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STEVENS-JOHNSON SYNDROME: A
REVIEW OF THE LITERATURE
Van J. Stitt Jr., MD
Fayetteville, North Carolina

Stevens-Johnson syndrome is both a physically and psychologically

devastating disease. This paper primarily deals with the physiological
complications of the disease process, but the psychological trauma often
associated with such an initially disfiguring disease leaves wounds that
are not visible. Constant support of both the patient and the nursing staff
is necessary to relieve some of the anxiety associated with this syndrome. Education and reassurance should be as much a part of the
treatment process as drug therapy.
Although minimal drug therapy is required in the treatment of StevensJohnson syndrome, early aggressive management is necessary. Treatment should include management of pain and fluid losses as well as
supportive care of the respiratory and ocular complications. It is essential
that nutrition be maintained and that treatment of infections is appropriate
to the identified cultures. Antacids, H2 receptor antagonists, or both have
proven beneficial in the prevention or reduction of gastrointestinal ulcers.
Most important, however, is psychological support of the patient.

did not affect mucous membranes.

Epidermal lesions are symmetrical
and located on the extremities. The
terms erythema multiforme minor
and erythema multiforme major are
currently used to differentiate the
milder form of the disease from the
more severe form; the form described
by Hebra is called erythema multiforme minor. Stevens-Johnson syndrome is classified as a major variant
of erythema multiforme. It is defined
as an acute, self-limiting eruption of
the skin and membranes, characterized by a target lesion and diagnostic
histologic changes.

ETIOLOGY
Stevens-Johnson syndrome was
first described in 1922 as an extraordinary, generalized epidermal eruption. It is accompanied by fever, inflammation of the buccal mucosa,
and severe purulent conjunctivitis.
Incidence of this disorder is unknown,
but it is thought to be very low. The
etiology of this disorder is multiple,
From the Fayetteville Area Health Education
Center, North Carolina. Requests for reprints
should be addressed to Dr. Van J. Stitt, Jr.,
Fayetteville Area Health Education Foundation, Inc., 1601-B Owen Drive, Fayetteville,
NC 28304.

including drugs, infectious agents,

and idiopathic causes. The mortality
rate mainly depends on the age and
health of the patient, and rates can
range from 30 to 100 percent. Individuals at opposite ends of the age
spectrum, ie, the very young and the
old, are usually fatal cases. Death is
commonly due to infectious complications. "
Stevens-Johnson syndrome is a
disease listed under the category of
erythema multiforme. Erythema
multiforme was first described by
Hebra, in 1866, as a mild disease that

Many etiologic factors have been

identified in the pathogenesis of Stevens-Johnson syndrome. It is usually
categorized as iatrogenic, infectious,
or idiopathic.3'4 latrogenic causes are
usually drug related and include antibiotics and anticonvulsants, as well
as a variety of anti-inflammatory
agents such as aspirin and phenylbutazone. Antibiotics most often implicated are the combination sufonamides, penicillins, tetracycline,
erythromycin, and cephalosporins.
Determining the causative factor is
often very difficult; and, occasionally,
no known drugs have been ingested,
continued on page 106

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STEVENS-JOHNSON SYNDROME

continued from page 104

making a definition of the etiology

impossible. Idiopathic causes have
been estimated to occur in approximately 18 to 22 percent of all cases."
One of the more common infectious causes of Stevens-Johnson
syndrome is Mycoplasma pneumoniae7'8; however, herpes simplex
virus has also been implicated. It is
often difficult to determine whether a
drug utilized in treatment of the infectious process is the culprit or
whether an infectious microorganism
has caused the disease.4'9

PATHOPHYSIOLOGY AND
CLINICAL MANIFESTATIONS
The major pathologic change observed in Stevens-Johnson syndrome
is an acute lymphohistiocytic inflammatory infiltrate around blood vessels and degenerative changes in
the endothelial cells of capillaries.
Marked epidermal edema and epidermal necrosis and an immunecomplex process with hypocomplementic vasculitis are also evident.
With pressure, the epidermis is easily
separated from the dermis (Nikolsky's

edematous and papular, forming the

characteristic skin lesions of StevensJohnson syndrome: target lesions.
Target lesions are concentric rings resembling the iris of the eye. They may
extend over the entire body and form
bullae or vesicles within 24 to 96
hours after onset of the rash. Nikolsky's sign (separation of the epidermis
from the dermis with pressure) is
usually present. When confluent, the
lesions may resemble a second-degree
burn. Oftentimes, sloughing of the
epidermis results. " This characteristic
resemblance of a burn injury often
results in the application of silver sulfadiazine, which has its own complications.

