four per cent of all patients receiving PAS eventually develop PAS
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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
TABLE III INH reactions
1. Erythematous maculopapular pruritic generalized eruptions, (with or without fever). 2. Vesico bullous eruptions. 3. Erythroderma generalized. 4. Pellagra. 5. Urticaria and angioneurotic edema. 6. Nummular eczema. 7. Jaundice.
8. Purpura and/or capillary hemorrhages. 9. Herpes zoster. 10. Contact dermatitis. 11. Desensitization usually successful. tion reactions. It is a neurotoxic agent. One case
of urticaria and one generalized crythematous maculo-papular eruption were observed with cycloscrine. Herpes zoster has been seen by me on twelve occasions and also one case of varicella
(38) (See table III). III. ACNE DUE TO DRUGS
Fm. 3. Hemorrhagic macular reaction (PAS).
The antituberculous drugs observed for the past six years have been found to produce certain specific cutaneous reactions. One such reaction observed from the very first, was an aeneform,
follieular drug eruption seen in a number of individuals under combined treatment with para-amino-salicylic acid and isonicotinic hydrazide. This has never been previously reported. At first, it was thought that these patients receiving
combined therapy might be having an acne flare-up of pre-existing acne, particularly where
the age of the individual was below thirty.
However, even individuals in their forties and fifties were observed with the acne-like condition associated with their drug therapy. Statistically, 16% of all individuals receiving combined INH and PAS therapy developed acne-like, follicular
lesions on the acne areas on the face and trunk (fig. 5, 6, 7, 8). This was true regardless of age. Several of the men in their sixties developed this
Fzo. 4. Hemorrhagic vesicular reaction (PAS) and cycloserine. Pyrazinamide produces elevated uric acid, giving arthralgia and gout. Viomycin
drug induced acne. Nine per cent of the acne eases had a history of adolescent acne in their teens which was no longer present for many years prior to the onset of the antituberculous therapy.
1.5% of the eases had acne at the time of onset appears to produce many of the sensitization of the antitubereulous drug therapy with INH reactions associated with streptomycin. Cyclo- and PAS, but they found, that after therapy was serine appeared to be relatively free of sen sitiza- instituted, their acne flared and became worse.
REACTIONS TO ANTITUBERCULOTJS DRUGS
431
In most patients the drugs were administered in dosage of 300 mg. a day of INH and 12 grams a day of PAS. Only occasionally were there variations from this dosage schedule. Usually two to four months of such therapy were necessary before the symptoms began to appear. In a small percentage of cases lesions made their appearance as early as 4 to 6 weeks after the onset of therapy. The degree of severity of the acne was variable. In some patients 4 to 6 months or so of therapy were required to bring on the acne lesions. The onset of the lesions occurred as a papular, follicular eruption of the face, chest, shoulders and back.
In many cases, pustules made an early appearance. In others, they developed later. Treatment of all these individuals by means of acne diets,
thorough washing, ultra-violet light therapy three times a week, vitamin A 100,000 units daily,
lotio alba and similar local therapy resulted in very little, if any, improvement in the lesions, so long as the drug therapy was continued. When the
drug routine was changed, or the drugs were discontinued, the acne like lesions disappeared
FIG. 5. Follicular acneform eruption (PAS and gradually in 4 to 12 weeks. (Changing to strepto- INH)
mycin and INH, or PAS and streptomycin caused disappearance of the acne lesions.) This was established in hospitalized patients as well
as in patients who left the hospital, by posthospital checkup. In some of the individuals stopping or changing PAS and INH routine resulted in improvement or clearing of the acne and re-institution of the same therapy brought about a recurrence of the acne some months later. The histo]ogy of the follicular acne lesions in several biopsy specimens was consistent with the same picture as seen in acne vulgaris according to readings made by Dr. Francis Ellis. One such specimen showed an acute abscess in the midcutis with a slight amount of foreign body reaction (Fig. 9a & b). He considered this to be compatible with acne vulgaris. Patch tests to PAS and INH—1 to 100 dilution—and intradermal tests with one tenth cc. in a 1 to 100 dilution were negative in 226 of 248
FIG. 6. Follicular acneform eruption (PAS and INH)
acne cases. In eight cases 1 plus to four plus tests were one pius to three plus in three of the reactions were present to INH and in six cases cases and were negative in three more. All intrato PAS on patch testing. Intradermal tests re- dermal readings were at ten to thirty minutes,
vealed three of eight of the INH patch test 24 hours and 48 hours. No correlation between positive cases giving one plus or 2 plus reactions positive patch or intradermal test and the acne to the INH and the other five were negative. In could be established at any time. Individuals with six patch test positive PAS cases, intradermal acne in whom either INH alone or PAS alone was
432
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
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FIG. 7. Follicular acneform eruption (PAS and INH)
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433
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REACTIONS TO ANTITUBERCTJLOUS DRUGS
FIG. 9A (top). Low power view of acneform lesion. FIG. 9B (bottom). High power view of aeneform lesion showing abscess in cutis.
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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
TABLE IV Drug Toxicity
Drug Hyperseusitivity
Relation to dosage
Predictability Manifestations Specificity Mechanism Desensitization
Abnormal, altered or unusual and oc- Normal or usual, related to dosage cur even to small dosage proper Usually cannot be anticipated in ad- Usually can be anticipated in advance vance Essentially physiologic or pharmacoEssentially allergic logic Non-specific and variable with differ- Constant identical features in different individuals ent features in different individuals Pharmacologic Immunologic Not possible Possible with protein drugs
discontinued usually lost their acne in one to two months time. This points to a symbiotic effect of thc two drugs in producing the eruption. DISCUSSION
tion is produced by minute quantities far too small to produce an effect in the non-sensitized person.
Hypersensitivity to non-protein or crystalloid drugs such as PAS are based on combination of
Morse et al. (42) have shown that PAS administered with INH may increase the blood
the drug with protein in the body to form a
Fifty per cent of the patients treated with INH
fixed in tissue cells and not circulating or de-
alone cannot maintain a level of 0.8 micrograms or more, of INH per milliliter of serum at 6 hours, after a 4 mg. per Kg. dose. This position of INH
monstrable in the blood. The removal of the drug as soon as the symptoms start results in cure. The
in the body is on the basis of individuality and depends on constitutional biochemistry. Concomitant PAS administration causes elevated INH serum levels (42). Both drugs arc antimicrobial, but PAS elevated INH blood level. Decrease in the rate of metabolic inactivation of INH is reasonably attributed to competition between INH and PAS for the biochemical process
toxicity.
foreign protein or antigen, capable of stimulating Concentration of active or unconjugated INH by antibody production. Lansdowne postulates that Consuming the acetylating capacity of the body. sensitivity to drugs occurs after a period of sensiThere are rapid and slow inactivators of INH. tization to protein drug complex. Antibodies are
acne described appears to be a form of drug There are certain eczematous complications
observed in individuals under treatment for tuberculosis with continued therapy (43). Crissy,
Osborne and Jordan suggest three patterns. Nummular eczema and scborrheic dermatitis have been observed in this study as well as by
others (41, 43). 1. The eruption resembling nummular eczema of acetylation. Inactivation of INH is rapid in approximately on the extremities, mostly, occasionally on the 40% of Americans white or Negro, while in trunk and appearing usually at the sites of other orientals it is rapid in 90% of individuals. Of the dermatoses or in connection with stasis derma16% of patients with acne due to INH and PAS, titis, dermatitis venenata, or epidermophytosis 11% were slow inactivators of INH. This coupled of the feet. Later hyperpigmentation and lieheniwith the tendency of PAS to elevate blood levels fication. 2. Eruptions resembling seborrheic dermatitis. of INH may be one of the reasons that the acneSeborrheic dermatitis of the hairlines, the ears, form eruptions develops.
