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Toxic shock syndrome or toxic epidermal necrolysis
Toxic shock syndrome or toxic epidermal necrolysis? Case reports showing clinical similarity and histologic separation Robert M. Hurwitz, M.D., Hector P. Rivera, M.D., Mark H. Gooch, M.D., Thomas G. Stama, M.D., Alan Handt, M.D., and Jay Weiss, M.D.
Indianapolis, IN A case of toxic shock syndrome and a case of drug-induced toxic epidermal necrolysis with renal involvement are described. The two patients had similar early clinical manifestations and therefore posed a difficult differential diagnosis. Diagnostic distinction is important because therapy differs considerably. A skin biopsy in each case proved helpful in establishing the correct diagnosis, since there appears to be a different histologic pattern for each condition: superficial perivascular dermatitis for toxic shock syndrome and an interface dermatitis for toxic epidermal necrolysis. (J AM ACAD DERMATOL 7:246-254, 1982.)
Toxic shock syndrome and drug-induced toxic epidermal necrolysis with renal involvement may have many of the same clinical manifestations and thus pose a difficult clinical differential diagnosis. This distinction is not solely academic, since treatment differs significantly in these two conditions. Avoidance of the offending drug and the use of systemic corticosteroids are lifesaving in druginduced toxic epidermal necrolysis with renal involvement, whereas supportive measures and the use of systemic antistaphylococcal antibiotics are the mode of therapy in toxic shock syndrome. A case report of each follows, with special emphasis on the cutaneous histologic features.
Fig. 1, Conjunctival hemorrhage syndrome.
in toxic
shock
CASE R E P O R T S
Toxic shock syndrome A 21-year-old white woman was admitted to the intensive care unit with a 2-day history of fever greater From the Departments of Medicine and Pathology, St. Vincent Hospital. Accepted for publication Nov. 24, 1981. Reprint requests to: Dr. RobertM. Hurwitz, St. Vincent Professional Bldg., Suite 401, 8402 Harcourt Rd., Indianapolis, IN 46260.
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than 105° F, chills, nausea and vomiting, diarrhea, a sunburnlike rash over the face and trunk, and a vaginal discharge. Sore throat, weakness, and extreme lethargy had developed the day prior to hospitalization. She used tampons, and her last menstrual period had begun 6 days prior to admission. Examination showed the patient to be acutely ill. Temperature was 102 ° F, pulse 96, respiration 20, and blood pressure 80/50 mm Hg. She had bilateral con0190-9622/82/080246 +09500.90/0 © 1982 Am Acad Dermatol
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Fig. 2. Adbomen on day 2 of illness in toxic shock syndrome. Note scattered maculopapules within an area of generalized macular erythema. junctival hemorrhages (Fig. 1), pharyngeal erythema with scattered peteehiae and superficial ulcers, a ' 'strawberry" tongue, and a sunburnlike macular erythema over the face, trunk, and extremities. A few scattered erythematous maculopapules were noted over the chest and abdomen (Fig. 2). A creamy cervical discharge was noted on pelvic examination. On admission, the patient had cloudy urine with 10 to 25 white blood cells, 4+ bacteria, and 3+ amorphous crystals per high-power field, as well as 25 to 50 coarse granules per low-power field. The hematocrit was 44.2%. The white blood cell count was 13,200, with 75% band forms and 19% segmented neutrophils. The platelet count was 184,000 and fell to 99,000 within 12 hours. Prothrombin time was 17 seconds with a control of 11 seconds. Activated partial thromboplastin time (PTT) was 53 seconds. Fibrinogen was 310 rag/all, and fibrin-split products were greater than 10 /xg/ml but less than 20 /xg/ml. Arterial blood gases obtained on room air showed a pH of 7.41, Po2 of 85, and Pco2 of 24. The serum sodium level was 129
•
j
Fig. 3. Desquamation of thumb on day 9 of illness m toxic shock syndrome. mEq/liter; potassium, 2.7 mEq/liter; chloride, 97 mEq/liter; ,and CO~, 17 mEq/liter. The blood urea nitrogen (BUN) was 46 mg/dl. The serum creatinine level was 3.2 mg/dl; glucose, 132 mg/dl; calcium, 7.5 mg/dl; phosphorus, 3.7 rag/all; bilirubin, 2.8 mg/dl;
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Fig. 4. Abdomen on day 11 in toxic shock syndrome. Note secondary urticarial erythematous papules and macular erythema.
alkaline phosphatase, 55 mU/ml; lactic dehydrogenase (LDH), 228 mU/ml; and serum aspartate aminotransferase (AST), 26 mU/ml. Chest radiograph and electrocardiogram were unremarkable. A Gram's stain of the patient's cervical discharge showed neutrophils and gram-positive cocci. Culture of the discharge grew /3-1actamase-positive Staphylococcus aureus. Blood cultures and a urine culture showed no growth.
