Toxic Dermatoses

North America Medical Clinics of N ortb A111erica January, 1942. Chicago Number

TOXIC DERMATOSES M.O.· MAX S. WIEN, M.D.·

THAT certain dermatoses are of toxic origin is well estabTHAT lished. Eruptive lesions of varied character may follow the ingestion of certain foods or drugs in some individuals. The frequency of drug eruptions has greatly increased in the past decade with the introduction of a large number of new synthetic drugs to the therapeutic armamentarium of the physserunlS and sulfonamides are ician. The coal tar derivatives, serums well recognized by most practitioners as being capable of producing toxic eruptions in certain persons. SKIN ETIOLOGY OF THE ERYTHEMA E R Y THE M A GROUP OF. SKI N DISEASES

In the clinic today, in addition to the aspects mentioned, ~ruptions in their broadest aspects, inI shall discuss toxic eruptions cluding allusion to the broad concept of the toxic erythema group of dermatoses discussed by Osler, ll when he stressed the occurrence of certain eruptions that were related to vascular lesions. These eruptions are sometimes sometinles associated with joint pains and exceptionally with effusion in and about the joint. In a small proportion of cases the mucous membrane of the mouth is also affected. It is very important that practitioners recognize that certain cutaneous eruptions, in many instances, are visible morphologic manifestations that are intimately related to certain underlying constitutional conditions. By cataloging these eruptions properly and by recognizing their role in visceral diseases, this visible linl{ link (in the skin) can be readily utilized as a diagnostic aid. With a full appreciation of this enlarged concept in medicine, the taunt of some medical practitioners "that dermatology is a •.. Associate Professor of Dermatology, University of Illinois College of Medicine; Attending Dermatologist, Michael Reese Hospital; Professor of Dermatology and Syphilology, Cook County Graduate School of Medicine. 139

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specialty with long names and conditions that are treated with calamine lotion" will cease to "hold water." W eiss, 22 in an excellent discussion on "The Engman and Weiss, Erythema Group of Skin Diseases," said: "There undoubtedly exists a close clinical, pathologic and etiologic relationship between the following conditions: urticaria, erythema multiforme, dermatitis herpetiformis, pemphigus, purpura and certain types of cutaneous gangrene. These so-called clinical entities should probably be included in one group on account of the fact that various etiologic factors may cause the same type of these eruptions or anyone etiologic factor may cause varied types of these eruptions. It is also highly probable that certain types of lupus erythematosus disseminatus and the scarlatiniform or toxic erythemas should be included." OsIer for the best They state that "we are indebted to Osler point of view of this group of diseases, as he has ShOWl1 shown its relation to general medicine, and that the cutaneous symptoms are, in many cases, only a symptom of various constitutional conditions or diseases of the internal organs. However, attention had previously been called to the apparent relationship by Gilbert, Rayer, Besnier and Doyon, and others, but not so forcibly as in the masterly series of articles by Osler." OsIer." The data from Engman and Weiss, given in Table 1, on the etiology of the erythema group, will indicate to the practitioner the extent and diverse character of the etiologic effiorescences that agents in the production of cutaneous efflorescences may be dependent upon the action of noxious agents on the vascular endothelium at the affected site. It will be seen that under the head of "Eruptions of Toxic Origin" are a vast number of cutaneous entities, some of which are manifestations of the vascular injury due to food, micro-organisms, serums or vaccines in diseases of the viscera, ll and another group that may be due to the ingestion or injection of certain drugs. The acute exanthemata are not inmarked cluded because they are characterized by such well marl{ed common features as a definite course and general constitutional disturbances that they form an easily separable group and are well recognized by all. The toxic eruptions of which

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I shall speak are those due to drugs and certain eruptions for which we are usually unable to ascribe a definite cause but which we know are caused by toxins and deserve a place in the group of toxic eruptions, e.g., urticaria, purpura and erythema no,dosum. nodosum. TABLE 1

ETIOLOGY O~ OF.. THE ERYTHEMA GROUP2 GROUP"

Foods Helminths

Endocrine ~~~~crine Liver Disease of the in- Kidney ternal organs..... Lungs Pleura Uterus

l

Drugs Serums

Foci. .. . . .. Foci . . . . . . .'..

Vaccines Burns

Internal origin. ... origin....