Drug allergy is different from drug toxicity nasal, labial and presternal areas. It may later (See table IV). Toxic actions are constant for become moist. 3. Eruptions resembling both nummular ecmost persons and specific for a given drug. Allergy is only found in a few hypersensitive per- zema and seborrheic dermatitis. They make the observations that no eczema sons. Allergic reactions present a wide variety of forms, none of which is characteristic for any appears unless PAS or Streptomycin are given. single drug or group of drugs. The allergic reac- Thirdly, that eczema might disappear or not
REACTIONS TO ANTITUBERCIJLOUS DRUGS
disappear if PAS was stopped, and streptomycin continued. And fourthly, INH had no effect at all
in these individuals, in this type of eruption. There was no epidermal sensitivity as the patch tests were negative. Becker's drug neurodermatitis (10) is similar to these cases. Becker did not consider seborrheic dermatitis related to chemotherapy, and Becker includes as reaction to drugs other neuroderma toses such as dyshidrosis, pruritus ani and alo-
pecia areata as due to neurotoxic effects of streptomycin, INH and PAS. Crissy, Osborne and Jordan (43) disagree with this as does this author. PAS continuance prevents relapse of tuberculosis. Treatment of the nummular eczema controls the lesions, so chemotherapy can be con-
CONCLUSIONS
1. A follicular acneform drug eruption due to concomitant INH and PAS therapy is reported. 2. Histologically the acne is similar to acne vulgaris. 3. Incidence of antituberculous drug sensitiza-
tion as demonstrated by cutaneous tests is low, PAS being greatest, followed by streptomycin and
INH. 4. Correlation of cutaneous tests with clinical hypersensitivity is not conclusive.
5. Desensitization to antituberculous drugs is frequently possible. 6. Neurosomatic or psychosomatic dermatoses
are not as prevalent in this series as reported by other authors.
tinued. Seborrhea does not respond to antiseborrheic drugs, but clears if PAS is stopped. Steroids in the exfoliative types of dermatitis permit therapy to be continued. Becker (10) states of 239 patients receiving streptomycin or INH for treatment of T.B. 32% presented eruptions characteristic of the neuro-
dermatoses. He states that association with administration of neurotoxic drugs is the appearance of eruptions thought to be of neurogenie origin. Stressing the hypothesis that such eruptions arise by a nervous mechanism, he
435
ACKNOWLEDGMENTS
Thanks are due to Miss Mildred Taylor, librarian and to Mr. Rowland B. Schmick, photographer at the Veterans Hospital for unusual cooperation.
REFERENCES 1. SULZBERGER, M.: Dermatologic Allergy,
page 46, Springfield, Ill., Charles C Thomas, 1947.
2. WAKSMAN, S. A.: Streptomyein, page 525, Balto. William & Wilkins Co., 1949.
3. SANDER, A.: Management of hypersensitive
reactions to streptomycin & PAS. Br. J.
claims that eruptions healed rapidly in the exudative type and if they were dry they healed slowly. Continuation of the drugs often necessary intro-
of T.B. and Dis. of Chest, 2: 31, 1955. 4. MCCAFFREY, L.: Fatal exfoliative dermatitis
duced therapeutic resistance on the part of the eruption. Dermatoses produced by para-aminosalicylic acid seem to be for the most part of an
5. SILVERMAN, J. D. AND SWENSON, E. W.:
allergic nature. None of the neurodermatoses seen were caused by para-amino-salicylic acid, according to Becker (10).
6. WEISEL, W., BARRELL, H. AND STEELE, J. D.:
due to treatment of urinary T.B. with streptomycin. Urol & Cutan. Rev. 52: 525— 1948.
Simultaneous hypersensitivity to streptomycin and PAS. Dis. of Chest, 30: 103, 1956.
It was not our feeling in this Veterans Tuberculosis Hospital that any greater incidence of
Toxic reactions to streptomycin—patient with pulmonary tuberculosis having thoracic surgery. Surg. Clinics of N. America, 28: 1663, 1948. 7. WELCH, H.: Severe reactions to antibiotics.
neurodermatoses were seen than would be seen in
8. RUDENSEY, H. AND FISHER S.: Thrombopenic
cant in the overall picture. Metabolic antagonism between INH and Nicotinamide precipitates the pellagra in individuals on an inadequate diet.
Amer. Rev. Tuberc., 60: 564, 1949. 12. FEIN, B. T.: Exfoliative dermatitis from dihy-
Antibiotic Med., 4: 800, 1957.
purpura during streptomycin therapy of ordinary dermatologic hospital practice. Those tuberculous empyema. J.A.M.A, 147: 311, drug reactions seen appear to be clear-cut drug 1951. R. A.: Death from dermatitis and reactions due to sensitization, and in the case of 9. PALLISTER, stomatitis during therapy. Brit. M. J., 2: the acne due to toxic reaction. Few, if any of our 1271, 1949. cases were of neurosomatic or neurotoxic origin. 10. BECKER, S. W.: Dermatosis in patients receiving chemotherapy for systemic tubercuThe incidence of neurodermatoses in the patients losis. Arch. Dermat. & Syph., 75: 333, 1957. C. M.: Clinical study of toxic effects seen in the Veterans Hospital has been insignifi- 11. DOMAN, of dihydrostreptomycin and streptomycin. drostreptomycin. Texas J. Med., 46: 712, 1950.
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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
13. HARms, W. C.: Exfoliative dermatitis com- 31. ALRMQUER, M.: Severe hypersensitivity reactions to PAS. Am. Rev. Tuberc., 78: 462, plicating therapy. Lancet, 1: 112, 1950. 14. LINDAR's, D. C.: Severe urticaria complicat1958. 32. HORNR, N. W.: Complications of PAS therapy. ing therapy. Lancet, 1: 110, 1950. Lancet, 2: 348, 1949. 15. COHEN, A. C.: (a) Hypersensitivity to streptomycin. J. Allergy, 22: 63 1951. 33. HRASLRR, N. M., SINGER, E. P. AND HILL, HANSON, J. E.: (b) Fatal hypersensitivity to H. E.: Cholangitic hepatitis due to PAS. PAS and streptomycin. Dis. of Chest, 28: Am. Rev. Tuberc., 76: 132, 1957. 577, 1955. 16. WEISMANN-NETTER, R.: Erythroderma. Bulle-
tin et Mem. Soc. Med. Hospital Paris, 66:
34. Baowa, H., GOLDSTRIN, G. AND CHAPMAN, G.
Allergy to TNH. Am. Rev. Tuberc., 74: 783, 1956.
137, 1947.
35. MANN, B.: TNH Allergy. Brit. M. J. 2: 391,
tivity reaction to oral PAS. Dis. of Chest,
36. MARTIN, H., CHABBERT, L. AND SURRAU, B.:
JR.: Allergic reactions to PAS. Am. Rev.
bactericides, application clinique. Presse
17. HAYES, R. H. AND WEISS, M.: Hypersensi23: 645, 1953. 18. WARRING, F. C., Ja. AND HOUSLETY, K. S.,
Tuberc., 65: 235, 1952.
1952.
Les Associations d'antibiotiques. Etude et valeur de leur pouvoirs bacteriostatiques et med., 61: 168, 1953.
19. CUTIIBRRT, R. J.: Loefflers syndrome occur- 37. MCCONNELL, R. B.: Acute pellagra during ring during streptomycin and para amino therapy. Lancet, 2: 959, 1952. salicylie acid therapy. Brit. M. J., 54: 398, 38. SCHWADRRER, A.: Herpes Zoster caused by 1954. therapy of tuberculosis. Neuro-tropic toxic
20. KORST, D. R.: Severe reactions to PAS. A case report and brief review of literature. Ann. Tnt. Med., 40: 1011, 1954. 21. MAHEER, R. A.: Agranulocytosis complicating
effect of INH. Ztschr. f. Tuberk., 104: 61, 1954.
PAS and streptomycin therapy. U. S.
39. Woon, M. M.: Central nervous system complications (Chiefly Pellagra) during treatment of pulmonary tuberculosis. Brit. J.
Ann. Tnt. Med., 45: 541, 1956.
40. MANN, B.: Isoniazid Allergy. Brit. M. J., 59:
Armed Forces Med. Journal, 6: 1193, 1955. 22. ALT, W. J.: Severe systemic reactions to PAS.
23. HENSLER, H. M.: Hypersensitivity reactions
due to PAS. Am. Rev. Tubere., 76: 132, 1957.
24. PAINE, D.: Allergic reactions to PAS. Arch. Tnt. Med., 96: 768, 1955.
25. MADIGAN, D. G.: PAS in T.B. Lancet, 1: 239, 1950.
26. SANDLER, A.: Hypersensitivity to PAS. Brit. J. Tubere., 49: 231, 1955. 27. LUIPPOLD, E. J.: Dermatitis due to PAS. Ann. Allergy, 9: 97, 1951. 28. KIERLAND, R. R. AND CAIN, D. T.: Reactions
to PAS. Proc. Staff Meet. Mayo Clinic, 24: 539, 1949.