The patient was treated initially with intravenous cefamandole nafate, methylprednisolone, and dopamine. Increasing respiratory distress the second day of hospitalization necessitated intubation and assisted ventilation, A chest radiograph at that time was consistent with acute respiratory distress syndrome, and an arterial Po2 was 35 on room air. By the end of the first week, improvement in the patient's cardiopulmonary
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function allowed weaning from dopamine and the mechanical ventilation. Slight peeling of the patient's fingers and thumbs (Fig. 3) was noted on day 9. On day 11, she developed a secondary pmritic erythematous maculopapular rash over the trunk and extremities (Fig. 4), which responded to a topical corticosteroid. By day 13, distinct desquamation was also present over the forehead, cheeks, and nose. Her respiratory, renal, and henaodynamic status normalized by the end of two weeks, and she was discharged from the hospital with no apparent sequelae of her disease. Toxic e p i d e r m a l neerolysis A 66-year-old white woman was admitted with a 5-day history of chills, fever (102 ° to 104° F), generalized malaise, watery diarrhea, vaginal discharge, a generalized macular rash, and rapidly rising BUN and creatinine levels. Her medications included methyldopa (Aldomet), trichlormethiazide (Metahydrin) for hypertension, and ibuprofen (Motrin) for a recent knee effusion. Admission physical examination showed an alert and oriented woman with a temperature of 102.4 ° F, pulse 124, respirations 22, and blood pressure 110/70. She had a sunburnlike rash over her chest, face, and arms, with a few flaccid blisters over the sternum, on the right flank, and under the right breast (Fig. 5). Her skin was exquisitely sensitive to the slightest touch. She had no conjunctivitis or pharyngeal exudate; however, multiple oral mucosal ulcerations were present. Cardiac and pulmonary examinations were unremarkable. The abdominal findings were hypoactive boweI sounds with generalized tenderness, guarding, mild rebound, and no hepatosplenomegaly. Pelvic examination revealed a few scattered erythematous labial ulcerations and a foul-smelling, yellowish vaginal discharge. The laboratory values of significance prior to admission were as follows: white blood cell count, I 1,000 with 43% bands; Westergren erythrocyte sedimentation rate, 25 mm/hr; platelet count, 65,000/mm:3; AST, 81 mU/ml; BUN, 78 mg/dl; creatinine, 4.3 mg/dl; and prothrombin time (PT), 14.3 seconds (control, 11.8). Throat cultures, urine culture, and blood cultures were negative. Vaginal culture grew Lactobacillus species. A rectal swab showed no pathogenic organisms. Admitting laboratory values were as follows: white blood cell count, 8,700 with 58% bands; hemoglobin, 14.7 gm/dl; hematocrit, 30.2%; platelet count, 94,000 ram3; PT, 14.5 seconds (control, 1 I); PTT, 42 seconds;
Fig. 5. Toxic epidermal necrolysis. Note generalized erythema and macular purpura over lower abdomen and suprapubic area, as well as a few papulovesicles on chest. urinalysis, trace blood and protein with no casts; negative antistreptolysin O (ASO) titer, rheumatoid arthritis screen, and antinuclear antibody test; calcium, 6.6 mg/dl; phosphorus, 6.2 mg/dl; glucose, 174 mg/dl; uric acid, 12 mg/dl; total protein, 4.7 gm/dl; albumin, 2.9 gm/dl; total bilirubin, 0.9 mg/dl; direct bilirubin, 0.5 mg/dl; alkaline phosphatase, 167 mU/ml; lactate dehydrogenase, 600 mU/rnl; AST, 100 mU/ml; BUN, 100 mg/dl; creatinine, 4.3 mg/dl; serum ammonia, 54 /xmole/liter; serum amylase, 169 IU/liter; and creatine phosphokinase, 421 mU/ml with a negative heart fraction. Throat culture was negative for beta streptococci. A pelvic culture grew Lactobacillus species, Bacteroides species, and Staphylococcus epidermidis. Blood cultures were negative, and a second urine culture grew Escherichia coli. A conjunctival smear grew S. epidermidis; a rectal smear showed no pathogenic organisms. An abdominal x-ray survey revealed mild hepatomegaly with ileus but no free air. The chest x-ray and electrocardiogram were unremarkable.
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,r,
'~
Fig. 6. Toxic epidermal necrolysis showing subepidermal vesiculations, Note necrotic keratinocytes within the epidermis, severe papillary edema, and adnexal necrosis.
