Drug reactions

P e r i o d i c svnopsis IIIII I

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III

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I II

This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data; and the results of future studies may require alteration of the conclusions or recommendations set forth in this report.

Drug reactions Robert S. Stern, M.D.,* Bruce U. Wintroub, M.D.,** and Kenneth A. Arndt, M.D.* Boston, MA, and San Francisco, CA

In this periodic synopsis we present recent literature and some classic references on various topics related to drug eruptions, including articles that review the results of the American Academy of Dermatology's Adverse Drug Reaction Reporting System (ADRRS). This system permits dermatologists both to share their experience with adverse reactions to drugs and to obtain information about such reactions as contained in this registry and in the medical literature. Reports to the ADRRS can be made using a toll-free telephone line: 1-800323-1473, 24 hours a day, 7 days a week. This system is a function of the American Academy of Dermatology (AAD). Reporter and patient confidentiality are assured. This synopsis concentrates on literature about adverse drug reactions published after 1981. Several classic articles published prior to 1981 are included. For information that summarizes drug reaction experience up to 1982, and for good reviews of pathophysiology, we suggest the following book chapter, which will be published in 1986, and review articles.

From the Department of Dermatology, Harvard Medical School and Beth Israel Hospital, Boston,* and the Department of Dermatology, University of California, San Francisco.** Repdnt requests to: Dr. Robert S. Stem, Department of Dermatology, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02214.

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I. General A. Wintroub BU, Amdt KA, Stern RS: Adverse cutaneous reactions to drugs, in Fitzpatrick TB, et al, editors: Dermatology in general medicine, ed. 3. New York, McGraw-Hill Book Co. (In press.) B. Wintroub BU, Stern R: Cutaneous drug reactions: Pathogenesis and clinical classification. J AM ACAD DERMATOL13:167-179, 1985. C. Kaplan AP: Drug-induced skin disease. J Allergy Clin Immunol 74:573-579, 1984. D. VanArsdel PP Jr: AUergy and adverse drug r e a c t i o n s . J A M ACAD DERMATOL 6:833-845, 1982. II. Drug use A. Baum C, Kennedy DL, Forbes MB, Jones JK: Drug use in the United States in 1981. JAMA 251:1293-1297, 1984. This study provides national estimates of outpatient prescription drug use by patient age and sex, geographic region, and physician specialty. Data are presented for the most frequently used drug categories and therapeutic classes. B. Kennedy DL, Forbes MB: Drug therapy for ambulatory pediatric patients in 1979. Pediatrics 70:26-29, 1982. Anti-infective drugs and cough and cold preparations accounted for approximately 50% of drugs used in patients aged 0 to 9. In spite of permanent discoloration to permanent teeth that can result from childhood

Volume 15 Number 6 December, 1986 use, tetracycline and its congeners continue to be used in pediatric patients. III. Epidemiology, incidence, and reaction type A. Amdt KA, Jick H: Rates of cutaneous reactions to drugs. A report from the Boston Collaborative Drug Surveillance Program. JAMA 235:918-923, 1976. Rates of skin reactions to commonly used drugs were estimated from data obtained on medical inpatients. A total of fifty-seven drugs were implicated with skin reactions. Five or more reactions were attributed to each of twenty-two drugs (or drug groups). The study provides drug-specific quantitative data on drug-induced rash, itching, or hives in hospitalized patients. B. Kauppinen K, Stubb S: Drug eruptions: Causative agents and clinical types. A series of inpatients during a 10-year period. Acta Derm Venereol (Stockh) 64:320-324, 1984. This study is an update of the classic study in which patients with drug eruptions were rechallenged. Data on the relative frequency of cutaneous reactions of different morphologic types seen in a university setting are also provided. IV. The ADRRS and voluntary reporting A. Stem RS, Bigby M: An expanded profile of cutaneous reactions to nonsteroidal anti-inflammatory drugs. Reports to a specialtybased system for spontaneous reporting of adverse reactions to drugs. JAMA 252:14331437, 1984. This study illustrates results that can be obtained when dermatologists pool their observations using the AAD ADRRS, a voluntary Academy-sponsored effort. V. Clinical assessment of drug eruptions A. Kramer MS, Leventhal JM, Hutchinson TA, Feinstein AR: An algorithm for the operational assessment of adverse drug reactions. I. Background, description, and instructions for use. JAMA 242:623-632, 1979. The key steps in assessing if a given drug is likely to be responsible for a reaction include (1) previous general experience with the drug, (2) alternative etiologic candidates, (3) time of events, (4) drug level, and (5) results of dechallenge and rechallenge.