29. KORST, D. R.: Severe Reactions to PAS. Ann. Tnt. Med., 40: 1011, 1954. 30. FRIEDMAN, E.: Reactions to PAS., Am. Rev. Tuberc., 72: 833, 1953.
Tuberc., 49: 20, 1955.
685, 1957. 41. BIEHL, J. P. AND SHEvLEIN, J. H.: Toxicity of TNH. Am. Rev. Tuberc., 68: 296, 1953. 42. MORSE, W. C., CURRY, F. J., MORSE, P. 0., CHAMBERS, J. S. AND LINCOLN, A. F.: Tr.
15th Conf. on Chemotherapy of Tubercu-
losis V. A. Army and Navy, Page 283, 1956. 43. Cmssv, JOHN., OSBORNE, EARL, AND JORDAN,
J. W.: Eczematous complications in treatment of tuberculosis. J.A.M.A., 165: 1526,
1957. 44. MEARR, R. AND WEINRRICH, J.: Untersuchun-
gen zur Frage der Blutungeneigung wShrend
der Therapie mit Isonicotinsaure hydrazid.
KIm. Wochenschrift, 32: 212, 1954. 45. SCHWAETz, W. S. AND MAYER, R. E. Use of
TNH Alone in treatment of pulmonary T. B. Am. Rev. Tuberc., 70: 924, 1954.
DISCUSSION DR. S. War. BECKER (Long Beach, Calif.): I taking treatment for tuberculosis with INH and think this is important because it calls attention streptomycin and it seemed to me that they to the fact that with the newer drugs we are going presented dermatoses of functional rather than to have to look for drug eruptions which are not allergic origin. On investigation both INH and strictly allergic. streptomycin are potent neurotoxie or neuroDr. Ben Newman gave a talk at the Pacific allergic drugs. Dermatologic Association a couple of years ago We concluded (Becker, S. W., & Mounee, calling attention to this phenomenon. He pre- S. H.: Dermatoses in Patients Receiving Chemosented a patient who had been taking Miltown therapy for Systemic Tuberculosis, AMA Arch. for a long period of time with impunity. Sud- Dermat. 75: 333—344 (Mar) 1957) that the denly small petechial hemorrhages developed, got eruptions probably resulted from this neurotoxic worse and were relieved only by discontinuing or neuro-allergie action. Miltown. There is one difficulty in the treatment of When I first came to the VA Hospital in Long tuberculosis. You practically have to give the Beach there was a backlog of patients who were patients streptomycin or isonicotinic hydrazide
REACTIONS TO ANTITUBERCULOUS DRUGS
437
because there are as yet no substitutes for these different from those in patients without antitwo drugs; you can hyposensitize the individuals tuberculous medication. There are no characteristic aeneform lesions by injection (SM) or by mouth (INH) and in case the patient still has difficulty we have had developing in patients treated with antitubercusome success by giving the individuals half doses. bus drugs. Based on studies done many years Dn. RUDOLF BARR (New York, N. Y.): I ago in Switzerland and also on more recent would like to ask Dr. Bereston what technic he observations in this country I have found that used to hyposensitize with P.A.S. What proof patients with active pulmonary tuberculosis do was there that hyposensitization actually was not usually have acne at all or show a mild form achieved and were patients known to be sensitive of acne only. to P.A.S. but not "hyposeasitized" followed up DR. Louis H. WINER (Beverly Hills, Calif.): to see whether perhaps some of them spontane- In a histopathobogie study of the various drug ously lost their drug sensitivity, as is the ease in eruptions from urtiearial, papular, purpuric, some drug sensitizations? nodular, and even nodose type drug eruptions, Also were the patients who had become sensi- we found a characteristic fundamental histologic tive to P.A.S. cross-sensitive to other salicylates pattern primarily always involving the blood such as aspirin, as has been reported previously? vessel. These vessels showed intimal proliferation Dn. LAWRENCE C. GOLDBERG (Cincinnati,
with inhanging of the nuclei into the vessel
Ohio): I have been an attending dermatologist for some twenty years at a tuberculosis sanitarium in Cincinnati and long befere these newer drugs were used. The most common dermatosis in tubereulous patients was an aeneform eruption. These patients were admitted to the sani-
lumens. Unlike other allergic skin reactions where
vulgaris. After they had been there for a period of time, at least thirty per cent of these patients developed this type of eruption. I think we have to be careful in evaluating reactions to a drug. It is very simple to say a drug produced this or that reaction unless we have been following them for a long, long time. I have seen eruptions due to p-amino salieylic acid, but only a very few due
cases of erythema multiforme type of drug eruption, this edema is so intense as to be suggestive
one finds many eosinophils, we found them numerous only in two of a hundred eases we biopsied. Otherwise there was only a few eosinophils present. The predominant perivascular cell
was the lymphocyte. There is always a very tarium without aeneform eruptions or acne pronounced edema of connective tissue and in of diffuse myxedema.
I would like to ask Dr. Bereston if these cases of the acne vulgaris-like eruption showed vascular changes as I indicated.
DR. CARL T. NRLSON (New York, N. Y.): Apparently it has not been sufficiently empha-
to I.N.H. I suggest caution before making a sized that there is little relationship between diagnosis of aeneform eruption in patients who
hypersensitivity to ingested or injected drugs and
are in a tuberculosis sanitarium and taking the results of skin testing with such compounds. specific drugs. This is so generally the ease that I thought it
Dn. ALFERD HOLLANDRE (Springfield, Mass.): had been accepted that cutaneous testing is of I appreciate hearing Dr. Bereston's paper. It is little value in establishing the specific diagnosis my experience that except for generalized skin of a dermatitis medicamentosa. My question is, eruptions of morbilliform type no distinct pattern what prompted Dr. Bereston to engage in such exists to characterize skin eruptions caused by extensive skintestingprocedures during the course antituberculous drugs. Seborrheic dermatitis-like of this study? Wasn't he beating a dead horse? In reply to Dr. Baer, eross-semitivity between eruptions as reported 2 years ago by Osborne and p-amino salicylic acid and acetyl salicylie acid is his group and dyshidrotic eruptions develop not uncommon. without any etiologic connection with antituberDR, F. KALz (Montreal, Canada): I should culous therapy. In patients with dyshidrotie like to make one short remark: There is a very eczema of the hands discontinuation of antitu- extensive literature on the incidence of acne berculous drugs does not have any influence on vulgaris in patients with tuberculosis in sanithe course of the dyshidrotic eczema. Pattern and taria. Unfortunately, I am not in the position to course of these dyshidrotie eruptions are not quote references, but there are several dozens of
438
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
reports, claiming a very high incidence of acne vulgaris among those patients, and it was claimed that 40 to 50% show this coincidence, though I recall no valid control series. This was of course long before the time of antituberculous drugs. I remember that some authors went as far as to claim that acne vulgaris must have in some cases a tuberculous etiology. DR. EUGENE S. BERESTON (in closing): I have a long list to answer. Dr. Becker was the first discusser. He mentioned the fact that he considers nummular eczema and seborrheic eczema
a number of months later, on follow-up, we found that the acne lesions had disappeared; in some of these individuals I was able to reinstitute therapy with the drugs and the acne reappeared in one to two months. It was my belief and the concensus
were seen, were not truly neurodermatoses. I felt
edema for the most part except in the area where
of the other physicians in our hospital that we were dealing with a drug toxicity type of acne rather than just a coincidental acne developing in a tuberculous patient on a high carbohydrate diet. The incidence of acne in patients in the hospital with the same diet and not receiving INH and PAS was 1%. as being so-called functional or neurodermatoses. Dr. Winer was asking about the histologic Dr. Hollander expressed the opposite view- picture in some of these drug eruptions. In the point and it was my feeling that most of the acneform drug eruption, which was described, nummular eczema and seborrheic eczemas that there was very little evidence of connective tissue that most of these cases were similar to those an abscess was present in the cutis with zonal seen in non-tuberculous patients not under drug edema. But the rest of the dermis showed very treatment, and that they could just as easily not little edema. However, I would say that in most be neurodermatoses as he intimates. Dr. Baer asked about the follow-up on patients
of the so-called dermatitis medicamentosa, lesions due to sensitivity that were biopsied, considerable
reacting to PAS. Some of these patients do
tissue edema was seen. Occasional eosinophils and lymphocytes were much in evidence, especially in perivascular arrangement. This is not true however, for the acneform eruptions. Dr. Nelson asked why did we do intradermal and patch tests on our patients? First of all, we
spontaneously desensitize themselves while under treatment or after cessation of treatment and reinstitution of it; and there are case reports in
the literature to that effect that even though treatment is continued in the people with PAS reaction, the mild and moderate ones can continue on therapy with the drug. This is also true of streptomycin in some instances where the eruptions are mild and the person is not very ill,
did them to see whether we could tie up the intradermal test and the patch test with the development of dermatitis medicamentosa and thus predict reactors. Originally we wanted to see
that continuation of the drug therapy results if a person could be followed from the time he apparently in spontaneous desensitization even started treatment and observed whether there though the drug is being continued. This, of was any change in the patch or intradermal testcourse, is not true in the more severe reactions with either drug.