Table I. Previously reported cases o f toxic shock s y n d r o m e No. Day
cases
Author
with skin biopsy
of Cutaneous histologic finding
] Skin
biopsy , texture
I
S . aurelts
. culture (site)
Todd et al z
1
No abnormalities
NS
M
Abdul-Karim et al a
1
NS
V
Fisher et aP
2
3,4
M
+ (cervix)
Tofte et al ~ Chesney et at 6
2 2
Intraepidermal and subepidermal edema with subepidermal blister formation; mononuclear inflammatory cell upper dermal blood vessels Perivasculitis of the reticular dermis with sparing of the papillary dermis Small vessel vasculitis Mild hyperkeratosis, slight lymphocytic and neutrophilic perivascular infiltrate of middermal region; no evidence of vasculitis
+ (throat, vagina) -
NS NS
?MP ?MP
NS NS
NS: Not stated; M: macular; V: vesicular; MP: maculopapular.
The patient was admitted with a diagnosis of toxic shock syndrome and started on intravenous fluids and vancomycin while simultaneously stopping methyldopa, trichlormethiazide, and ibuprofen. Frozen sections of a skin papulovesicle revealed subepidermal separation with epidermal and adnexal necrosis (Fig. 6), as commonly seen in cases of drug-induced toxic
epidermal necrolysis. Systemic corticosteroids were administered. Over the course of 1 week, the rash over the patient's trunk, face, and neck proceeded to desquamate, her cutaneous tenderness resolved, and her laboratory values normalized. She was discharged after 8 days of hospitalization with a diagnosis of toxic shock syn-
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drome. Approximately 1 month after discharge, she was restarted on methyldopa and ibuprofen, and within 12 hours she became febrile, developing chills and an erythematous rash. She was rehospitalized and treated with intravenous fluids and corticosteroids with rapid resolution of her symptoms. In 3 days, she was discharged with a diagnosis of methyldopa hypersensitivity. Three weeks later, she restarted ibuprofen with a subsequent return of rash and fever. She was rehospitalized and successfully treated once again with corticosteroids. Ibuprofen (Motrin) thus proved on three occasions to be the precipitating medication that led to the final diagnosis of toxic epidermal necrolysis.
Cutaneous findings by light microscopy Histologic examination of a maculopapule obtained on day 2 from the patient with toxic shock syndrome showed a pattern of superficial perivascular dermatitis with numerous neutrophils, lymphocytes, and a few eosinophils within an edematous papillary dermis (Fig. 7). Slight epidermal spongiosis was noted, and neurophils were present within the basal, spinous, and granular cell layers (exocytosis). Necrotic keratinocytes and keratinocytes undergoing mitosis were common findings (Fig. 8). Similar involvement of an adjacent hair follicle and sweat duct was also noted (Fig. 9). Histologic examination from a secondary maculopapule obtained on day 12 from the same patient showed only a mild superficial perivascular lymphohistiocytic infiltrate (Fig. 10). Histologic examination of an early vesiculopapule on day 6 from the patient with toxic epidermal necrolysis showed a pattern of an interface (dermoepidermal) dermatitis with severe papillary edema, subepidermal vesiculation, and vacuolar alteration (hydropic degeneration) of the basal cell layer (Fig. 6). The separated overlying epidermis contained individual and groups of necrotic keratinocytes. Necrotic keratinocytes were also noted within an adjacent sweat duct. The papillary dermis contained a mild superficial perivascular lymphohistiocytic infiltrate. DISCUSSION The clinical manifestations of toxic shock syndrome and toxic epidermal necrolysis may be similar. Both conditions have multisystem involvement and early in their course have a diffuse sunburnlike erythema. Early clinical manifestations in toxic shock syndrome include fever greater than 102 ° F; diffuse erythroderma; conjunctival, oropharyngeal,
Fig. 7. Toxic shock syndrome on day 2 of illness. Note superficial perivascular mixed cell infiltrate with neutrophils and mild papillary edema. Epidermal changes include slight spongiosis, scattered neutrophils, necrotic keratinocytes, and keratinocytes in mitosis. and vaginal hyperemia; hypotension; and involvement of three or more organ systems.~ In our case of toxic shock syndrome, an early skin biopsy showed a superficial perivascular mixed-cell infiltrate with epidermal involvement. A later skin biopsy showed a less intense perivascular reaction that was purely lymphohistiocytic with no epidermal involvement. A review of previously reported cutaneous histologic findings in toxic shock syndrome is listed in Table I. "-~ Six of the eight reported skin biopsies showed a perivascular dermatitis, one biopsy showed no abnormalities, and one biopsy showed a subepidermal blister with negative cultures for S. a u r e u s . The latter, vis-~tvis the other tabulated cases, as well as those cases here reported, brings to bear the need for histologically differentiating toxic shock syndrome from toxic epidermal necrolysis.