Infections

sign). I0
Skin lesions are usually preceded
by a prodrome of respiratory tract and
systemic symptoms that are suggestive of viral illness. Symptoms include
sore throat, headache, fever, and
malaise, and may be present for a
week or two before cutaneous manifestations appear. Stomatitis and
conjunctivitis usually occur one or
two days before the onset of the exanthema. Bianchine et a14 noted in a
retrospective analysis of 138 patients
that manifestations of Stevens-Johnson syndrome were preceded by upper respiratory tract symptoms in approximately 50 percent of cases.

Patients presenting with StevensJohnson syndrome will have complicating infections in 60 to 75 percent
of cases. Impaired host defense probably contributes to the high incidence
of infection. Infections are the single
greatest cause of mortality in these
patients. 2,11 Common infections are
gram-negative pneumonias and septicemias. Organisms that have been
isolated include Pseudomonas aeruginosa, Klebsiella, Staphylcoccus aureus, and Candida species.
Leukopenia generally occurs
within 72 hours after the skin lesions
have appeared. Etiology of this leukopenia is uncertain. Evidence suggests that humoral toxins may be
released into the circulation, suppressing the bone marrow. Another cause
could be the silver sulfadiazine. As
noted, skin sloughing oftentimes resembles that of a burn patient and is
commonly treated with silver sulfadiazine. This drug has been associated
with leukopenia in burn patients.'2

Dermatologic

Respiratory Manifestations

Skin lesions that first appear as erythematous macules soon become

Respiratory complications are frequently associated with Stevens-

106

Johnson syndrome and are often the

cause of death. Pneumonitis, bronchial pneumonia, and bronchiolitis
have been reported to occur in approximately 30 percent of cases with
severe Stevens-Johnson syndrome.
More than half of these individuals
subsequently develop respiratory
failure, requiring intubation and ventilatory support to prevent increased
morbidity and mortality. Respiratory
failure is associated with mucus retention and sloughing of the tracheobronchial mucosa, which contributes
to the prolonged need for support
when such failure occurs.
Many patients experience a late respiratory deterioration. This deterioration may be caused by immune
complexes that are formed in response to an inciting antigen. Such
immune complexes have been isolated from cutaneous lesions during
early stages. Immune complexes have
been known to produce alveolar disease, but the antigen has not been
identified. 12-15

Ocular Manifestations
The incidence of serious ocular
disease is reported to range from 50
to 100 percent. These complications
vary from chronic conjunctivitis to
complete blindness. Incidence and
severity of chronic eye complications
apparently depends upon the degree
of systemic involvement.
Conjunctivitis is the most frequent
ocular complication. This purulent
conjunctivitis causes the eyelids to
become swollen, crusted, and ulcerated, with ensuing pain and photophobia. In severe cases, revascularization of ulcerated lesions may result
in opacification and decreased visual
acuity. Occasionally, adhesions form,
immobilizing the eye. '1,16-18
Ocular recovery is usually complete
and without long-term complications
in patients with mild disease. Rarely,

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STEVENS-JOHNSON SYNDROME

irreversible blindness results. The incidence of irreversible blindness is reported as 6 to 10 percent.'5"18

Gastrointestinal Involvement
Both oral and pharyngeal cavities
are typically involved in StevensJohnson syndrome. Oral lesions,
which commonly begin as vesicles,
rupture, forming a gray-white membrane. The lips are often painful
and crusted with blood. Many patients suffer severe dysphagia, preventing them from ingesting adequate
amounts of fluids and nutrition. Oral
mucous membranes are usually severely eroded for 10 to 14 days; however, prolonged ulceration of the
gastrointestinal tract months after
recovery has been reported.10,20
Although typically the oropharyngeal
cavity is involved, erosion and
sloughing may extend the entire
length of the gastrointestinal tract, resulting in malnutrition, pain, and
bleeding. The most severe gastrointestinal complication is bleeding.
Mortality is rarely associated with this
complication, however, transfusion
may be required.10'20'22

Fluid and Electrolyte Losses

Fluid losses are not as severe as
with thermal burns of equal surface
area, however, fluid-replacement
therapy is needed. Factors that contribute to massive fluid shifts are
evaporation from skin lesions and
leakage from capillaries. Both result
in the loss of blood-borne proteins.
Such fluid shifts may be prevented by
early covering of the area with xenografts.23 As with burns, aggressive
fluid replacement may prevent some
of the complications of volume depletion.

MANAGEMENT
Dermatologic
Skin lesions have traditionally been
treated with topical antibacterial
agents. A relatively new procedure,
which involves the application of biologic dressings, indicates that rapid
closure of the wound with xenografts
may permit rapid re-epithelization
and perhaps decrease morbidity and
mortality in severe cases of StevensJohnson syndrome.23 Such grafts,
usually porcine xenografts or human
allografts, often heal completely
within 10 to 12 days, and the patient's
own skin grows under the grafts.
Scarring of the new skin is minimal,
and major physical deformities are
prevented.24 Grafting of the new skin
onto the damaged area has an additional advantage. It decreases some of
the severe pain often associated with
this disease.