ing in the course of the therapy which lasted from
In answer to the question about PAS and
point of curiosity to see whether we could predict which individual would develop sensitization and which individual would not. As you can see, as Dr. Nelson mentioned, the
Aspirin, I can say that we have had some individuals who have reacted first to PAS and then later to Aspirin when given to them for some
six months to a year or longer. This was just a
results were inconclusive. We were not able to other reason. predict these things. We did not find out which Dr. Goldberg asked about, and so did several patient would develop a reaction because the other people, the incidence of acne in tuberculosis
sensitization on testing appears to be extremely sanitaria. I can only say that most of the indi- low with all the antituberculous drugs. viduals that were seen, developed acne within a The question of acne in tuberculosis is in the specific period while under therapy. If we dis- older literature and I looked very thoroughly in continued the drug therapy when possible, or if all the literature, but found very little written on the patient was finally discharged with an active acne in relation to tuberculosis, at least in this acne and we saw them after they wer' off drugs country. Acne as a drug eruption to the anti-
REACTIONS TO ANTITUBERCULOTJS DRUGS
439
tuberculous drugs has never been described. I absence of acne in other patients treated with discussed this with many of the internists in other drug combinations with the same diet and Baltimore, and they felt that the acneform le- environment and the production of acne with the sions in tbe incidence we had, about 16 per cent drugs and its disappearance on stopping the drugs of the patients, on tbe 2 drugs, would be con- plus its reappearance on starting the same drugs sidered rather high in an ordiaary tuberculosis again, led to the conclusion that the acne was a sanitarium even with the enriched diets. The near form of drug eruption.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
24. Wynn, C. H. and Iqbal, M.: Isolation of rat
skin lysosomes and a comparison with liver Path., 80: 91, 1965. and spleen lysosomes. Biochem. J., 98: lOP, 37. Nicolaides, N.: Lipids, membranes, and the 1966.
human epidermis, p. 511, The Epidermis
Eds., Montagna, W. and Lobitz, W. C. Acascopic localization of acid phosphatase in demic Press, New York. human epidermis. J. Invest. Derm., 46: 431, 38. Wills, E. D. and Wilkinson, A. E.: Release of 1966. enzymes from lysosomes by irradiation and 26. Rowden, C.: Ultrastructural studies of kerathe relation of lipid peroxide formation to tinized epithelia of the mouse. I. Combined enzyme release. Biochem. J., 99: 657, 1966. electron microscope and cytochemical study 39. Lane, N. I. and Novikoff, A. B.: Effects of of lysosomes in mouse epidermis and esoarginine deprivation, ultraviolet radiation and X-radiation on cultured KB cells. J. phageal epithelium. J. Invest. Derm., 49: 181, 25. Olson, R. L. and Nordquist, R. E.: Ultramicro-
No warranty is given about the accuracy of the copy.
Users should refer to the original published dermal cells. Nature, 216: 1031, 1967. version of1965. the material. vest. Derm., 45: 448, 28. Hall, J. H., Smith, J. G., Jr. and Burnett, S. 41. Daniels, F., Jr. and Johnson, B. E.: In prepa1967.
Cell Biol., 27: 603, 1965.
27. Prose, P. H., Sedlis, E. and Bigelow, M.: The 40. Fukuyama, K., Epstein, W. L. and Epstein, demonstration of lysosomes in the diseased J. H.: Effect of ultraviolet light on RNA skin of infants with infantile eczema. J. Inand protein synthesis in differentiated epi-
C.: The lysosome in contact dermatitis: A ration. histochemical study. J. Invest. Derm., 49: 42. Ito, M.: Histochemical investigations of Unna's oxygen and reduction areas by means of 590, 1967. 29. Pearse, A. C. E.: p. 882, Histochemistry Theoultraviolet irradiation, Studies on Melanin, retical and Applied, 2nd ed., Churchill, London, 1960.
30. Pearse, A. C. E.: p. 910, Histacheini.stry Thearetscal and Applied, 2nd ed., Churchill, London, 1960.
31. Daniels, F., Jr., Brophy, D. and Lobitz, W. C.: Histochemical responses of human skin fol-
lowing ultraviolet irradiation. J. Invest. Derm.,37: 351, 1961.
32. Bitensky, L.: The demonstration of lysosomes by the controlled temperature freezing section method. Quart. J. Micr. Sci., 103: 205, 1952.
33. Diengdoh, J. V.: The demonstration of lysosomes in mouse skin. Quart. J. Micr. Sci., 105: 73, 1964.
34. Jarret, A., Spearman, R. I. C. and Hardy, J. A.:
Tohoku, J. Exp. Med., 65: Supplement V, 10, 1957.
43. Bitcnsky, L.: Lysosomes in normal and pathological cells, pp. 362—375, Lysasames Eds., de Reuck, A. V. S. and Cameron, M. Churchill, London, 1953.
44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.
45. Herion, J. C., Spitznagel, J. K., Walker, R. I. and Zeya, H. I.: Pyrogenicity of granulocyte lysosomes. Amer. J. Physiol., 211: 693, 1966.
46. Baden, H. P. and Pearlman, C.: The effect of ultraviolet light on protein and nucleic acid synthesis in the epidermis. J. Invest. Derm.,
Histochemistry of keratinization. Brit. J. 43: 71, 1964. Derm., 71: 277, 1959. 35. De Duve, C. and Wattiaux, R.: Functions of 47. Bullough, W. S. and Laurence, E. B.: Mitotic control by internal secretion: the role of lysosomes. Ann. Rev. Physiol., 28: 435, 1966. the chalone-adrenalin complex. Exp. Cell. 36. Waravdekar, V. S., Saclaw, L. D., Jones, W. A. and Kuhns, J. C.: Skin changes induced by
Res., 33: 176, 1964.
This paper represents a six year study in the evaluation of drug toxicity and sensitization reactions to the commonly used anti-tubereulous ehemo-therapeutie agents such as streptomycin, isonieotinie hydrazide, and para-amino-salicylie acid. There were approximately 2600 patients seen in 6 years from 1953 through 1958 in the Veterans Administration Hospital, Baltimore, Md. and treated for tuberculosis with these drugs.
developed sensitization on either patch testing or
intradermal testing better than 99% never developed any known drug sensitization reactions. Therefore, this showed hardly any correlation be-
tween sensitization testing and actual clinical sensitivity reactions (1). However, in the remaining almost 1% of the individuals, sensitization to 1 or several of the drugs occurred in the form of
I. CUTANEOUS TESTS
some of the cutaneous reactions that are to be described. Positive skin tests in the presence of other signs of beginning sensitivity reactions should be considered to be a warning of a possible drug reaction (2).