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Fig. 8. Higher-power view of epidermis, showing neutrophils, necrotic keratinocytes, and
slight spongiosis (day 2, toxic shock syndrome). Table II. Comparison of histologic findings in toxic epidermal necrolysis and toxic shock syndrome Histologi¢ findings
[
TEN
[
TSS
Vacuolar alteration and subepidermal vesiculation (interface dermatitis)
-J[-
Severe papillary edema lntracellular edema (ballooning) Confluent epidermal necrosis Superficial perivascular lymphohistiocytic infiltrate
+ + + +
--; + *
Superficial perivascular mixed-cell infiltrate (neutrophils)
--
+
-t
+
+ +
+ +
Neutrophils; epidermai and adnexal exocytosis Individual necrotic epidermal and adnexal keratinocytes Intercellular edema (spongiosis) TEN; Toxle epidermal necrolysis; TSS toxic shock syndrome. *Biopsy from secoadary eruption in the reported ease does show a purely lymphohistiocytie infiltrate. tMay find a few neutrophils in association with necrotic keratinocytes.
Toxic epidermal necrolysis is thought to be a variant of erythema multiforme, or the StevensJohnson syndrome. The early signs and symptoms include malaise, pyrexia, and inflammation of the eyelids and mucous membranes, including the genitalia, as well as a generalized pain%l erythema. Later, flaccid blisters may arise. Various systemic medications have been implicated, e.g., penicillin, sulfonamides, barbiturates, and phenylbutazone.7 Renal disease is not unusual in toxic
epidermal necrolysis, as noted in Lyell's series of 128 cases. He included twenty-two patients with acute renal failure caused by acute tubular necrosis, six of whom died. 8 The skin biopsy findings of toxic epidermal necrolysis are well known "~and consist of an interface dermatitis with subepidermal vesiculation. These findings differ significantly from the pattern noted with the primary and secondary rash in toxic shock syndrome, i.e., superficial perivascular dermatitis
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m
Fig. 9. Eccrine sweat duct with slight spongiosis and neutrophils (day 2, toxic shock syndrome). as listed in Table II. However, it is interesting to note that although neutrophils were predominant in the early rash, the secondary rash was purely lymphohistiocytic. Chesney et al ~ noted a rash within the second week in five of their twenty-one patients with toxic shock syndrome. Deetz et aP ° also noted a secondary rash, consisting of maculopapular morbilliform eruptions, in three of their four patients with toxic shock syndrome. The skin of the latter three patients cleared within 48 to 72 hours even though one continued to receive oral penicillinaseresistant semisynthetic penicillin. Thus, we may speculate that the secondary rash in our patient was part of the toxic shock syndrome. In summary, the early clinical manifestations of toxic shock syndrome and toxic epidermal necrolysis may appear similar and thus be confused. The characteristic rash of toxic shock syndrome is not vesicular, whereas the characteristic rash in toxic epidermal necrolysis is vesicular. This may be an
Fig. 10. Toxic shock syndrome on day 12 o f illness. Biopsy from secondary maculopapule on abdomen. Note superficial perivascular lymphohistiocytic infiltrate and mild papillary edema. Absence o.f neutrophils and epidermal changes distinguishes this later skin biopsy from the early skin biopsy in toxic shock syndrome.
important consideration in the clinical differential diagnosis. We believe that this distinction deserves special emphasis and that a skin biopsy with examination by frozen section technic or routine hematoxylin-eosin stain may prove helpful in establishing or confirming the diagnosis of either toxic shock syndrome or toxic epidermal necrolysis, since the latter shows an interface dermatitis and the former manifests as a superficial perivascular dermatitis. We wish to thank Dr. Joseph Frederick and Dr. William Gosnell for referring their patients with toxic epidermal necrolysis and toxic shock syndrome, respectively, to our attention. REFERENCES 1. Follow-up on toxic shock syndrome. Morbid Mortal Weekly Rep 29:441-445, 1980.
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2, Todd J, et al: Toxic shock syndrome associated with phage group I staphylococci. Lancet 1:1116-1118, 1978. 3. Abdul-Karim FW, et al: Toxic shock syndrome: Clinieopathologic findings in a fatal case, Hum Pathol 12:16-22, 1981. 4. Fisher RF, et al: Toxic shock syndrome in menstruating women. Ann Intern Med 94:156-163, 1981, 5. Tofte RW, et al: Toxic shock syndrome: Clinical and laboratory features in 15 patients. Ann intern Med 94:149-156, 1981. 6. Chesney PJ, et ,-zl:Clinical manifestations of toxic shock syndrome. JAMA 246:741-748, 198l.
Journal of the American Academy of Dermatology
7. Malkinson FD, Pearson BW: The year book of dermatology. Chicago, 1977, Year Book Medical Publishers, Inc., pp. 37-39. 8. Krnmlovsky FA, et al: Renal disease associated with toxic epidermal necrolysis (Lyell's disease). Am J Med 57:817-825, 1974. 9. Ackerman AB: Histologic diagnosis of inflammatory skin disease. Philadelphia, 1978, Lea & Febiger, pp. 581-639. 10. Deetz TR, et al: Secondary rash in toxic shock syndrome? N Engl J Med 304: 174, 1981.
