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Stevens–Johnson Syndrome: A Challenging Diagnosis

Davis, Wesley D., DNP, ENP-C, FNP-C, AGACNP-BC, CEN; Schafer, Phillip A., BSN, RN

Section Editor(s): Martinez, Nicole MSN, RN, FNP-BC, ENP-C, PHN; Column Editor

doi: 10.1097/TME.0000000000000197
DERMATOLOGY DILEMMAS

Stevens–Johnson syndrome is a rare, yet life-threatening, delayed-type hypersensitivity reaction characterized by mucocutaneous epidermal necrolysis. Toxic epidermal necrolysis is a severe manifestation of Stevens–Johnson syndrome, defined as greater than 30% skin detachment. Stevens–Johnson syndrome with toxic epidermal necrolysis is characterized as an adverse cutaneous drug reaction and is associated with the use of sulfonamides, antiepileptics, and some classes of nonsteroidal anti-inflammatory drugs. The case presented in this report is that of a 17-year-old female who presented to her primary care provider with a chief complaint of headache; she was initially diagnosed with a urinary tract infection and prescribed nitrofurantoin (Macrobid). Over the next 2 days, her symptoms worsened, she presented to the emergency department twice, and was transferred to a burn unit for definitive care. This case highlights the importance of prompt identification and diagnosis of Stevens–Johnson syndrome and underscores the need for emergency providers to have a comprehensive knowledge of adverse cutaneous drug reactions.

Department of Adult Health Nursing (Dr Davis) and College of Nursing (Mr Schafer), University of South Alabama, Mobile; and PHI Air Medical, Phoenix, Arizona (Mr Schafer).

Corresponding Author: Wesley D. Davis, DNP, ENP-C, FNP-C, AGACNP-BC, CEN, Department of Adult Health Nursing, University of South Alabama, 5721 USA Dr, North, Mobile, AL 36688 (wesleydavis@southalabama.edu).

Disclosure: The authors report no conflicts of interest.

STEVENS–JOHNSON SYNDROME (SJS) is a rare and potentially life-threatening delayed-type hypersensitivity reaction characterized by epidermal necrolysis of cutaneous and mucosal tissue (Lerch, Mainetti, Terziroli Beretta-Piccoli, & Harr, 2017). Stevens–Johnson syndrome is part of a spectrum of disease processes ranging from SJS (less than 10% skin detachment) to toxic epidermal necrolysis (TEN; greater than 30% skin detachment); 10%–30% skin detachment is characterized as SJS/TEN (Lerch et al., 2017). The development of SJS has been correlated with the use of numerous medications (see Table 1; Roujeau et al., 1995). Although SJS is often associated with adverse drug reactions, the etiology of SJS is complex and not entirely understood (Dunn, 2017 ; Maverakis et al., 2017).

Table 1

Table 1

Despite recent attention to the importance of early diagnosis of adverse cutaneous drug reactions (Briggs, 2011), SJS/TEN represents a continuing challenge for emergency department (ED) providers. The ability of SJS to mimic less critical conditions requires that practitioners be familiar with the features and associated symptoms of SJS/TEN. The following is a case report of a 17-year-old female who was discharged home from both her primary care provider (PCP) and the ED on two consecutive days before the diagnosis of TEN. On the third day, the patient re-presented to the ED in acute respiratory distress and greater than 50% skin detachment, requiring emergency intubation and transfer to an outside burn unit at a tertiary care center. The purpose of this report is to highlight the early signs and symptoms of SJS, which may have been overlooked and misattributed to other causes.

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PATHOPHYSIOLOGY

Stevens–Johnson syndrome results from widespread keratinocyte apoptosis, or programmed cell death, which is induced by a cell-mediated cytotoxic reaction involving T lymphocytes and natural killer cells (Harris, Jackson, & Cooper, 2016). There are several cytotoxic proteins that have been suggested to induce apoptosis in SJS, including granulysin, Fas–Fas ligand, perforin-granzyme B, tumor necrosis factor α, and tumor necrosis factor–related apoptosis-inducing ligand. The evidence implicating granulysin is strongest. Research has shown that the concentration of granulysin in patient blisters correlates with the severity of the disease (Chung et al., 2008). Furthermore, granulysin from the blisters of patients is sufficient to induce keratinocyte cell death and blistering in mouse skin in a dose-dependent manner (Chung et al., 2008).