Patch testing to the three drugs of 100 random selected patients utilizing 1—100 dilutions was made on patients with varying length of treatment. Reading at 48 hours disclosed that individuals who had no signs of any sensitization or drug reactions, and who were under treatment up to three months with one or more of these drugs, had only a .5% sensitization to streptomycin, .9% sensitization to PAS and 0.1% to INH. In
II. DRUG REACTIONS
Streptomycin reactions in order of frequency are as follows: (see table I)
Concomitant to streptomycin sensitivity re-
individuals under treatment for 6 months the
actions there were often observed conjunctivitis, malaise, headaches, leg pains. It was found that desensitization in these individuals was feasible
following percentages of sensitization reactions to
(3,4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16).
patch testing were obtained: .8% to streptomyem, 1% for PAS and 0.2% for INH. For individuals under treatment for a year or more with these drugs, the incidence of sensitization on patch testing read by same technic shows 3% had developed sensitization to streptomycin, 3.5% had developed sensitization to PAS, and .4% had developed sensitization to INH. Intradermal testing in a similar group of individuals discloses that at the end of three months of treatment, streptomyein sensitivity reached a level of .8% and at six months advanced to 1.5% and at
Sensitivity reactions to streptomycin are usually demonstrated in many instances after five days
of therapy. Waksman (2), has shown that the severity of streptomycin sensitivity reactions is
determined by the size and frequency of the dosage used. Five per cent of all streptomyein reactions have associated fever. In mild eases of streptomycin sensitization reactions, therapy is
continued, or a rest period is decreed and the drug started again in small dosage. In either ease good results were obtained. However, in exfolia-
a year to 3.2% on intradermal testing. PAS intradermal testing disclosed sensitization in three months of treatment in 1%, 2.5% at 6 1. months and 3.1% at a year. With INH sensitiza-
TABLE I erythematous maeular and papular reactions (either febrile or afebrile). (See Generalized
figure 1)
tion on intradermal testing after 3 months of treatment was at a level of .1%, at 6 months it advanced to .3% and at a year it advanced to .5%. In the vast majority of the individuals who
2. Exfoliative dermatitis. (See figure 2)
3. Eosinophilia (5% or more in 30% of patients receiving Streptomyein). 4. Urticaria or angio-neurotie edema. 5. Morbilliform Eruptions. 6. Searlatiniform Eruptions. *From the Veterans Administration Hospital, 7. Hemorrhagic Eruptions (non-fatal usually). Baltimore, Maryland. Presented at the Twentieth Annual Meeting of 8. Milians' Ninth Day Erythema. the Society for Investigative Dermatology, Inc., 9. Local reactions at the site of injection. Atlantic City, N. J., June 7, 1959. 427
tJa
____ FIG. 1. Generalized maeulo-papular reaction (Streptomyein)
i/
Fio. 2. Exfoliative dermatitis (Streptomyein) 428
REACTIONS TO ANTITUBERCULOUS DRUGS
tive dermatitis the drug has to be stopped until the exfoliative dermatitis can be controlled either with steroids or other measures, but after the exfoliative dermatitis has subsided, streptomycin
treatment may be instituted in small dosage satisfactorily. In dihydro-streptomycin there is less sensitivity and little eosinophilia and very
little fever and only occasional dermatitis. Dihydro-streptomycin can be used in individuals
with severe sensitivity to streptomycin. Fiftyfive per cent of streptomycin sensitivity reaction patients have positive patch tests while only 31% had positive intradermal tests (1). To desensitize
individuals to streptomycin or PAS, steroids either oral or in the form of ACTH-injectible can
429
TABLE hA PAS reactions
Mild reactions Coryza Headache Lacrimation Conjunctivitis Spasmodic coughing Wheezing
Fever
TABLE JIB PAS reactions Severe reactions
be used to prevent severe reactions during the
Hemorrhagic disease with purpura hemor-
course of the desensitization. PAS reactions: Reactions to PAS may be mild or severe (17). The mild ones usually consist of
rhagica Eosinophilia' Loeffler s syndrome Pneumonitisf Meningitis (Guillian Barr syndrome) Hepatitis (cholangitic with jaundice) Maculopapules generalized Scarlatiniform eruptions Exfoliative dermatitis Ijrticaria and angioneurotic edema Vesico-bullous erosive eruptions Blood dyscrasias (agranulocytosis)
coryza, headache, lacrimation, conjunctivitis, spasmodic coughing, wheezing and fever (18). (See table hA) In the severe ones, (See table JIB) one sees hemorrhagic disease with purpura, menorrhagia, eosinophilia and pneumonitis (Loefflers syndrome), meningitis, or hepatitis (19, 20, 21, 22, 23, 24). The eruptions from PAS may be either macular or papular generalized erythematous eruptions, or may be scarletiniform or in the
form of an exfoliative dermatitis. In some PAS sensitization reactions, if on the drug one year or reactions, the eruption may be urticarial, mor- longer (24). The most frequent cause of sensitizabilliform, vesico-bullous erosive lesions or hemor- tion reactions with antituberculous drugs was rhagic (fig. 3 and 4). Occasionally the hemorrhagic PAS, with streptomyciri a runner-up and INH cases may be fatal with internal hemorrhages. as a rare cause. Desensitization to streptomycin Some of these patients are febrile others are not, and to PAS and to INH has been successfully patch tests are often strongly positive in PAS carried out in many instances. PAS delays the sensitization, cholangitic hepatitis with jaundice emergence of resistant strains of tuberele bacilli. INH Reactions: In INH reactions miliary and in some instances acute yellow atrophy and death are seen (25, 26, 27, 28, 29, 30, 31, 32, 33).
pruritic eruptions have been seen as well as
Blood dyscrasias, such as agranulocytosis (21),
purpuric eruptions (Table III) and also capillary hemorrhages, bullous dermatitis, jaundice, erythroderma, pellagra and maculo-papular eruptions with fever. Patch tests are often positive in these individuals, but intradermal tests are rarely found positive (34, 35, 36, 37, 38, 39, 40, 41, 44, 45). Desensitization has been successfully carried out. INH can cause aggravation of nummular eczema (41). INH administered alone permits drug resistant tubercle bacilli to emerge according to the joint Army, Navy VA. conferences on therapy (42). Metabolic antagonism between INH and nicotinamide precipitates pellagra in individuals on inadequate diets (37, 39). Other drugs used at this Hospital included pyrazinamide, viomycin
are found and occasionally pneumonitis and eosinophilia or Loeffler's syndrome (19). In these
patients with PAS sensitivity reactions 20% of the intradermal tests are positive, and 30% of the patch tests are positive. Occasionally concomitant
sensitivity to streptomycin and INH are seen along with the PAS sensitization reaction (5). The Guillian Barre syndrome is sometimes seen, as is also alopecia.
Patients allergic to PAS and who are also on streptomycin, occasionally get non-specific flares
of dermatitis when streptomycin alone is insti-
tuted (Sulzberger) (1). Four per cent of all patients receiving PAS eventually develop PAS
430
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
TABLE III INH reactions
1. Erythematous maculopapular pruritic generalized eruptions, (with or without fever). 2. Vesico bullous eruptions. 3. Erythroderma generalized. 4. Pellagra. 5. Urticaria and angioneurotic edema. 6. Nummular eczema. 7. Jaundice.
8. Purpura and/or capillary hemorrhages. 9. Herpes zoster. 10. Contact dermatitis. 11. Desensitization usually successful. tion reactions. It is a neurotoxic agent. One case
of urticaria and one generalized crythematous maculo-papular eruption were observed with cycloscrine. Herpes zoster has been seen by me on twelve occasions and also one case of varicella
(38) (See table III). III. ACNE DUE TO DRUGS
Fm. 3. Hemorrhagic macular reaction (PAS).
The antituberculous drugs observed for the past six years have been found to produce certain specific cutaneous reactions. One such reaction observed from the very first, was an aeneform,
follieular drug eruption seen in a number of individuals under combined treatment with para-amino-salicylic acid and isonicotinic hydrazide. This has never been previously reported. At first, it was thought that these patients receiving
combined therapy might be having an acne flare-up of pre-existing acne, particularly where
the age of the individual was below thirty.
However, even individuals in their forties and fifties were observed with the acne-like condition associated with their drug therapy. Statistically, 16% of all individuals receiving combined INH and PAS therapy developed acne-like, follicular
lesions on the acne areas on the face and trunk (fig. 5, 6, 7, 8). This was true regardless of age. Several of the men in their sixties developed this
Fzo. 4. Hemorrhagic vesicular reaction (PAS) and cycloserine. Pyrazinamide produces elevated uric acid, giving arthralgia and gout. Viomycin
drug induced acne. Nine per cent of the acne eases had a history of adolescent acne in their teens which was no longer present for many years prior to the onset of the antituberculous therapy.
1.5% of the eases had acne at the time of onset appears to produce many of the sensitization of the antitubereulous drug therapy with INH reactions associated with streptomycin. Cyclo- and PAS, but they found, that after therapy was serine appeared to be relatively free of sen sitiza- instituted, their acne flared and became worse.
REACTIONS TO ANTITUBERCULOTJS DRUGS
431
In most patients the drugs were administered in dosage of 300 mg. a day of INH and 12 grams a day of PAS. Only occasionally were there variations from this dosage schedule. Usually two to four months of such therapy were necessary before the symptoms began to appear. In a small percentage of cases lesions made their appearance as early as 4 to 6 weeks after the onset of therapy. The degree of severity of the acne was variable. In some patients 4 to 6 months or so of therapy were required to bring on the acne lesions. The onset of the lesions occurred as a papular, follicular eruption of the face, chest, shoulders and back.