Indianapolis, IN A case of toxic shock syndrome and a case of drug-induced toxic epidermal necrolysis with renal involvement are described. The two patients had similar early clinical manifestations and therefore posed a difficult differential diagnosis. Diagnostic distinction is important because therapy differs considerably. A skin biopsy in each case proved helpful in establishing the correct diagnosis, since there appears to be a different histologic pattern for each condition: superficial perivascular dermatitis for toxic shock syndrome and an interface dermatitis for toxic epidermal necrolysis. (J AM ACAD DERMATOL 7:246-254, 1982.)
Toxic shock syndrome and drug-induced toxic epidermal necrolysis with renal involvement may have many of the same clinical manifestations and thus pose a difficult clinical differential diagnosis. This distinction is not solely academic, since treatment differs significantly in these two conditions. Avoidance of the offending drug and the use of systemic corticosteroids are lifesaving in druginduced toxic epidermal necrolysis with renal involvement, whereas supportive measures and the use of systemic antistaphylococcal antibiotics are the mode of therapy in toxic shock syndrome. A case report of each follows, with special emphasis on the cutaneous histologic features.
Fig. 1, Conjunctival hemorrhage syndrome.
in toxic
shock
CASE R E P O R T S
Toxic shock syndrome A 21-year-old white woman was admitted to the intensive care unit with a 2-day history of fever greater From the Departments of Medicine and Pathology, St. Vincent Hospital. Accepted for publication Nov. 24, 1981. Reprint requests to: Dr. RobertM. Hurwitz, St. Vincent Professional Bldg., Suite 401, 8402 Harcourt Rd., Indianapolis, IN 46260.
246
than 105° F, chills, nausea and vomiting, diarrhea, a sunburnlike rash over the face and trunk, and a vaginal discharge. Sore throat, weakness, and extreme lethargy had developed the day prior to hospitalization. She used tampons, and her last menstrual period had begun 6 days prior to admission. Examination showed the patient to be acutely ill. Temperature was 102 ° F, pulse 96, respiration 20, and blood pressure 80/50 mm Hg. She had bilateral con0190-9622/82/080246 +09500.90/0 © 1982 Am Acad Dermatol
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Fig. 2. Adbomen on day 2 of illness in toxic shock syndrome. Note scattered maculopapules within an area of generalized macular erythema. junctival hemorrhages (Fig. 1), pharyngeal erythema with scattered peteehiae and superficial ulcers, a ' 'strawberry" tongue, and a sunburnlike macular erythema over the face, trunk, and extremities. A few scattered erythematous maculopapules were noted over the chest and abdomen (Fig. 2). A creamy cervical discharge was noted on pelvic examination. On admission, the patient had cloudy urine with 10 to 25 white blood cells, 4+ bacteria, and 3+ amorphous crystals per high-power field, as well as 25 to 50 coarse granules per low-power field. The hematocrit was 44.2%. The white blood cell count was 13,200, with 75% band forms and 19% segmented neutrophils. The platelet count was 184,000 and fell to 99,000 within 12 hours. Prothrombin time was 17 seconds with a control of 11 seconds. Activated partial thromboplastin time (PTT) was 53 seconds. Fibrinogen was 310 rag/all, and fibrin-split products were greater than 10 /xg/ml but less than 20 /xg/ml. Arterial blood gases obtained on room air showed a pH of 7.41, Po2 of 85, and Pco2 of 24. The serum sodium level was 129
•
j
Fig. 3. Desquamation of thumb on day 9 of illness m toxic shock syndrome. mEq/liter; potassium, 2.7 mEq/liter; chloride, 97 mEq/liter; ,and CO~, 17 mEq/liter. The blood urea nitrogen (BUN) was 46 mg/dl. The serum creatinine level was 3.2 mg/dl; glucose, 132 mg/dl; calcium, 7.5 mg/dl; phosphorus, 3.7 rag/all; bilirubin, 2.8 mg/dl;
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Fig. 4. Abdomen on day 11 in toxic shock syndrome. Note secondary urticarial erythematous papules and macular erythema.
alkaline phosphatase, 55 mU/ml; lactic dehydrogenase (LDH), 228 mU/ml; and serum aspartate aminotransferase (AST), 26 mU/ml. Chest radiograph and electrocardiogram were unremarkable. A Gram's stain of the patient's cervical discharge showed neutrophils and gram-positive cocci. Culture of the discharge grew /3-1actamase-positive Staphylococcus aureus. Blood cultures and a urine culture showed no growth.