It is widely accepted that SJS is initiated by an immunological reaction to a drug or its metabolized product. The mechanism of activation for cytotoxic T lymphocytes is a subject of debate. In one theory, a drug or its metabolized form is presented as an antigen to the T-cell receptor (Schwartz, McDonough, & Lee, 2013). Another theory is that the drug binds noncovalently to the major histocompatibility complex, which alters the binding cleft and results in a self-peptide that is responsible for activation of cytotoxic T lymphocytes (Wolkenstein & Wilson, 2016). In any case, the activated lymphocytes induce apoptosis in keratinocytes throughout the entire depth of the dermis resulting in painful blistering and sloughing of the skin (see Figure 1) and mucous membranes (see Figure 2).

Figure 1

Figure 1

Figure 2

Figure 2

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ENCOUNTER

Chief Complaint

Day 1 (PCP)—Headache

Day 2 (ED visit no. 1)—Hives

Day 3 (ED visit no. 2)—Fever, difficulty breathing, and worsening rash

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History of Present Illness

The patient was a 17-year-old Caucasian female who initially presented to her PCP for the evaluation of a headache. The patient subsequently presented to the ED on two consecutive days with progressively worsening symptoms prior to eventual diagnosis and admission.

Upon initial presentation to her PCP, the patient reported a throbbing frontal headache with associated pressure and burning behind the eyes. Vital signs were stable and physical examination was unremarkable. Complete blood count and comprehensive metabolic panel were within normal limits. Urinalysis (UA) was positive for leukocytes and leukocyte esterase, suggestive of a urinary tract infection (UTI). A prescription for nitrofurantoin (Macrobid) was provided for the treatment of suspected UTI.

The following day, the patient presented to the ED with a chief complaint of hives; she also reported generalized myalgias, a burning sensation in her eyes, and “soreness” in and around her mouth. Physical examination revealed tachycardia and diffuse urticarial lesions. Given these findings, the patient was treated for a suspected anaphylactic reaction to Macrobid. The patient received 1 L of 0.9% normal saline, methylprednisolone (Solu-Medrol) 125 mg intravenously (IV), diphenhydramine 25 mg IV, and ketorolac (Toradol) 30 mg intramuscularly. No laboratory tests were performed. The patient was monitored for several hours per protocol and discharged home with instructions to return if symptoms progressed. Of note, the patient's heart rate was 120 beats per minute (bpm) at discharge.

Following discharge home from the ED, the patient reported worsening rash, high-grade fever (self-reported axillary temperature of 105.1 °F), and difficulty breathing. Emergency medical services (EMS) was called because of worsening respiratory status and inability to tolerate oral intake.

The patient was brought in to the ED by EMS approximately 12–18 hr after initial discharge. On arrival, the patient was noted to have extensive, large bullous lesions on her trunk, extremities, genitalia, scalp, and oral mucosa. In addition, the patient was noted to have rapidly expanding bullae in her pharynx that threatened her airway.

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Past Medical and Surgical History

No known past medical or surgical history.

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Family and Social History

The patient denied tobacco, alcohol, and illicit drug use. Family history was noncontributory.

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Allergies

No known food or drug allergies. Nickel allergy noted in chart.

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Current Medications

Naproxen 220 mg PO as needed, prior to initial presentation.

Macrobid 100 mg PO twice daily, prescribed at initial PCP visit.

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Review of Systems

Review of systems upon initial presentation to the ED (Day 2) was notable for rash, headache, burning and pressure behind eyes, and nausea. At the time, the patient denied fevers, chills, chest pain, shortness of breath, difficulty tolerating oral intake, vomiting, dysuria, and urinary frequency. The patient was unable to provide a thorough review of systems at the third ED visit (Day 3) because of rapidly progressive rash and worsening respiratory distress.