In many cases, pustules made an early appearance. In others, they developed later. Treatment of all these individuals by means of acne diets,
thorough washing, ultra-violet light therapy three times a week, vitamin A 100,000 units daily,
lotio alba and similar local therapy resulted in very little, if any, improvement in the lesions, so long as the drug therapy was continued. When the
drug routine was changed, or the drugs were discontinued, the acne like lesions disappeared
FIG. 5. Follicular acneform eruption (PAS and gradually in 4 to 12 weeks. (Changing to strepto- INH)
mycin and INH, or PAS and streptomycin caused disappearance of the acne lesions.) This was established in hospitalized patients as well
as in patients who left the hospital, by posthospital checkup. In some of the individuals stopping or changing PAS and INH routine resulted in improvement or clearing of the acne and re-institution of the same therapy brought about a recurrence of the acne some months later. The histo]ogy of the follicular acne lesions in several biopsy specimens was consistent with the same picture as seen in acne vulgaris according to readings made by Dr. Francis Ellis. One such specimen showed an acute abscess in the midcutis with a slight amount of foreign body reaction (Fig. 9a & b). He considered this to be compatible with acne vulgaris. Patch tests to PAS and INH—1 to 100 dilution—and intradermal tests with one tenth cc. in a 1 to 100 dilution were negative in 226 of 248
FIG. 6. Follicular acneform eruption (PAS and INH)
acne cases. In eight cases 1 plus to four plus tests were one pius to three plus in three of the reactions were present to INH and in six cases cases and were negative in three more. All intrato PAS on patch testing. Intradermal tests re- dermal readings were at ten to thirty minutes,
vealed three of eight of the INH patch test 24 hours and 48 hours. No correlation between positive cases giving one plus or 2 plus reactions positive patch or intradermal test and the acne to the INH and the other five were negative. In could be established at any time. Individuals with six patch test positive PAS cases, intradermal acne in whom either INH alone or PAS alone was
432
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
-
-
FIG. 7. Follicular acneform eruption (PAS and INH)
r 7-
4-
.4
A.: FIG. 8. Follicular acneform eruption (PAS and INH)
433
a
: a
—2
a
4 a
'I;
sin.
, 14*
'Cv
—
aS
0
H
-w
-S.
•
S
a', S
''S
S
(12
4,
.4
,2
REACTIONS TO ANTITUBERCTJLOUS DRUGS
FIG. 9A (top). Low power view of acneform lesion. FIG. 9B (bottom). High power view of aeneform lesion showing abscess in cutis.
434
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
TABLE IV Drug Toxicity
Drug Hyperseusitivity
Relation to dosage
Predictability Manifestations Specificity Mechanism Desensitization
Abnormal, altered or unusual and oc- Normal or usual, related to dosage cur even to small dosage proper Usually cannot be anticipated in ad- Usually can be anticipated in advance vance Essentially physiologic or pharmacoEssentially allergic logic Non-specific and variable with differ- Constant identical features in different individuals ent features in different individuals Pharmacologic Immunologic Not possible Possible with protein drugs
discontinued usually lost their acne in one to two months time. This points to a symbiotic effect of thc two drugs in producing the eruption. DISCUSSION
tion is produced by minute quantities far too small to produce an effect in the non-sensitized person.
Hypersensitivity to non-protein or crystalloid drugs such as PAS are based on combination of
Morse et al. (42) have shown that PAS administered with INH may increase the blood
the drug with protein in the body to form a
Fifty per cent of the patients treated with INH
fixed in tissue cells and not circulating or de-
alone cannot maintain a level of 0.8 micrograms or more, of INH per milliliter of serum at 6 hours, after a 4 mg. per Kg. dose. This position of INH
monstrable in the blood. The removal of the drug as soon as the symptoms start results in cure. The
in the body is on the basis of individuality and depends on constitutional biochemistry. Concomitant PAS administration causes elevated INH serum levels (42). Both drugs arc antimicrobial, but PAS elevated INH blood level. Decrease in the rate of metabolic inactivation of INH is reasonably attributed to competition between INH and PAS for the biochemical process
toxicity.
foreign protein or antigen, capable of stimulating Concentration of active or unconjugated INH by antibody production. Lansdowne postulates that Consuming the acetylating capacity of the body. sensitivity to drugs occurs after a period of sensiThere are rapid and slow inactivators of INH. tization to protein drug complex. Antibodies are
acne described appears to be a form of drug There are certain eczematous complications
observed in individuals under treatment for tuberculosis with continued therapy (43). Crissy,
Osborne and Jordan suggest three patterns. Nummular eczema and scborrheic dermatitis have been observed in this study as well as by
others (41, 43). 1. The eruption resembling nummular eczema of acetylation. Inactivation of INH is rapid in approximately on the extremities, mostly, occasionally on the 40% of Americans white or Negro, while in trunk and appearing usually at the sites of other orientals it is rapid in 90% of individuals. Of the dermatoses or in connection with stasis derma16% of patients with acne due to INH and PAS, titis, dermatitis venenata, or epidermophytosis 11% were slow inactivators of INH. This coupled of the feet. Later hyperpigmentation and lieheniwith the tendency of PAS to elevate blood levels fication. 2. Eruptions resembling seborrheic dermatitis. of INH may be one of the reasons that the acneSeborrheic dermatitis of the hairlines, the ears, form eruptions develops.
Drug allergy is different from drug toxicity nasal, labial and presternal areas. It may later (See table IV). Toxic actions are constant for become moist. 3. Eruptions resembling both nummular ecmost persons and specific for a given drug. Allergy is only found in a few hypersensitive per- zema and seborrheic dermatitis. They make the observations that no eczema sons. Allergic reactions present a wide variety of forms, none of which is characteristic for any appears unless PAS or Streptomycin are given. single drug or group of drugs. The allergic reac- Thirdly, that eczema might disappear or not
REACTIONS TO ANTITUBERCIJLOUS DRUGS
disappear if PAS was stopped, and streptomycin continued. And fourthly, INH had no effect at all
in these individuals, in this type of eruption. There was no epidermal sensitivity as the patch tests were negative. Becker's drug neurodermatitis (10) is similar to these cases. Becker did not consider seborrheic dermatitis related to chemotherapy, and Becker includes as reaction to drugs other neuroderma toses such as dyshidrosis, pruritus ani and alo-
pecia areata as due to neurotoxic effects of streptomycin, INH and PAS. Crissy, Osborne and Jordan (43) disagree with this as does this author. PAS continuance prevents relapse of tuberculosis. Treatment of the nummular eczema controls the lesions, so chemotherapy can be con-
CONCLUSIONS
1. A follicular acneform drug eruption due to concomitant INH and PAS therapy is reported. 2. Histologically the acne is similar to acne vulgaris. 3. Incidence of antituberculous drug sensitiza-
tion as demonstrated by cutaneous tests is low, PAS being greatest, followed by streptomycin and
INH. 4. Correlation of cutaneous tests with clinical hypersensitivity is not conclusive.
5. Desensitization to antituberculous drugs is frequently possible. 6. Neurosomatic or psychosomatic dermatoses
are not as prevalent in this series as reported by other authors.
tinued. Seborrhea does not respond to antiseborrheic drugs, but clears if PAS is stopped. Steroids in the exfoliative types of dermatitis permit therapy to be continued. Becker (10) states of 239 patients receiving streptomycin or INH for treatment of T.B. 32% presented eruptions characteristic of the neuro-
dermatoses. He states that association with administration of neurotoxic drugs is the appearance of eruptions thought to be of neurogenie origin. Stressing the hypothesis that such eruptions arise by a nervous mechanism, he
435
ACKNOWLEDGMENTS
Thanks are due to Miss Mildred Taylor, librarian and to Mr. Rowland B. Schmick, photographer at the Veterans Hospital for unusual cooperation.
REFERENCES 1. SULZBERGER, M.: Dermatologic Allergy,
page 46, Springfield, Ill., Charles C Thomas, 1947.