The patient was treated initially with intravenous cefamandole nafate, methylprednisolone, and dopamine. Increasing respiratory distress the second day of hospitalization necessitated intubation and assisted ventilation, A chest radiograph at that time was consistent with acute respiratory distress syndrome, and an arterial Po2 was 35 on room air. By the end of the first week, improvement in the patient's cardiopulmonary
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function allowed weaning from dopamine and the mechanical ventilation. Slight peeling of the patient's fingers and thumbs (Fig. 3) was noted on day 9. On day 11, she developed a secondary pmritic erythematous maculopapular rash over the trunk and extremities (Fig. 4), which responded to a topical corticosteroid. By day 13, distinct desquamation was also present over the forehead, cheeks, and nose. Her respiratory, renal, and henaodynamic status normalized by the end of two weeks, and she was discharged from the hospital with no apparent sequelae of her disease. Toxic e p i d e r m a l neerolysis A 66-year-old white woman was admitted with a 5-day history of chills, fever (102 ° to 104° F), generalized malaise, watery diarrhea, vaginal discharge, a generalized macular rash, and rapidly rising BUN and creatinine levels. Her medications included methyldopa (Aldomet), trichlormethiazide (Metahydrin) for hypertension, and ibuprofen (Motrin) for a recent knee effusion. Admission physical examination showed an alert and oriented woman with a temperature of 102.4 ° F, pulse 124, respirations 22, and blood pressure 110/70. She had a sunburnlike rash over her chest, face, and arms, with a few flaccid blisters over the sternum, on the right flank, and under the right breast (Fig. 5). Her skin was exquisitely sensitive to the slightest touch. She had no conjunctivitis or pharyngeal exudate; however, multiple oral mucosal ulcerations were present. Cardiac and pulmonary examinations were unremarkable. The abdominal findings were hypoactive boweI sounds with generalized tenderness, guarding, mild rebound, and no hepatosplenomegaly. Pelvic examination revealed a few scattered erythematous labial ulcerations and a foul-smelling, yellowish vaginal discharge. The laboratory values of significance prior to admission were as follows: white blood cell count, I 1,000 with 43% bands; Westergren erythrocyte sedimentation rate, 25 mm/hr; platelet count, 65,000/mm:3; AST, 81 mU/ml; BUN, 78 mg/dl; creatinine, 4.3 mg/dl; and prothrombin time (PT), 14.3 seconds (control, 11.8). Throat cultures, urine culture, and blood cultures were negative. Vaginal culture grew Lactobacillus species. A rectal swab showed no pathogenic organisms. Admitting laboratory values were as follows: white blood cell count, 8,700 with 58% bands; hemoglobin, 14.7 gm/dl; hematocrit, 30.2%; platelet count, 94,000 ram3; PT, 14.5 seconds (control, 1 I); PTT, 42 seconds;
Fig. 5. Toxic epidermal necrolysis. Note generalized erythema and macular purpura over lower abdomen and suprapubic area, as well as a few papulovesicles on chest. urinalysis, trace blood and protein with no casts; negative antistreptolysin O (ASO) titer, rheumatoid arthritis screen, and antinuclear antibody test; calcium, 6.6 mg/dl; phosphorus, 6.2 mg/dl; glucose, 174 mg/dl; uric acid, 12 mg/dl; total protein, 4.7 gm/dl; albumin, 2.9 gm/dl; total bilirubin, 0.9 mg/dl; direct bilirubin, 0.5 mg/dl; alkaline phosphatase, 167 mU/ml; lactate dehydrogenase, 600 mU/rnl; AST, 100 mU/ml; BUN, 100 mg/dl; creatinine, 4.3 mg/dl; serum ammonia, 54 /xmole/liter; serum amylase, 169 IU/liter; and creatine phosphokinase, 421 mU/ml with a negative heart fraction. Throat culture was negative for beta streptococci. A pelvic culture grew Lactobacillus species, Bacteroides species, and Staphylococcus epidermidis. Blood cultures were negative, and a second urine culture grew Escherichia coli. A conjunctival smear grew S. epidermidis; a rectal smear showed no pathogenic organisms. An abdominal x-ray survey revealed mild hepatomegaly with ileus but no free air. The chest x-ray and electrocardiogram were unremarkable.
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,r,
'~
Fig. 6. Toxic epidermal necrolysis showing subepidermal vesiculations, Note necrotic keratinocytes within the epidermis, severe papillary edema, and adnexal necrosis.