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B. Leventhal JM, Hutchinson TA, Kramer MS, Feinstein AR: An algorithm for the operational assessment of adverse drug reactions. III. Results of tests among clinicians. JAMA 242:1991-1994, 1979. VI. Mechanism of drug reactions A. de Weck AL: Pathophysi01ogic mechanisms of allergic and pseudo-allergic reactions to foods, food additives and drugs. Ann Allergy 53:583-586, 1984. Allergic reactions elicited by drugs may be based on one or several of the following immunopathologic mechanisms: (1) specific IgE bound to mast cells and/or basophils, (2) antigen-IgE soluble complexes hitting various target cells, (3) antigen-IgG complexes generating anaphylatoxins, (4) generation of anaphylatoxins by alternative pathway complement activation, (5) release of mast cell mediators by other direct triggering mechanisms (e.g., basic peptides), (6) effects on other target cells such as neutrophils and platelets, and (7) reactions mediated by specific effector lymphocytes. B. Yancey KB, Lawley TJ: Circulating immune complexes: Their immunochemistry, biology, and detection in selected dermatologie and systemic diseases. J AM ACAD DERMATOL 10:711-731, 1984. Circulating immune complexes (CICs) are a heterogeneous group of immunoreactants formed by the union of antigen and antibody. Drug-induced immune complexes probably play an important role in the pathogenesis of serum sickness and cutaneous necrotizing vasculitis. C. Mitsuyasu R, Gr0opman J, Volberding P: Cutaneous reaction to trimethoprim-sulfamethoxazole in patients with AIDS and Kaposi's sarcoma. N Engl J Med 308:15351536, 1983. Patients with immunologic disorders such as acquired immunodeficiency syndrome (AIDS) may have far higher rates of developing cutaneous reactions to certain drugs. D. Lewis PS: Sexually transferred drug adverse reaction to isosorbide dinitrate cream. Lancet 1(8339):1441, 1983. (Letter to Editor.)

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Drugs administered by any route can cause an adverse reaction. E. Spielberg SP, Gordon GB, Blake DA, et al: Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 307:722725, 1981. Phenytoin hypersensitivity syndrome is associated with an inherited deficiency of epoxide hydrolase, an enzyme that detoxifies a toxic arene oxide intermediate derived from phenytoin. Thus, this clinical syndrome may result from an inherited enzyme deficiency. VII. Toxic epidermal necrolysis A. Westly ED, Wechsler HL: Toxic epidermal necrolysis. Granulocytic leukopenia as a prognostic indicator. Arch Dermatol 120: 721-726, 1984. Drug-induced toxic epidermal necrolysis is a disease of severe morbidity and high mortality. In the ten cases reported herein, the administration of corticosteroids was of no apparent benefit and may have been detrimental. Young age seemed to have a favorable influence on survival. Severe granulocytopenia is a poor prognostic factor. Persistence of the granulocytopenia portended a fatal outcome. B. Leads from the MMWR. Revised recommendations for preventing malaria in travelers to areas with chloroquine-resistant Plasmodiumfalciparum. JAMA 253:2483-2486, 1985. Fansidar has been implicated in toxic epidermal necrolysis. This finding of severe cutaneous reaction, documented by the ADRRS, resulted in the Centers for Disease Controls changing its recommendations about Fansidar's use for travelers to malarial areas. C. Hurwitz RM, Rivera HP, Gooch MH, et al: Toxic shock syndrome or toxic epidermal necrolysis? Case reports showing clinical similarity and histologic separation. J AM ACAD DERMATOL 7:246-254, 1982. These two diseases may be difficult to distinguish on clinical grounds alone. Diagnostic distinction is important because therapy differs considerably. A skin biopsy can be helpful in establishing the correct diagnosis. There is superficial perivascular dermatitis in