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Physical Examination—Key Findings

Day 1—PCP

  • Vitals: Within normal limits.
  • General: Well-appearing female in no acute distress.
  • Skin: No rashes, bruising, or lesions.
  • HEENT: Head—normocephalic, atraumatic. Eyes—conjunctiva clear, no drainage; PERRLA, EOMI. Ears—no abnormalities noted. Oral cavity—No lesions, erythema, exudate, or edema. Pharynx—no erythema, exudate, or edema. No other abnormalities noted. Neck—supple, nontender; trachea midline; no lymphadenopathy or other abnormalities noted.
  • Respiratory: Clear to auscultation bilaterally.
  • Cardiovascular: Regular rate and rhythm; no murmurs, rubs, or gallops. Normal S1 and S2.
  • Abdomen: Soft, nontender, nondistended. Bowel sounds present in all four quadrants.
  • Back: No deformities noted. No costovertebral angle tenderness.
  • Extremities: Well-perfused; pulses symmetric and intact.
  • Neurologic: Cranial nerves II–XII grossly intact. Motor, strength, and sensation intact bilaterally. No gait or balance abnormalities noted. Appropriate and symmetric deep tendon reflexes.
  • Psychiatric: Alert and oriented to person, time, place, and location. Appropriate mood and affect.
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Day 2—ED Visit No. 1

Unchanged from prior with the following exceptions:

  • Vitals: Heart rate 150 bpm
  • General: Well-appearing patient in mild distress
  • Skin: Diffuse urticarial lesions on face, extremities, and trunk
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Day 3—ED Visit No. 2

Unchanged from prior with the following exceptions:

  • Vitals: Heart rate 122 bpm, temperature 100.9 °F, respiratory rate 30 breaths per minute, O2 saturation 95% on 15 L/min nonrebreather.
  • General: Sick-appearing patient in acute distress
  • Skin: Large (up to 7–8 cm) bullous lesions on trunk, extremities, scalp, genitalia, and mucous membranes. Positive Nikolsky's sign.
  • HEENT: Eyes—bullous lesions on eyelids, unable to open eyes fully; reduced visual acuity. Oral cavity—multiple bullous lesions of buccal mucosa. Pharynx—multiple, expanding bullous lesions of pharyngeal mucosa
  • Medications: Advised to stop Macrobid. Repeat microscopic urinalysis does not contain leukocytes.
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Initial Management and Findings

Shortly after arrival in the ED, the decision was made to intubate the patient given progressing respiratory distress. An initial attempt at intubation with a 7.0 endotracheal tube (ETT) was unsuccessful due to airway edema; a second attempt with a 6.0 ETT was successful. Cutaneous and mucosal lesions noted on physical examination raised concern for SJS.

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Consults/Referrals

Given concern for SJS, the patient was transferred to a burn unit at a tertiary care center for further evaluation and treatment.

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Radiological Imaging

Imaging studies are of limited diagnostic value in SJS. In this case, a chest radiograph was obtained during the patient's second presentation to the ED; no abnormalities were noted.

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Treatment Course and Outcome

The patient was transferred to a burn unit for further management of suspected SJS. Upon transfer, the patient quickly deteriorated, requiring a tracheostomy and Swan–Ganz catheter placement. On admission, the patient was noted to have severe alopecia along with dermal sloughing; avulsion of the finger and toenails was also noted. The patient was diagnosed with TEN involving 56% of her body surface area (BSA). The patient was placed in a medically induced coma and started on intravenous immunoglobulin treatment (IVIG). The patient underwent multiple debridement procedures throughout her hospitalization. The patient was discharged home after 3 weeks. At the time of publication, the patient continues to have severe and debilitating complications of SJS, requiring thrice daily dressing changes and weekly follow-up in specialty clinics. Eligibility for skin-grafting procedures has yet to be determined.

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Differential Diagnosis

The differential diagnosis of SJS/TEN includes infection (e.g., staphylococcal scalded skin syndrome, erythema multiforme), autoimmune blistering diseases (e.g., pemphigus vulgaris, IgA dermatosis), and other adverse drug reactions (e.g., disseminated fixed bullous drug eruption; Harr & French, 2010). Definitive diagnosis of SJS/TEN is made by skin biopsy showing full-thickness dermal necrosis in the absence of immunoglobulin deposition (Harr & French, 2010). Many patients with SJS/TEN experience a “flu-like” prodrome characterized by malaise, fever, sore throat, burning of the eyes, and fatigue (Harris, Jackson, & Cooper, 2016); thus, clinicians should consider SJS/TEN when such generalized symptoms are associated with cutaneous manifestations.