Table I. Previously reported cases o f toxic shock s y n d r o m e No. Day
cases
Author
with skin biopsy
of Cutaneous histologic finding
] Skin
biopsy , texture
I
S . aurelts
. culture (site)
Todd et al z
1
No abnormalities
NS
M
Abdul-Karim et al a
1
NS
V
Fisher et aP
2
3,4
M
+ (cervix)
Tofte et al ~ Chesney et at 6
2 2
Intraepidermal and subepidermal edema with subepidermal blister formation; mononuclear inflammatory cell upper dermal blood vessels Perivasculitis of the reticular dermis with sparing of the papillary dermis Small vessel vasculitis Mild hyperkeratosis, slight lymphocytic and neutrophilic perivascular infiltrate of middermal region; no evidence of vasculitis
+ (throat, vagina) -
NS NS
?MP ?MP
NS NS
NS: Not stated; M: macular; V: vesicular; MP: maculopapular.
The patient was admitted with a diagnosis of toxic shock syndrome and started on intravenous fluids and vancomycin while simultaneously stopping methyldopa, trichlormethiazide, and ibuprofen. Frozen sections of a skin papulovesicle revealed subepidermal separation with epidermal and adnexal necrosis (Fig. 6), as commonly seen in cases of drug-induced toxic
epidermal necrolysis. Systemic corticosteroids were administered. Over the course of 1 week, the rash over the patient's trunk, face, and neck proceeded to desquamate, her cutaneous tenderness resolved, and her laboratory values normalized. She was discharged after 8 days of hospitalization with a diagnosis of toxic shock syn-
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drome. Approximately 1 month after discharge, she was restarted on methyldopa and ibuprofen, and within 12 hours she became febrile, developing chills and an erythematous rash. She was rehospitalized and treated with intravenous fluids and corticosteroids with rapid resolution of her symptoms. In 3 days, she was discharged with a diagnosis of methyldopa hypersensitivity. Three weeks later, she restarted ibuprofen with a subsequent return of rash and fever. She was rehospitalized and successfully treated once again with corticosteroids. Ibuprofen (Motrin) thus proved on three occasions to be the precipitating medication that led to the final diagnosis of toxic epidermal necrolysis.
Cutaneous findings by light microscopy Histologic examination of a maculopapule obtained on day 2 from the patient with toxic shock syndrome showed a pattern of superficial perivascular dermatitis with numerous neutrophils, lymphocytes, and a few eosinophils within an edematous papillary dermis (Fig. 7). Slight epidermal spongiosis was noted, and neurophils were present within the basal, spinous, and granular cell layers (exocytosis). Necrotic keratinocytes and keratinocytes undergoing mitosis were common findings (Fig. 8). Similar involvement of an adjacent hair follicle and sweat duct was also noted (Fig. 9). Histologic examination from a secondary maculopapule obtained on day 12 from the same patient showed only a mild superficial perivascular lymphohistiocytic infiltrate (Fig. 10). Histologic examination of an early vesiculopapule on day 6 from the patient with toxic epidermal necrolysis showed a pattern of an interface (dermoepidermal) dermatitis with severe papillary edema, subepidermal vesiculation, and vacuolar alteration (hydropic degeneration) of the basal cell layer (Fig. 6). The separated overlying epidermis contained individual and groups of necrotic keratinocytes. Necrotic keratinocytes were also noted within an adjacent sweat duct. The papillary dermis contained a mild superficial perivascular lymphohistiocytic infiltrate. DISCUSSION The clinical manifestations of toxic shock syndrome and toxic epidermal necrolysis may be similar. Both conditions have multisystem involvement and early in their course have a diffuse sunburnlike erythema. Early clinical manifestations in toxic shock syndrome include fever greater than 102 ° F; diffuse erythroderma; conjunctival, oropharyngeal,
Fig. 7. Toxic shock syndrome on day 2 of illness. Note superficial perivascular mixed cell infiltrate with neutrophils and mild papillary edema. Epidermal changes include slight spongiosis, scattered neutrophils, necrotic keratinocytes, and keratinocytes in mitosis. and vaginal hyperemia; hypotension; and involvement of three or more organ systems.~ In our case of toxic shock syndrome, an early skin biopsy showed a superficial perivascular mixed-cell infiltrate with epidermal involvement. A later skin biopsy showed a less intense perivascular reaction that was purely lymphohistiocytic with no epidermal involvement. A review of previously reported cutaneous histologic findings in toxic shock syndrome is listed in Table I. "-~ Six of the eight reported skin biopsies showed a perivascular dermatitis, one biopsy showed no abnormalities, and one biopsy showed a subepidermal blister with negative cultures for S. a u r e u s . The latter, vis-~tvis the other tabulated cases, as well as those cases here reported, brings to bear the need for histologically differentiating toxic shock syndrome from toxic epidermal necrolysis.