Micrc~-organisms .... Micn~-organisms....

j Il l

Arthritis Vaccinia Pyorrhea, etc. Nasal Tonsil Urethra Visceral

Typhoid Rheumatism Syphilis . . Malaria Micro-organisms.... Micro-organisms. . . . Streptococci Exanthemata Other u~known ~,known orgamsms organIsms

!

i~~~~tism

I

ll

Toxins ........... Toxins. . . . . . . . . . ...

Diphtheria Tetanus Botulism Plague Pyocyaneus Other unknown organisms

Pregnancy Hydatid { Involution growths.... New growths. . . . . .. Necrosis Radiotherapy Breaking down of pathological tissue DRUG ERUPTIONS

A number of eruptions are produced in susceptible persons by absorption and hematogenous spread of a drug or its split product following ingestion or injection of the drug. 33 In

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TABLE 2 MORPHOLOGIC CLASSIFICATION OF DRUG ERUPTIONS, WITH CAUSAL DRUGS

Erythematous eruptions Papular ......... . Macular and patchy ....

Morbilliform .... Scarlatiniform ....

(after MacLeod)

. .. Antipyrine; belladonna; bismuth; chloralamide; copaiba; cubebs; gold; iodides; phenacetin, etc. . Animal serum; antipyrine; arsenic; belladonna; bismuth; bromides; chloral; chloralamide; copaiba; cubebs; gold; iodides; morphine; opium; phenacetin; potassium chlorate; quinine; salicylates; turpentine. turpentine . . . . Animal serum; antipyrine; arsenic; belladonna; copaiba; cubebs; luminal; sulfonal; turpentine; sulfanilamide . sulfanilamide. . . Animal serum; antipyrine; arsenic; belladonna; chloral; copaiba; cubebs; hyoscyamus; luminal; opium; pilocarpine; sulfonal; turpentine.

Exfoliative dermatitis ... . Chrysarobin and derivatives and tar externally; Secondary erythrodermia ..... arsenic and gold by injection; luminal and sulfanilamide. Urticarial eruptions . ........... Animal serum; arsenic; bromides; copaiba; cubebs; Urticaridl iodides; luminal; mercury; opium; phenacetin; phenolphthalein; quinine; salicylate of sodium; santonin; turpentine, etc.; sulfonamides. . . Antimony; antipyrine; arsenic; bromides; chloral; Vesicular eruptions .. copaiba; gold; iodides; phenolphthalein; quinine; turpentine; etc. Herpetic eruptions (Herpes zoster or Herpes simplex) .................... ... Arsenic. Bullous eruptions .... _......... Antipyrine; bromides; chloral; iodides; opium; quinine; salicylates; sulfanilamide; etc. Polymorphous eruptions of the multiforme type . .... Animal serum; antipyrine; chloral; copaiba; cuerythema multiforme bebs; iodides; opium; potassium chlorate; etc. eruptions. . . . .. Antimony; antipyrine; arsenic; bromides; iodides; Pustular eruptions , opium; salicylates; turpentine. (Of these the most common causes are bromides and iodides.) Acneform .................. Antipyrine; arsenic; bromides; chloral; iodides; opium. Ulcerative fficerative .................. Arsenic; bromides; chloral hydrate; iodides. Condylomatous or Anthracoid Bromides; iodides. Gangrenous ................ Arsenic; iodides; quinine. Purpuric and petechial eruptions.Animal serum; antipyrine; bromides; copaiba; ergot; iodides; potassium chlorate; quinine; salicylates; sulfonal; sulfathiazole; estrogenic substances. Keratotic eruptions eruptions. . . . .. Arsenic; bismuth. Kera/otic Pigmented eruptions . .......... Arsenic; gold; silver nitrate; phenolphthalein.

some cases there appears to be an idiosyncrasy and small doses ,viII will produce an eruption, while in others large doses or administration of the drug over a prolonged period