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Management

The treatment of SJS/TEN is similar to that of severe thermal burns and consists primarily of supportive care. It is imperative that ED providers recognize the signs and symptoms of SJS/TEN, as outcomes of care are largely dependent on prompt transfer to specialized burn units (Creamer et al., 2016). In addition to supportive therapy, the patient described in this report also received IVIG, which is thought to attenuate necrolysis by inhibiting a cell death receptor, CD95 (Viard et al., 1998).

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DISCUSSION

This case report highlights the early manifestations of SJS/TEN and underscores the importance of early recognition and prompt transfer; the misdiagnosis of Macrobid allergy in this patient likely contributed to her severe morbidities. Although the definitive etiology of SJS/TEN in this patient remains unknown, an adverse reaction to naproxen must be considered as a possible culprit. In addition, the nonsteroidal anti-inflammatory drug (NSAID) Toradol, which was administered at the first ED visit, may have worsened the situation. Previous studies have demonstrated a correlation between oxicam NSAID use and SJS/TEN (Roujeau et al., 1995). Although the risk of SJS/TEN with other classes of NSAIDs remains low, it is not nonexistent (Mockenhaupt, Kelly, Kaufman, Stern, & Group, 2003). A recent case report out of Nepal highlights a patient with a similar presentation of SJS/TEN after ibuprofen use (Angadi & Karn, 2016).

Recent guidelines published in the United Kingdom underscore the importance of obtaining a thorough history in the early recognition and diagnosis of SJS/TEN (Creamer et al., 2016). The authors of these guidelines suggest that all providers inquire about prodromal illness, prescription and over-the-counter medication use, and respiratory involvement in patients who present with blistering rash (Creamer et al., 2016). Ocular manifestations and cutaneous pain are also common in the early stages of SJS/TEN (Creamer et al., 2016). Once SJS/TEN is suspected, the progression of skin erythema and its extent need to be documented on a body map. Body surface area can be estimated by utilizing the Lund and Bowder (L&B) chart. Accurate calculations of BSA involvement are critical for determining disease prognosis (Creamer et al., 2016).

The patient described in this report continues to have severe morbidities that significantly limit her activities of daily living. She continues to require daily gynecological dressing changes and not regained visual acuity. The question remains as to whether these complications could have been avoided by prompt diagnosis and treatment.

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CONCLUSION

Stevens–Johnson syndrome is a rare but life-threatening delayed-hypersensitivity reaction. Stevens–Johnson syndrome/toxic epidermal necrolysis can quickly progress from a “flu-like” prodrome to widespread epidermal necrolysis, respiratory failure, and death. Early recognition and transfer to a tertiary care burn unit are critical to treatment of SJS/TEN. Emergency department providers must be familiar with the signs and symptoms of SJS/TEN to facilitate prompt suspicion and recognition. Obtaining a thorough medical history is critical to this process and can prove to be life-saving.

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REFERENCES

Angadi S. S., Karn A. (2016). Ibuprofen induced Stevens–Johnson syndrometoxic epidermal necrolysis in Nepal. Asia Pacific Allergy, 6(1), 70–73. doi:10.5415/apallergy.2016.6.1.70
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Chung W. H., Hung S. I., Yang J. Y., Su S. C., Huang S. P., Wei C. Y., Chen Y. T. (2008). Granulysin is a key mediator for disseminated keratinocyte death in Stevens–Johnson syndrome and toxic epidermal necrolysis. Nature Medicine, 14, 1343–1350. doi:10.1038/nm.1884
Creamer D., Walsh S. A., Dziewulski P., Exton L. S., Lee H. Y., Dart J. K., Smith C. H. (2016). U.K. guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults 2016. British Journal of Dermatology, 174(6), 1194–1227. doi:10.1111/bjd.14530
Dunn J. (2017). Genetics and Stevens–Johnson syndrome/toxic epidermal necrolysis: what have we learned? JAMA Ophthalmology, 135(4), 361–362. doi:10.1001/jamaophthalmol.2017.0136
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Keywords:

adverse cutaneous drug reactions; delayed-type hypersensitivity; Stevens–Johnson syndrome; toxic epidermal necrolysis

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