Journal of the American Academyof Dermatology

toxic shock syndrome and an interface dermatitis for toxic epidermal necrolysis. VIII. Erythema multiforme A. Huff JC, Weston WL, Tonnesen MG: Erythema multiforme: A critical review of characteristics, diagnostic criteria, and causes. J AM ACAD DERMATOL8:763-775, 1983. Excellent review. Only a limited number of factors are reasonably well documented as possible precipitating agents of erythema multiforme. Recurrent herpes simplex is an important etiologic factor in erythema multiforme minor. Mycoplasmal infections and drugs may be associated with erythema multiforme major (e.g., more severe and with mucous membrane involvement). B. Howland WW, Golitz LE, Weston WL, Huff JC: Erythema multiforme: Clinical, histopathologic, and immunologic study. J AM ACAD DERMATOL10:438-446, 1984. In a prospective study of erythema multiforme, only 10% were related to administration of drugs. Sulfa-associated erythema multiforme was a nonrecurrent illness with widespread cutaneous and mucosal damage associated with prominent histologic necrosis of epidermal cells. Although herpes and drug-related erythema multiforme may have somewhat clinical and histologic features, there is significant overlap in the pattern of tissue damage. C; Ruiz-Maldonado R: Acute disseminated epidermal necrosis types 1, 2, and 3: Study of sixty cases. J AM ACADDERMATOL13:623635, 1985. D. Guill MA, Goette DK, Knight CG, et al: Erythema multiforme and urticaria. Eruptions induced by chemically related ophthalmic anticholinergic agents. Arch Dermatol 115:742-743, 1979. Scopolamine hydrobromide ophthalmic drops induced erythema multiforme. Tropicamide, an anticholinergic ophthalmic preparation, also caused a generalized urticarial eruption when administered to the same patient. E. Genvert GI, Cohen EJ, Donnenfeld ED, Blecher MH: Erythema multiforme after use

Volume 15 Number 6 December, 1986

of topical sulfacetamide. Am J Ophtbalmol 99:465-468, 1985. F. Ansel J, Petrozzi JW, Kumar V: Possible drug-induced pemphigus-like antibodies with the clinical manifestation of erythema multiforme. Arch Dermatol 119:1006-1009, 1983. A patient with bullae and target lesions on the extremities and mucous membranes was seen with the clinical picture of erythema multiforme. He had high titer of intercellular circulating antibodies, but direct lesional immunofluorescence microscopy study results were negative, suggesting that they might be related to the observed drag eruption. G. Fitzpatrick JE, Thompson PB, Aeling JL, Huff C: Photosensitive recurrent erythema multiforme. J A M ACAD DERMATOL9:419423, 1983. This includes a case report of photosensitive recurrent erythema multiforme occurring in a 31-year-old man not using drags. Lesions clinically and histologically resembling erythema multiforme were reproduced with light testing, suggesting an alternative form of erythema multiforme. IX. Photosensitivity A. Chalmers RJ, Muston HL, Srinivas V, Bennett DH: High incidence of amiodarone-induced photosensitivity in North-west England. Br Med J [Clin Res] 285(6338):341, 1982. Amiodarone is a potent phototoxic drug used in the treatment of cardiac arrhythmia and is now available in the United States. B. Bruce S, Wolf JE Jr: Quinidine-induced photosensitive livedo reticularis-like eruption. J AM ACAD DERMATOL12:332-336, 1985. A man who was taking quinidine developed a purpuric eruption in a photodistributed liredo reticularis-like pattern, an unusual pattern for photosensitivity. C. Stern RS: Phototoxic reactions to piroxicam and other nonsteroidal antiinflammatory agents. N Engl J Med 309:186-187, 1983. (Letter to Editor.) Piroxicam (Feldene) can cause a distinctive vesiculobullous or eczematous photosensitivity eruption. This was first documented by