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(cumulative effect) are necessary before the eruption appears. The skin eruption may at times be the only symptom but it is also often accompanied by mucosal lesions and by constitutional symptoms, e.g., headache, nausea, vomiting and diarrhea. Drug eruptions most commonly involve the trunk and extremities and are usually generalized, profuse and symmetrical, with a predilection for the dependent portions of the body. Table 2 indicates the morphologic characteristics of certain drug eruptions, and enumerates some of the causal drugs. Phenolphthalein Some years ago I saw an Indiana physician, aged fifty attaCKS of coin size, polychroyears, who had had recurring attacks matic, ecchymotic lesions on the trunk and extremities. After a very thorough "going over" by his colleagues at home and the finding of cloudy sinuses on the x-ray plates, they had decided he had erythema multiforme with sinus infection as the focus. The consulting otolaryngologist to whom he was referred did not feel that that there was enough evidence of sinus infection to warrant radical operative treatment of his sinuses skin and referred him to me for an opinion regarding the sl{in lesions. In any case of drug eruption when the index of suspicion of a drug as the causal agent is high, based upon one's knowledge that a certain morphologic picture in the skin is often due to the ingestion of certain drugs, it becomes necessary for the physician to assume the role of a detective and question his patient very carefully regarding the ingestion of any type of drug and particularly certain proprietaries. Unfortunately, many patients do not look lool{ upon pills or tablets taken for constipation as medicine and, since many of these proprietaries contain phenolphthalein44 and this drug is capable of producing a characteristic eruption in the skin, one must check and re-clleck re-check the l1istory history of drug ingestion with the patient. Upon close questioning of the patient under consideration, it was found that he had been in the llabit habit of pouring phenol-

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phthalein powder into the palm of his hand and then taking up these unmeasured doses with his tongue and swallowing them with a draught of water. He had been doing this for a long period of time. When it was pointed out to him that the eruption he presented was compatible with that produced by phenolphthalein and was most probably related to drug ingestion rather than a focus of infection in his sinuses, he recalled a definite "time relation" between the cutaneous efflorescence and the ingestion of phenolphthalein. The eruption cleared when the phenolphthalein was discontinued. Later a colleague in St. Louis informed me that the patient had consulted him concerning a recurrence that came on shortly after the funher further ingestion of phenolphthalein for constipation. I wish to re-emphasize the need for questioning and re-quesre-qzlestioning with great patience any individual in whom you suspect a drug eruption. This patient fulfilled the criteria for diagnosis of a drug eruption, viz., improvement on withdrawal of the drug and a flare-up or recurrence of the eruption upon the re-ingestion of the drug. Bromides

A woman, aged fony-seven forty-seven years, had been suffering with nervousness and insomnia for a period of weeks, for which she consulted a physician who prescribed a medicine internally. She subsequently developed furunculoid nodules over the tibiae. Another physician was called, after the skin erupasI{ed for dertion appeared, who suspected pemphigus and asked matologic consultation. When first seen by me the patient presented erythematous nodular lesions on the lower extremities. When questioned about drug ingestion she stated that she had taken no medicine except a sedative for the past six weeks. On checking this sedative we found, found. it contained bromides (Syrupus bromidorum, N.F.) and the cutaneous eruption fitted into the picture of a bromide eruption and bore a definite time relation to the previous ingestion of the medicament. On withdrawal of this sedative and the adminisn1edicament. tration of fluids and sodium chloride, the eruption cleared.

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Barbiturates

A white ~an, aged forty-eight years, had been operated upon for ureteral stone. He received a barbiturate for postgel1operative insomnia and shortly afterwards developed a generalized erythematous eruption, with the greatest involvement on the dependent portions of the body. The eruption promptly cleared on withdrawal of the drug. Sulfonamide Group

The lit~rature lit~rature is full of reports of varied cutaneous eruptions55 ,• 7 resulting from the wide use of the excellent chemotherapeutic agents in the sulfonamide group, and I have emphasized in a recent article 55 the need for recognizing these cutaneous manifestations in order to give security in the prescribing of these valuable drugs and prevent baneful effects from their use by early recognition of the toxic manifestations. URTICARIA

The eruption known as urticaria, or "hives," which is due to a variety of causes, is well known to all of you. The characteristic wheal, which in most instances is the only essential lesion, appears rapidly, mayor may not be associated with erythema and is usually associated with severe itching. The condition is frequently self-diagnosed by the patient, who will come in and say, "Doctor, I have the 'hives' which I believe are due to some strawberries or shellfish I ate yesterday." With this history, where there is a characteristic eruption and a definite time relation between the ingestion of some unusual article of diet and the appearance of the eruption-and in some cases associated gastro-intestinal distressthe diagnosis is easy and it is only necessary for the physician to institute the proper topical and internal therapy to alleviate the condition which, as a rule, promptly subsides. In certain chronic urticarias the problem is more complicated and bowel infection66 and the emotioris emotions88 must be investig;ted g~ted and ruled out as causal agents. Drugs, e.g., aspirin and the sulfonamides, may also be responsible.