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Fig. 8. Higher-power view of epidermis, showing neutrophils, necrotic keratinocytes, and
slight spongiosis (day 2, toxic shock syndrome). Table II. Comparison of histologic findings in toxic epidermal necrolysis and toxic shock syndrome Histologi¢ findings
[
TEN
[
TSS
Vacuolar alteration and subepidermal vesiculation (interface dermatitis)
-J[-
Severe papillary edema lntracellular edema (ballooning) Confluent epidermal necrosis Superficial perivascular lymphohistiocytic infiltrate
+ + + +
--; + *
Superficial perivascular mixed-cell infiltrate (neutrophils)
--
+
-t
+
+ +
+ +
Neutrophils; epidermai and adnexal exocytosis Individual necrotic epidermal and adnexal keratinocytes Intercellular edema (spongiosis) TEN; Toxle epidermal necrolysis; TSS toxic shock syndrome. *Biopsy from secoadary eruption in the reported ease does show a purely lymphohistiocytie infiltrate. tMay find a few neutrophils in association with necrotic keratinocytes.
Toxic epidermal necrolysis is thought to be a variant of erythema multiforme, or the StevensJohnson syndrome. The early signs and symptoms include malaise, pyrexia, and inflammation of the eyelids and mucous membranes, including the genitalia, as well as a generalized pain%l erythema. Later, flaccid blisters may arise. Various systemic medications have been implicated, e.g., penicillin, sulfonamides, barbiturates, and phenylbutazone.7 Renal disease is not unusual in toxic
epidermal necrolysis, as noted in Lyell's series of 128 cases. He included twenty-two patients with acute renal failure caused by acute tubular necrosis, six of whom died. 8 The skin biopsy findings of toxic epidermal necrolysis are well known "~and consist of an interface dermatitis with subepidermal vesiculation. These findings differ significantly from the pattern noted with the primary and secondary rash in toxic shock syndrome, i.e., superficial perivascular dermatitis
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Fig. 9. Eccrine sweat duct with slight spongiosis and neutrophils (day 2, toxic shock syndrome). as listed in Table II. However, it is interesting to note that although neutrophils were predominant in the early rash, the secondary rash was purely lymphohistiocytic. Chesney et al ~ noted a rash within the second week in five of their twenty-one patients with toxic shock syndrome. Deetz et aP ° also noted a secondary rash, consisting of maculopapular morbilliform eruptions, in three of their four patients with toxic shock syndrome. The skin of the latter three patients cleared within 48 to 72 hours even though one continued to receive oral penicillinaseresistant semisynthetic penicillin. Thus, we may speculate that the secondary rash in our patient was part of the toxic shock syndrome. In summary, the early clinical manifestations of toxic shock syndrome and toxic epidermal necrolysis may appear similar and thus be confused. The characteristic rash of toxic shock syndrome is not vesicular, whereas the characteristic rash in toxic epidermal necrolysis is vesicular. This may be an
Fig. 10. Toxic shock syndrome on day 12 o f illness. Biopsy from secondary maculopapule on abdomen. Note superficial perivascular lymphohistiocytic infiltrate and mild papillary edema. Absence o.f neutrophils and epidermal changes distinguishes this later skin biopsy from the early skin biopsy in toxic shock syndrome.
important consideration in the clinical differential diagnosis. We believe that this distinction deserves special emphasis and that a skin biopsy with examination by frozen section technic or routine hematoxylin-eosin stain may prove helpful in establishing or confirming the diagnosis of either toxic shock syndrome or toxic epidermal necrolysis, since the latter shows an interface dermatitis and the former manifests as a superficial perivascular dermatitis. We wish to thank Dr. Joseph Frederick and Dr. William Gosnell for referring their patients with toxic epidermal necrolysis and toxic shock syndrome, respectively, to our attention. REFERENCES 1. Follow-up on toxic shock syndrome. Morbid Mortal Weekly Rep 29:441-445, 1980.
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2, Todd J, et al: Toxic shock syndrome associated with phage group I staphylococci. Lancet 1:1116-1118, 1978. 3. Abdul-Karim FW, et al: Toxic shock syndrome: Clinieopathologic findings in a fatal case, Hum Pathol 12:16-22, 1981. 4. Fisher RF, et al: Toxic shock syndrome in menstruating women. Ann Intern Med 94:156-163, 1981, 5. Tofte RW, et al: Toxic shock syndrome: Clinical and laboratory features in 15 patients. Ann intern Med 94:149-156, 1981. 6. Chesney PJ, et ,-zl:Clinical manifestations of toxic shock syndrome. JAMA 246:741-748, 198l.
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7. Malkinson FD, Pearson BW: The year book of dermatology. Chicago, 1977, Year Book Medical Publishers, Inc., pp. 37-39. 8. Krnmlovsky FA, et al: Renal disease associated with toxic epidermal necrolysis (Lyell's disease). Am J Med 57:817-825, 1974. 9. Ackerman AB: Histologic diagnosis of inflammatory skin disease. Philadelphia, 1978, Lea & Febiger, pp. 581-639. 10. Deetz TR, et al: Secondary rash in toxic shock syndrome? N Engl J Med 304: 174, 1981.