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the combined efforts of dermatologists reporting to the ADRRS. D. Morison WL, McAuliffe DJ, Parrish JA, Bloch KJ: In vitro assay for phototoxic chemicals. I Invest Dermatol 78:460-463, 1982. A new, in vitro, test system based on lymphocyte testing has potential as a predictive assay for detecting additional phototoxic chemicals. X. Drugs of special interest A. Nonsteroidal anti-inflammatory agents Bigby M, Stern R: Cutaneous reactions to nonsteroidal anti-inflammatory drugs. J AM ACAD DERMATOL12:866-876, 1985. Review article incorporating the results of the ADRRS. B. Insulin Grammer LC, Metzger BE, Patterson R: Cutaneous allergy to human (recombinant DNA) insulin. JAMA 251:1459-1460, 1984. Even human (recombinant DNA) insulin can cause cutaneous allergies. C. Heparin vs coumarin necrosis Shelley WB, S~iyen JJ: Hepadn necrosis: An anticoagulant-induced cutaneous infarct. J AM ACAD DEgMATOL 7:674-677, 1982. A rare complication of subcutaneous heparin therapy is the development of a large, erythematous, tender plaque in the skin overlying the injection sites. Skin testing revealed that the patient had a delayed type of hypersensitivity to heparin. In contrast to coumarin necrosis, heparin necrosis is felt to be a thrombotic phenomenon resulting from immunologically induced platelet aggregation in heparin-sensitive patients. Thrombocytopenia is usually present. The diagnosis can be confirmed by tests for platelet aggregation and calls for immediate cessation of the heparin injections. D. Chemotherapeutic agents Bronner AK, Hood AF: Cutaneous complications of chemotherapeutic agents. J AM ACAD DERMATOL9:645-663, 1983. This excellent review of reactions to chemotherapeutic agents. The most common cutaneous side effects include alopecia, stomatitis, and hyperpigmentation. Radiation

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enhancement and recall phenomena, photosensitivity and hypersensitivity reactions, and phlebitis or chemical cellulitis occur less commonly. E. Isotretinoin 1. Bone/joint changes Ellis CN, Madison KC, Pennes DR, et al: Isotretinoin therapy is associated with early skeletal radiographic changes. J AM ACAD DERMATOL 10:1024-1029, 1984. Of eight patients treated with isotretinoin for 9 months (1 patient) to 1 year (7 patients) for disorders of keratinization, six had small but unequivocal skeletal hyperostoses. Five of the patients had multiple hyperostoses. Similar changes have been observed in patients treated for ache for 4 months. Novick NL, Lawson W, Schwartz IS: Bilateral nasal bone osteophytosis associated with short-term oral isotretinoin therapy for cystic acne vulgaris. Am J Med 77:736-739, 1984. ClinicaUy significant nasal bone osteophytosis may be another bony change related to oral isotretinoin therapy. Matsuoka LY, Wortsman J, Pepper JJ: Acute arthritis during isotretinoin treatment for ache. Arch Intern 144:18701871, 1984. Treatment with isotretinoin (retinoic acid), which is frequently used in the control of acne, is associated with transient arthralgias in up to 16% of patients. The authors report two cases of acute, aseptic arthritis, with joint efffusion of the knee, in male patients receiving isotretinoin. 2. Teratogenesis Stern RS, Rosa F, Baum C: Isotretinoin and pregnancy. J AM ACAD DERMATOL 10:851-854, 1984. Lammer EJ, Chen DT, Hoar RM, et al: Retinoic acid embryopathy. N Engl J Med 313:837-841, 1985. This study gives a full description of the dysmorphogenesis syndrome associated with first trimester isotretinoin exposure and an estimate of the extremely high

Journal of the American Academy of Dermatology

risk of these malformations in exposed infants. Approximately 120,000 women of childbearing age used isotretinoin in the first 16 months after its release for the treatment of cystic acne. In September 1983, the AAD requested its members to relate the outcome of pregnancies of women inadvertently exposed to isotretinoin (Accutane) during pregnancy to its ADRRS. The most frequently reported severe birth defects involved the central nervous system (microcephaly or hydrocephalus) and the cardiovascular system (anomalies of the great vessels). Microtia, or absence of external ears, was also noted in a majority of cases. Physicians need to inform women fully and carefully of isotretinoin's teratogenic risk. 3. Metabolic Zech LA, Gross EG, Peck GL, Brewer HB: Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study. Arch Dermatol 119:987-993, 1983. Isotretinoin can increase cholesterol and triglycerides, especially in the obese, diabetic, or alcoholic patient. Bershad S, Rubinstein A, Patemiti JR Jr, et al: Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 313:981-985, 1985. Approximately one fifth of persons using isotretinoin for 20 weeks exhibit hypertriglyceridemia. Increases in lipoproteins that are considered to be risk factors for coronary artery disease also occur in many patients. F. Ketoconazole Stern RS: Ketoconazole: Assessing its risks. J AM ACAD DERMATOL6:544, 1982. (Editorial.) Duarte PA, Chow CC, Simmons F, Ruskin J: Fatal hepatitis associated with ketoconazole therapy. Arch Intern Med 144:10691070, 1984. Oral ketoconazole can cause a hepatitis that can be fatal. Van Dijke CPH, Veerman FR, Haverkamp,