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PURPURA

Purpura is included in the broad conception of the erythema group;2 it is an eruption of reddish or purplish spots due to multiple nodular hemorrhages into the skin or mucous membranes. Purpura is a physical sign and not a disease, and may occur in a large nUlnber number of conditions as revealed by Table 3. TABLE 3 PURPURA: TYPES AND ETIOLOGIC FACTORS (from Tidy, slightly modified) Primary Purpura Purpura simplex rheumatica}A th ·f Purpura rheum.atica}A Henoch's purpura r nn IC purpuras Purpura hemorrhagica Purpura fulminans For details of these diseases a textbook of medicine should be consulted.

Purpltra Secondary and Symptomatic Purpttra 1. Specific infectious fevers ...... Typhus, always. Smallpox, frequently. Cerebrospinal meningitis, frequently. Scarlet fever, in severe cases. Measles, in in severe cases. fe,"er, rarely. Typhoid fe\'er, Other diseases, occasionally. 2. Septic infections ............. Infective endocarditis, frequently. Septicemia. Pyemia. Pyenlia. 3. Blood diseases ............... Leukemia, especially the acute form. Aplastic anemia. Pernicious anemia, rarely. scrums. 4. Toxic conditions ............. Snake poison; serums. 5. Drugs, etc S. etc.. . . . . . . . . . .... Chloral; copaiba; quinine; belladonna; iodides; nitroglycerin; neosalvarsan, neosa]varsan, rarely. 12 Sulfonamides, occasionally. Estrogens.12 6. Constitutional and cachectic conditions ................. Scurvy; chronic nephritis; carcinoma; tuberculosis; old age. 7. Severe jaundice from any cause 8. Nervous diseases, rarely ....... Tabes, peripheral neuritis, hysteria. 9. Mechanical causes ............ Venous stasis, due to tight bandages; varicose veins; failing compensation in heart disease; on first standing up after long illness; paroxysms of whooping cough or epileptic attack. l3 10. Allergy in relation to purpura.13

In evaluating the purpuras it is important to include the hemorrhagic types, acute specific fevers, drug ingestion severe henlorrhagic or injection, scurvy, infectious endocarditis, and blood dyscrasias.

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ERYTHEMA NODOSUM

Erythema nodosum may occur as a definite affection with the appearance of subcutaneous nodules, which are usually symmetrical, and distributed over the legs anteriorly. The nodu~es are red and painful and may have the varied color nodu!es changes of a bruise and may come out in crops. They never ulcerate or breal{ break down, and may occur as part of the erythema group of skin diseases. 22 Erythema nodosum-like lesions may also be produced by lOb micro-organismslob and by drugs 77 and are occasionally seen in association with lymphogranuloma inguinale. lOa In adults99 the condition is commonly associated with rheumatoid pains. Its association with rheumatoid symptoms has been discussed Skiold,1l who in a study of 128 adu!ts adu~ts with erythema by Skiold,o nodosum found 21 per cent who showed symptoms and signs of arthritis. A concomitant rheumatoid involvement of the heart was demonstrated in two patients. Erythema nodosum has also been described as a toxic eruption from the use of sulfonamides. 77 Erythema nodosum may occur, especially in children, as part of a toxic eruption due to the bacillus of tuberculosis (tuberculid) . TUBERCULIDS

Cutaneous tuberculosis is of great importance to practitioners as a link between dermatology and general medicine. importance of recognizing the I want to emphasize the inlportance morphology of skin eruptions that may be cutaneous manifestations of a toxic reaction to a latent or manifest focus of tuberculosis in the sys'tem system and to urge you to make diligent clinical and laboratory investigation for a focus of tuberculosis in any patient presenting tuberculid-like lesions. \Vhen tuberculosis is present, these lesions are spontaneous examples of Koch's phenomenon resulting from endogenous inoculation of the skin. Lack of time precludes my discussing in detail the more than twenty-two cutaneous entities, listed by Senear,l1 Senear,11 which mayor may not relate to an underlying tuberculosis. Their presence, at least, should make the practitioner suspect the presence of a latent or manifest focus of