2. WAKSMAN, S. A.: Streptomyein, page 525, Balto. William & Wilkins Co., 1949.
3. SANDER, A.: Management of hypersensitive
reactions to streptomycin & PAS. Br. J.
claims that eruptions healed rapidly in the exudative type and if they were dry they healed slowly. Continuation of the drugs often necessary intro-
of T.B. and Dis. of Chest, 2: 31, 1955. 4. MCCAFFREY, L.: Fatal exfoliative dermatitis
duced therapeutic resistance on the part of the eruption. Dermatoses produced by para-aminosalicylic acid seem to be for the most part of an
5. SILVERMAN, J. D. AND SWENSON, E. W.:
allergic nature. None of the neurodermatoses seen were caused by para-amino-salicylic acid, according to Becker (10).
6. WEISEL, W., BARRELL, H. AND STEELE, J. D.:
due to treatment of urinary T.B. with streptomycin. Urol & Cutan. Rev. 52: 525— 1948.
Simultaneous hypersensitivity to streptomycin and PAS. Dis. of Chest, 30: 103, 1956.
It was not our feeling in this Veterans Tuberculosis Hospital that any greater incidence of
Toxic reactions to streptomycin—patient with pulmonary tuberculosis having thoracic surgery. Surg. Clinics of N. America, 28: 1663, 1948. 7. WELCH, H.: Severe reactions to antibiotics.
neurodermatoses were seen than would be seen in
8. RUDENSEY, H. AND FISHER S.: Thrombopenic
cant in the overall picture. Metabolic antagonism between INH and Nicotinamide precipitates the pellagra in individuals on an inadequate diet.
Amer. Rev. Tuberc., 60: 564, 1949. 12. FEIN, B. T.: Exfoliative dermatitis from dihy-
Antibiotic Med., 4: 800, 1957.
purpura during streptomycin therapy of ordinary dermatologic hospital practice. Those tuberculous empyema. J.A.M.A, 147: 311, drug reactions seen appear to be clear-cut drug 1951. R. A.: Death from dermatitis and reactions due to sensitization, and in the case of 9. PALLISTER, stomatitis during therapy. Brit. M. J., 2: the acne due to toxic reaction. Few, if any of our 1271, 1949. cases were of neurosomatic or neurotoxic origin. 10. BECKER, S. W.: Dermatosis in patients receiving chemotherapy for systemic tubercuThe incidence of neurodermatoses in the patients losis. Arch. Dermat. & Syph., 75: 333, 1957. C. M.: Clinical study of toxic effects seen in the Veterans Hospital has been insignifi- 11. DOMAN, of dihydrostreptomycin and streptomycin. drostreptomycin. Texas J. Med., 46: 712, 1950.
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13. HARms, W. C.: Exfoliative dermatitis com- 31. ALRMQUER, M.: Severe hypersensitivity reactions to PAS. Am. Rev. Tuberc., 78: 462, plicating therapy. Lancet, 1: 112, 1950. 14. LINDAR's, D. C.: Severe urticaria complicat1958. 32. HORNR, N. W.: Complications of PAS therapy. ing therapy. Lancet, 1: 110, 1950. Lancet, 2: 348, 1949. 15. COHEN, A. C.: (a) Hypersensitivity to streptomycin. J. Allergy, 22: 63 1951. 33. HRASLRR, N. M., SINGER, E. P. AND HILL, HANSON, J. E.: (b) Fatal hypersensitivity to H. E.: Cholangitic hepatitis due to PAS. PAS and streptomycin. Dis. of Chest, 28: Am. Rev. Tuberc., 76: 132, 1957. 577, 1955. 16. WEISMANN-NETTER, R.: Erythroderma. Bulle-
tin et Mem. Soc. Med. Hospital Paris, 66:
34. Baowa, H., GOLDSTRIN, G. AND CHAPMAN, G.
Allergy to TNH. Am. Rev. Tuberc., 74: 783, 1956.
137, 1947.
35. MANN, B.: TNH Allergy. Brit. M. J. 2: 391,
tivity reaction to oral PAS. Dis. of Chest,
36. MARTIN, H., CHABBERT, L. AND SURRAU, B.:
JR.: Allergic reactions to PAS. Am. Rev.
bactericides, application clinique. Presse
17. HAYES, R. H. AND WEISS, M.: Hypersensi23: 645, 1953. 18. WARRING, F. C., Ja. AND HOUSLETY, K. S.,
Tuberc., 65: 235, 1952.
1952.
Les Associations d'antibiotiques. Etude et valeur de leur pouvoirs bacteriostatiques et med., 61: 168, 1953.
19. CUTIIBRRT, R. J.: Loefflers syndrome occur- 37. MCCONNELL, R. B.: Acute pellagra during ring during streptomycin and para amino therapy. Lancet, 2: 959, 1952. salicylie acid therapy. Brit. M. J., 54: 398, 38. SCHWADRRER, A.: Herpes Zoster caused by 1954. therapy of tuberculosis. Neuro-tropic toxic
20. KORST, D. R.: Severe reactions to PAS. A case report and brief review of literature. Ann. Tnt. Med., 40: 1011, 1954. 21. MAHEER, R. A.: Agranulocytosis complicating
effect of INH. Ztschr. f. Tuberk., 104: 61, 1954.
PAS and streptomycin therapy. U. S.
39. Woon, M. M.: Central nervous system complications (Chiefly Pellagra) during treatment of pulmonary tuberculosis. Brit. J.
Ann. Tnt. Med., 45: 541, 1956.
40. MANN, B.: Isoniazid Allergy. Brit. M. J., 59:
Armed Forces Med. Journal, 6: 1193, 1955. 22. ALT, W. J.: Severe systemic reactions to PAS.
23. HENSLER, H. M.: Hypersensitivity reactions
due to PAS. Am. Rev. Tubere., 76: 132, 1957.
24. PAINE, D.: Allergic reactions to PAS. Arch. Tnt. Med., 96: 768, 1955.
25. MADIGAN, D. G.: PAS in T.B. Lancet, 1: 239, 1950.
26. SANDLER, A.: Hypersensitivity to PAS. Brit. J. Tubere., 49: 231, 1955. 27. LUIPPOLD, E. J.: Dermatitis due to PAS. Ann. Allergy, 9: 97, 1951. 28. KIERLAND, R. R. AND CAIN, D. T.: Reactions
to PAS. Proc. Staff Meet. Mayo Clinic, 24: 539, 1949.
29. KORST, D. R.: Severe Reactions to PAS. Ann. Tnt. Med., 40: 1011, 1954. 30. FRIEDMAN, E.: Reactions to PAS., Am. Rev. Tuberc., 72: 833, 1953.
Tuberc., 49: 20, 1955.
685, 1957. 41. BIEHL, J. P. AND SHEvLEIN, J. H.: Toxicity of TNH. Am. Rev. Tuberc., 68: 296, 1953. 42. MORSE, W. C., CURRY, F. J., MORSE, P. 0., CHAMBERS, J. S. AND LINCOLN, A. F.: Tr.
15th Conf. on Chemotherapy of Tubercu-
losis V. A. Army and Navy, Page 283, 1956. 43. Cmssv, JOHN., OSBORNE, EARL, AND JORDAN,
J. W.: Eczematous complications in treatment of tuberculosis. J.A.M.A., 165: 1526,
1957. 44. MEARR, R. AND WEINRRICH, J.: Untersuchun-
gen zur Frage der Blutungeneigung wShrend
der Therapie mit Isonicotinsaure hydrazid.
KIm. Wochenschrift, 32: 212, 1954. 45. SCHWAETz, W. S. AND MAYER, R. E. Use of
TNH Alone in treatment of pulmonary T. B. Am. Rev. Tuberc., 70: 924, 1954.