Volume 15 Number 6 December, 1986

HC: Anaphylactic reactions to ketoconazole. Br Ivied J 287:1673, 1983. Pont A, Williams P, Loose D, Feldman D, et al: Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 97"370-372, 1982. Ketoconazole blocks the cortisol response to adrenocorticotropic hormones. High doses of ketoconazole could lead to adrenal insufficiency. Pont A, Graybill JR, Crazen PC, et al: High dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 144:2150-2153, 1984. Ketoconazole therapy lowers serum testosterone in a dose-dependent manner. Oligospermia, impotence, decreased libido, and gynecomastia occur in some men treated with this drug. Lewis J, Zimmerman H, Benson G, Ishak K: Hepatic injury associated with ketoconazole therapy. Gastroenterology 86:503-513, 1984. This is a documentation of cases of hepatic injury associated with ketoconazole use. G. Corticosteroids Peller JS, Bardana EJ Jr: Anaphylactoid reaction to corticosteroid: Case report and review of the literature. Ann Allergy 54:302305, 1985. It has been suggested that corticosteroids can cause allergic reactions, including anaphylaxis. Thirty-five patients have been reported to have anaphylaxis-like reactions following exposure to hydrocortisone in topical and parenteral preparations. IgE-mediated immediate hypersensitivity has not been definitely proved in any case, and the authors believe that these are most likely pseudoallergic reactions. H. Risks of treatment of drug reactions with epinephrine Sullivan TJ: Cardiac disorders in penicillininduced anaphylaxis. Association with intravenous epinephrine therapy. JAMA 248: 2161-2162, 1982. This report describes cardiac dysfunction in two patients experiencing penicillin-induced anaphylaxis after intravenous injections of epinephrine chloride. Ventricular premature

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beats and apparent accelerated idioventricular rhythm occurred in one patient and possible ventricular tachycardia occurred in the other. The treatment of the reactions may have been the cause of the cardiac arrhythmia. XI. Drug interactions In this section we review some of the many interactions between drugs that have been documented for agents used in dermatologic therapy. A recent text that provides a comprehensive review of this topic is: Hansten PD: Drug interactions: Clinical significance of drug interactions. Philadelphia, 1985, Lea & Febiger. A. Ketoconazole Smith A: Potentiation of oral anticoagulants by ketoconazole. Br Med J 228:188-189, 1984. Ketoconazole can potentiate the anticoagulant effect of warfarin. B. Erythromycin Wroblewski B, Singer W, Whyte J: Carbamazepine-erythrornycin interaction: Case studies and clinical significance. JAMA 255: 1165-1167, 1986. Carbamazepine serum levels can be markedly increased in some patients who begin erythromycin. C. Tetracycline--antacid interaction Garry M, Hurwitz A: Effect of cimetidine and antacids on gastrointestinal absorption of tetracycline. Clin Pharmacol Ther 28:203-207, 1980. Tetracycline taken with antacids such as magnesium-aluminum hydroxide gel is poorly absorbed, but tetracycline absorption is not greatly decreased by cimetidine. D. Tetracycline--oral contraceptive interaction Bacon JF, Shenfield GM: Pregnancy attributable to interaction between tetracycline and oral contraceptives. Br Med J 280:293, 1980. Tetracycline may decrease absorption of oral contraceptives. XII. Key points A. Only a small proportion of adverse cutaneous reactions to drugs are currently reported. More comprehensive knowledge couId be gained if dermatologists would report unusual and severe reactions they observe to the ADRRS by calling 1-800-323-1473.

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D. Skeletal h y p e m s t o s i s has been seen in patients treated w i t h isotretinoin for acne. The clinical significance o f t h e s e changes is not yet k n o w n . E. S e v e r e h e p a t o t o x i c reactions can o c c u r with k e t o c o n a z o l e . T h i s drug also blocks adrenal steroid synthesis.

B. Patients w i t h altered i m m u n e function, inc l u d i n g patients w i t h A I D S , m a y be at substantially i n c r e a s e d risk o f d e v e l o p i n g cutan e o u s reactions. C. I s o t r e t i n o i n is a p o t e n t teratogen. Every effort m u s t be m a d e to b e sure e x p o s u r e to this drug d o e s not o c c u r in pregnancy.