Infection
High-dose corticosteroid therapy
has been used routinely to control or
reduce both skin lesions and sloughing in patients with Stevens-Johnson
syndrome. The use of these steroids,
however, may alter the immune
mechanism, making these patients
more susceptible to infections, and is
therefore considered controversial.
Several reports suggest that the use of
steroids in patients with StevensJohnson syndrome increases the incidence of morbidity and mortality
from infectious complications.6'22123
Steroid usage does not limit the progression of target lesions. Although
steroids are often used, there is no evidence to suggest that they provide
any benefit to the patient.
Other complications associated
with steroids include sepsis, gastrointestinal bleeding, psychosis, and
suppression of the signs of sepsis.
These complications have been noted

JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 80, NO. 1, 1988

to occur in up to 80 percent of patients.2223 Well-controlled, prospective, double-blind studies will be necessary to further define the usefulness
of steroids in this situation.
Prophylactic antibiotic treatment is
not currently recommended. It has
been associated with the development
of resistant organisms and candidal
sepsis.2' Antibiotics should be used in
accordance with local sensitivity patterns for organisms identified by culture. Prevention of infection by strict,
reverse isolation is an essential part
of infection control in patient care.

Respiratory Complications
Pulmonary support is critical to the
survival of the patient. Death is often
attributable to respiratory failure.
Respiratory failure results from a
combination of factors. These include
sloughing of the tracheobronchial
mucous membrane, retention of mucus, and possible immunodeficiency,
which makes these patients more susceptible to infections. Pulmonary
management includes ultrasonic
nebulation, incentive spirometry,
postural drainage, suctioning, physiotherapy, and appropriate treatment
of infection. Arterial blood gases.
should be closely followed for signs
of respiratory failure. At the first
signs of failure, intubation with ventilatory support should be seriously
considered.

Ocular Manifestations
Ophthalmic steroids and topical
antibiotics, recommended in the past,
are no longer considered the standard of care. Studies have shown no
improvement in either outcome
or severity of ocular disease by
their use.7",8
Both aggressive and supportive
ocular measures are imperative. Despite aggressive support, the incidence
107

STEVENS-JOHNSON SYNDROME

of ocular morbidity remains high. An

ophthalmologic consult is essential in
minimizing the complications of Stevens-Johnson syndrome. Sterile, liquid ocular lubricants should be applied to dry or photophobic eyes to
minimize the complications. Lubrication of the eyes may be required
months after resolution of the acute
episode in some cases.'5"17

Gastrointestinal Involvement
Management of gastrointestinal
disease is primarily supportive. Therapy may be required for months until
ulcers and irritation of the mucous
membranes resolve. Often, supportive management of the gastrointestinal tract includes antacids and H2
receptor antagonists (cimetidine or
ranitidine). Attempts should be made
to keep gastric pH > 5. This seems to
reduce both gastric irritation and the
formation of stress-induced ulcers. If
possible, the enteral route should be
used, because sepsis is associated with
parenteral nutrient therapy.2526 As
ulcerations of the gastrointestinal
tract may make tube feeding difficult
and painful, parenteral feeding may
be necessary so as to provide adequate
caloric intake.

Fluid and Electrolyte Loss

Immediate replacement of lost
fluids should be based on the percentage of the total body surface area
affected, the patient's weight, and an
estimation of the volume offluid lost.

108

The proper amount of replacement

fluids can then be maintained by adjusting the input to maintain adequate unne output. This assures adequate hydration. Over-hydration
should not be a problem, but should
be kept in mind. Electrolytes should
be checked a minimum of every six
hours until fluid status is stable.
Literature Cited
1. Huff JC, Weston WL, Tonnesen MG.
Erythema multiforme: Critical review of characteristics, diagnostic criteria, and causes. J
Am Acad Dermatol 1983; 8:763-775.
2. Ackerman AB, Penneys NS, Clark WH.
Erythema multiforme exudativum: Distinctive
pathological process. Br J Dermatol 1971; 84:

554-566.
3. Yetiv JZ, Bianchine JR, Owen JA. Etiologic factors of the Stevens-Johnson syndrome. South Med J 1980; 73:599-602.
4. Bianchine JR, Macaraeg PV, Lasagna
L, et al. Drugs as etiologic factors in the Stevens-Johnson syndrome. Am J Med 1968; 44:
390-405.
5. Carroll OM, Bryan PA, Robinson RJ.
Stevens-Johnson syndrome associated with
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dermal necrolysis: A pathophysiologic review

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