DISCUSSION DR. S. War. BECKER (Long Beach, Calif.): I taking treatment for tuberculosis with INH and think this is important because it calls attention streptomycin and it seemed to me that they to the fact that with the newer drugs we are going presented dermatoses of functional rather than to have to look for drug eruptions which are not allergic origin. On investigation both INH and strictly allergic. streptomycin are potent neurotoxie or neuroDr. Ben Newman gave a talk at the Pacific allergic drugs. Dermatologic Association a couple of years ago We concluded (Becker, S. W., & Mounee, calling attention to this phenomenon. He pre- S. H.: Dermatoses in Patients Receiving Chemosented a patient who had been taking Miltown therapy for Systemic Tuberculosis, AMA Arch. for a long period of time with impunity. Sud- Dermat. 75: 333—344 (Mar) 1957) that the denly small petechial hemorrhages developed, got eruptions probably resulted from this neurotoxic worse and were relieved only by discontinuing or neuro-allergie action. Miltown. There is one difficulty in the treatment of When I first came to the VA Hospital in Long tuberculosis. You practically have to give the Beach there was a backlog of patients who were patients streptomycin or isonicotinic hydrazide
REACTIONS TO ANTITUBERCULOUS DRUGS
437
because there are as yet no substitutes for these different from those in patients without antitwo drugs; you can hyposensitize the individuals tuberculous medication. There are no characteristic aeneform lesions by injection (SM) or by mouth (INH) and in case the patient still has difficulty we have had developing in patients treated with antitubercusome success by giving the individuals half doses. bus drugs. Based on studies done many years Dn. RUDOLF BARR (New York, N. Y.): I ago in Switzerland and also on more recent would like to ask Dr. Bereston what technic he observations in this country I have found that used to hyposensitize with P.A.S. What proof patients with active pulmonary tuberculosis do was there that hyposensitization actually was not usually have acne at all or show a mild form achieved and were patients known to be sensitive of acne only. to P.A.S. but not "hyposeasitized" followed up DR. Louis H. WINER (Beverly Hills, Calif.): to see whether perhaps some of them spontane- In a histopathobogie study of the various drug ously lost their drug sensitivity, as is the ease in eruptions from urtiearial, papular, purpuric, some drug sensitizations? nodular, and even nodose type drug eruptions, Also were the patients who had become sensi- we found a characteristic fundamental histologic tive to P.A.S. cross-sensitive to other salicylates pattern primarily always involving the blood such as aspirin, as has been reported previously? vessel. These vessels showed intimal proliferation Dn. LAWRENCE C. GOLDBERG (Cincinnati,
with inhanging of the nuclei into the vessel
Ohio): I have been an attending dermatologist for some twenty years at a tuberculosis sanitarium in Cincinnati and long befere these newer drugs were used. The most common dermatosis in tubereulous patients was an aeneform eruption. These patients were admitted to the sani-
lumens. Unlike other allergic skin reactions where
vulgaris. After they had been there for a period of time, at least thirty per cent of these patients developed this type of eruption. I think we have to be careful in evaluating reactions to a drug. It is very simple to say a drug produced this or that reaction unless we have been following them for a long, long time. I have seen eruptions due to p-amino salieylic acid, but only a very few due
cases of erythema multiforme type of drug eruption, this edema is so intense as to be suggestive
one finds many eosinophils, we found them numerous only in two of a hundred eases we biopsied. Otherwise there was only a few eosinophils present. The predominant perivascular cell
was the lymphocyte. There is always a very tarium without aeneform eruptions or acne pronounced edema of connective tissue and in of diffuse myxedema.
I would like to ask Dr. Bereston if these cases of the acne vulgaris-like eruption showed vascular changes as I indicated.
DR. CARL T. NRLSON (New York, N. Y.): Apparently it has not been sufficiently empha-
to I.N.H. I suggest caution before making a sized that there is little relationship between diagnosis of aeneform eruption in patients who
hypersensitivity to ingested or injected drugs and
are in a tuberculosis sanitarium and taking the results of skin testing with such compounds. specific drugs. This is so generally the ease that I thought it
Dn. ALFERD HOLLANDRE (Springfield, Mass.): had been accepted that cutaneous testing is of I appreciate hearing Dr. Bereston's paper. It is little value in establishing the specific diagnosis my experience that except for generalized skin of a dermatitis medicamentosa. My question is, eruptions of morbilliform type no distinct pattern what prompted Dr. Bereston to engage in such exists to characterize skin eruptions caused by extensive skintestingprocedures during the course antituberculous drugs. Seborrheic dermatitis-like of this study? Wasn't he beating a dead horse? In reply to Dr. Baer, eross-semitivity between eruptions as reported 2 years ago by Osborne and p-amino salicylic acid and acetyl salicylie acid is his group and dyshidrotic eruptions develop not uncommon. without any etiologic connection with antituberDR, F. KALz (Montreal, Canada): I should culous therapy. In patients with dyshidrotie like to make one short remark: There is a very eczema of the hands discontinuation of antitu- extensive literature on the incidence of acne berculous drugs does not have any influence on vulgaris in patients with tuberculosis in sanithe course of the dyshidrotic eczema. Pattern and taria. Unfortunately, I am not in the position to course of these dyshidrotie eruptions are not quote references, but there are several dozens of
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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
reports, claiming a very high incidence of acne vulgaris among those patients, and it was claimed that 40 to 50% show this coincidence, though I recall no valid control series. This was of course long before the time of antituberculous drugs. I remember that some authors went as far as to claim that acne vulgaris must have in some cases a tuberculous etiology. DR. EUGENE S. BERESTON (in closing): I have a long list to answer. Dr. Becker was the first discusser. He mentioned the fact that he considers nummular eczema and seborrheic eczema
a number of months later, on follow-up, we found that the acne lesions had disappeared; in some of these individuals I was able to reinstitute therapy with the drugs and the acne reappeared in one to two months. It was my belief and the concensus
were seen, were not truly neurodermatoses. I felt
edema for the most part except in the area where
of the other physicians in our hospital that we were dealing with a drug toxicity type of acne rather than just a coincidental acne developing in a tuberculous patient on a high carbohydrate diet. The incidence of acne in patients in the hospital with the same diet and not receiving INH and PAS was 1%. as being so-called functional or neurodermatoses. Dr. Winer was asking about the histologic Dr. Hollander expressed the opposite view- picture in some of these drug eruptions. In the point and it was my feeling that most of the acneform drug eruption, which was described, nummular eczema and seborrheic eczemas that there was very little evidence of connective tissue that most of these cases were similar to those an abscess was present in the cutis with zonal seen in non-tuberculous patients not under drug edema. But the rest of the dermis showed very treatment, and that they could just as easily not little edema. However, I would say that in most be neurodermatoses as he intimates. Dr. Baer asked about the follow-up on patients
of the so-called dermatitis medicamentosa, lesions due to sensitivity that were biopsied, considerable
reacting to PAS. Some of these patients do
tissue edema was seen. Occasional eosinophils and lymphocytes were much in evidence, especially in perivascular arrangement. This is not true however, for the acneform eruptions. Dr. Nelson asked why did we do intradermal and patch tests on our patients? First of all, we
spontaneously desensitize themselves while under treatment or after cessation of treatment and reinstitution of it; and there are case reports in
the literature to that effect that even though treatment is continued in the people with PAS reaction, the mild and moderate ones can continue on therapy with the drug. This is also true of streptomycin in some instances where the eruptions are mild and the person is not very ill,
did them to see whether we could tie up the intradermal test and the patch test with the development of dermatitis medicamentosa and thus predict reactors. Originally we wanted to see
that continuation of the drug therapy results if a person could be followed from the time he apparently in spontaneous desensitization even started treatment and observed whether there though the drug is being continued. This, of was any change in the patch or intradermal testcourse, is not true in the more severe reactions with either drug.
ing in the course of the therapy which lasted from
In answer to the question about PAS and
point of curiosity to see whether we could predict which individual would develop sensitization and which individual would not. As you can see, as Dr. Nelson mentioned, the
Aspirin, I can say that we have had some individuals who have reacted first to PAS and then later to Aspirin when given to them for some
six months to a year or longer. This was just a
results were inconclusive. We were not able to other reason. predict these things. We did not find out which Dr. Goldberg asked about, and so did several patient would develop a reaction because the other people, the incidence of acne in tuberculosis
sensitization on testing appears to be extremely sanitaria. I can only say that most of the indi- low with all the antituberculous drugs. viduals that were seen, developed acne within a The question of acne in tuberculosis is in the specific period while under therapy. If we dis- older literature and I looked very thoroughly in continued the drug therapy when possible, or if all the literature, but found very little written on the patient was finally discharged with an active acne in relation to tuberculosis, at least in this acne and we saw them after they wer' off drugs country. Acne as a drug eruption to the anti-
REACTIONS TO ANTITUBERCULOTJS DRUGS
439
tuberculous drugs has never been described. I absence of acne in other patients treated with discussed this with many of the internists in other drug combinations with the same diet and Baltimore, and they felt that the acneform le- environment and the production of acne with the sions in tbe incidence we had, about 16 per cent drugs and its disappearance on stopping the drugs of the patients, on tbe 2 drugs, would be con- plus its reappearance on starting the same drugs sidered rather high in an ordiaary tuberculosis again, led to the conclusion that the acne was a sanitarium even with the enriched diets. The near form of drug eruption.
THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
94
linolenic acid extract. Arch. This pdf is a scanned copy UV of irradiated a printed document.
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