ABSTRACTS

Evaluation of serological cross-reactivity between antibodies to plasmodium and HTLV-III/LAV

Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome

Greenberg AE, Schable CA, Sulzer AJ, et al: Lancet 2:247-250, 1986

Evans DJ, Burke CW. J R Soc Med 1986;79:451-3

Forty-eight hirsute women were treated with spironolactone, 100 Sera from 460 patients with existifig or r previous, plasmoditim . .nag twice daily, for 3 to 12 months. Twenty-four had evidence of polycystic Ovary syndrome (menstrual irregularity and increased infections, high antimalarial antibody titers, affd no apparent risk levels of luteinizing hormone with ultrasound evidence in eleven and exposure to human immunodeficiency vinis (HIV, .I-rrLV-III/LAV) history of infertility in nine), whereas twenty-four women had normal were assayed for antibody. Only one sam.pie was strongly reactive luteinizing hormone levels and were classified as having idiopathic and no samples from 100 antibody-positive Americar/homosexual hirsutism. Facial and body hirsutism was improved by 30% to 40%, men were strongly reactive to the four plaffrhodium species. Exposure and there was a threefold reduction in frequency of local treatment to plasmodium does not result in HIV seropositivity aiid HIV anti~ bodies are not strongly cross-reactive withmal~.al antigens.......... ............. such,as shaving or waxing. Although plasma testosterone levels fell J ; Grahgm Smith, Jr., M.D. by 30%, the improvement in hlrsutism grading did not correlate with * . ................ ihe fall in plfisma testosterone levels. Six subjects discontinued treatment because of lack of effect and four because of menstrual disClassification system for human T--lymphot~'opic virus turbance. type III/lymphadenopathy-associated virus infections : i J. Graham Smith, Jr., M.D. CDC: Ann Intern Med 105:234-237,~ ~1986 "° A system to classify patients with various manifestations of An- :. fection with human immunodeficiency virus (HTLV-~I/LA~V).is'pre- ' sented. The system comprises four mutually exclusive groups: (1) acute infection, (2) asymptomatic infection, (3) persistent generalized lymphadenopathy, and (4) other diseases with five subgroups and two subcategories. J. Graham Smith, Jr., M.D.

Interactions between • oral contraceptive steroids and broad-spectrum antibiotics Orme ML, Back DJ: Clin Exp Dermatol 11:327-331, 1986 Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine may cause contraceptive failure in women on birth control pills. The Committee on Safety of Medicines has received over sixtythree reports of women whose contraceptive failed while on antibiotics, the most commonly implicated ones being ampicillin, the tetraeyclines, and co-trimoxazole. Controlled clinical studies with ampieillin have failed to show any significant interaction between the antibiotic and contraceptive steroids; however, no fully controlled studies have been carried out in women taking tetracycline. No significant changes in plasma concentrations of either ethinyl estradiol or levonorgestrel were noted after 4 weeks of therapy with tetracycline, 500 rag/daily, or erythromycin, 500 rag/daily. Ethinyl estradiol plasma concentrations were significantly increased during co-trimoxazole therapy. There is very little experimental evidence in humans that broad-spectrum antibiotics will cause birth control pill failure. J. Graham Smith, Jr., M.D.

I-IIV infecfion with seroconversion after a superficial iieed[6stiel~ injury to the finger Oksenhendler E, Harzic M, Le Roux J-M, Rabian C, Clauvel JP. N Engl J Med 1986;315:582 While recapping the needle during a thoracentesis, a nurse received a superficial self-inflicted needle-stick injury contaminated by the bloody pleural fluid of a patient with persisteut generalized lymphadenopathy and seropositivity for human immunodeficieney virus (HIV) and hepatitis B surface antigen. Twenty-five days after the injury, fever, fatigue, and vomiting developed; results of a physical examination were normal. Serum samples were positive for t/IV antibody on days 68, 82, and 151, although blood cultures were negative. J. Graham Smith, Jr., M.D,

Phenotypic transformation of macrophages to Langerhans cells in the skin Murphy GF, Messadi D, Fonferko E, et al. Am J Pathol 1986;123:401-6 After bone marrow transplantation, Langerhans cells in skin are depleted. How do they regrow? Possibly they arise from a special monocytic-like macrophage in the dermis and climb up into their epidermal position. Philip C. Anderson, M.D.