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tuberculosis until he has completely ruled it out by proper clinical and laboratory examination. Examples are given in Table 4 of tuberculid and other lesions which require differentiation. I suggest that you refer to any of the standard textbooks on dermatology for a detailed discussion of these entities so that you may be familiar with their pictures. u TABLE 4411 TUBERCULID AND OTHER SKIN LESIONS WHICH REQUIRE DIFFERENTIATION

Lichen scrofulosorum Papulonecrotic tuberculids (a) Acnitis Folliclis (b) Follic1is Erythema induratum Acne scrofulosorum Acne varioliformis Acne cachecticorum Sarcoids . (a) Multiple benign sarcoids of Boeck (b) Subcutaneous sarcoids of Darier-Roussy (c) Erythema induratum-like sarcoids of the extremities

Lupus pernio Lupus erythematosus 2,14 Lichen nitidus Granuloma annulare Angiokeratoma (Mibelli) Pityriasis rubra (Hebra) Pityriasis rubra pilaris ' Erythema nodosum Erythema multiforme Purpura Parapsoriasis Eczema scrofulosorum

You will note that erythema nodosum is in the above list, and in children the occurrence of erythema nodosum must be given particular attention since it often represents a spontaneous example of Koch's phenomenon resulting from endogenous inoculation of the skin. The incidence of tuberculosis in children with erythema nodosum is so high that some writers have concluded that it represents active invasion; invasion' of the skin by the tubercle bacilli or its toxin, and might be a prodromal sign of an acute tuberculous septicemia and terminate in a fatal meningitis. BIBLIOGRAPHY

OsIer, Sir William: Brit. J. J. Dermat., 12: 227, 1900, and Amer. J. J. Med. 1. Osler, Sc., Vol. 127, 1904. 2. Engman, M. R. and Weiss, R. S.: The Erythema Group of Skin Diseases. Arch. Derm. & & Syph., 12: 325 (Sept.) 1925. 3. Loveman, A. B.: Allergic Drug Eruptions. J. Allergy, 11: 48 (Nov.) 1939. 4. Belote, G. H. and Whitney, H. K.: Phenolphthalein Compounds. Arch. Derm. & Syph., 36: 279 (Aug.) 1937.

5. Wien, M. S. and Lieberthal, E. P.: Pemphigus Foliaceus-like Toxic Reaction Following Sulfonamides. J.A.M.A., 117: 850 (Sept. 6) 1941.

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6. Traut, Eugene F.: Management of Intractable Urticaria. Arch. Derm. & Syph., 40: 368 (Sept.) 1939. 7. Volini, I. F., Levitt, S. O. and O'Neil, H.: Cutaneous and Conjunctival Manifestations of Sulfathiazole Intoxication. J.A.M.A., 116: 938 (Mar. 8) 1941.

8. Stokes, John H.: Psychoneurogenous Reactions of the Skin. Arch. Derm. & Syph., 42: 780 (Nov.) 1940. 9. Skiold, N.: Rheumatic Symptoms in Patients with Erythema Nodosum. Nord. med. tdskr., 15: IS: 595 (Apr. 15) 1938. lOa. Wien, M. S.: Lymphogranuloma Inguinale. In Modern Urology Vo!. 1, p. 234. (Cabot), Lea & Febiger, Philadelphia, 1936, Vol. lOb. Jadassohn, Samek and Fischer, Ulcus Vulvae Acutum Associated with Lesions of the Mouth. Quoted by Wien, M. S. and Perlstein, M. O. in J.A.M.A., 98: 471 (Feb. 6) 1932. 11. Senear, Francis E.: The Importance of the Tuberculides in Medical Diagnosis. Contributions to Medical Science, Dedicated to Alfred Scott Warthin, 1927, pp. 319-331. 12. Loftis, E. L.: Purpura Due to Injection of Estrogenic Substance. Arch. Derm. & Syph., 42: 138 (July) 1940. 13. Thomas, J. W. and Forsythe, J. R.: Allergy in Relation to Purpura. J. Lab. & Clin. Med., 26: 1105 (April) 1941. 14. Symposium on Lupus Erythematosus. Proc. Staff Meet. Mayo Clin., Vol. 15, No. 43.