Case 34-2005 — A 10-Year-Old Girl with a Bullous Skin Eruption and Acute Respiratory Failure
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《新英格兰医药杂志》
Presentation of Case
A 10-year-old girl was transferred to the Shriners Hospital for Children because of a bullous skin eruption, with sloughing of the skin and respiratory failure.
The patient had been well until two months before admission, when she had a generalized tonic–clonic seizure. She was examined at another hospital and treated with diazepam. An electroencephalogram obtained the next day revealed no abnormalities. A neurologist believed that the risk of a recurrent seizure was low, and therefore, no antiseizure medication was prescribed. Two weeks later, magnetic resonance imaging (MRI) of the brain showed a cyst, 7 mm in diameter, in the left choroidal fissure and several small nonspecific foci of increased T2-weighted signal in the right centrum semiovale.
One month before admission, during an episode of gastroenteritis in which the patient's body temperature rose to 39.2°C, intermittent twitching occurred in both legs. A diagnosis of seizure was made, and a neurologist prescribed carbamazepine, 100 mg twice daily for two weeks, after which the dose was increased to 150 mg twice daily. On examination by the neurologist two days after the seizure, the patient was alert and her behavior was appropriate, the weight was 28.8 kg, the height 132.5 cm, and the physical and neurologic examinations showed no abnormalities.
Nine days later, the temperature rose to 40.6°C, and a rash appeared on the patient's trunk. The next day her pediatrician noted an elevated temperature and petechiae and sent her to the emergency room of the hospital where she had been examined previously. The blood pressure was 101/62 mm Hg, the pulse 125 beats per minute, the temperature 39.0°C, the respiratory rate 28 breaths per minute, and the weight 28.8 kg. A diffuse, erythematous morbilliform rash with extensive confluence was present, most intensely visible on the trunk, back, and upper arms and thighs, with blanching. The skin was warm and dry, there was no palm or sole involvement, and approximately 5 to 10 isolated petechiae were seen on the abdomen, without purpura. The remainder of the examination was normal. A diagnosis of hypersensitivity reaction was made. The carbamazepine was discontinued, and lorazepam was begun. Specimens of blood and urine were sent for cultures, and a dose of ceftriaxone was administered. The patient was discharged to her home.
The next day, the temperature remained elevated, the rash had spread to involve most of her body, and vesicles had developed. The patient vomited twice. She returned to the emergency room of the first hospital. There was no history of diarrhea. Methylprednisolone (2 mg per kg of body weight), lorazepam, and ranitidine were administered intravenously, and she was admitted.
On examination, diffuse, erythematous, raised lesions involved the face, trunk, back, arms and legs, and lips. Nikolsky's sign (ready removal of the epidermis with slight tangential pressure) was present. There were multiple vesicles and ulcers on the oral and lingual mucosa, with desquamation of the lingual mucosa. The lungs were clear, and the heart sounds were normal. The abdomen was diffusely tender, a finding that was thought to be due to the skin lesions. A rectal examination revealed no abnormalities, and a guaiac stool test was negative. The results of laboratory tests are shown in Table 1 and Table 2.
Table 1. Hematologic Laboratory Data.
Table 2. Blood Chemical Values.
Over the course of the next 24 hours, increased pain in the mouth, pain on urination, and additional vesicular skin lesions developed. Ceftriaxone and morphine were administered intravenously. On the second hospital day, the patient was transferred to the intensive care unit. Sloughing of the skin and oral mucosa occurred; the trachea was intubated, and mechanical ventilation was instituted; a right femoral triple-lumen catheter was placed, and an infusion of lactated Ringer's solution was begun. The wounds were blistered and productive of a moderate amount of clear drainage fluid; bland petroleum dressings were applied. Acetaminophen, midazolam, morphine, immune globulin, ranitidine, cefazolin, oxacillin, and lorazepam were administered. The results of blood and urine cultures were pending. Later that day, the patient was transferred to the Shriners Hospital for Children, which is affiliated with this hospital.
The patient had no other medical problems, no known allergies, and her immunizations were up to date. Her father had had sloughing of the skin after taking a sulfa drug when he was five years of age, which had required hospitalization. He had had a tonic–clonic seizure when he was 10 years of age for which phenytoin was administered for nine months; no further seizures occurred. Other family members were well.
On examination, the patient was intubated and sedated, but she responded to tactile stimuli. The axillary temperature was 39.4°C, the pulse 158 beats per minute, the respiratory rate 22 breaths per minute, and the blood pressure 95/46 mm Hg. The weight was 30.15 kg. Her tongue was swollen, and the oral mucosa was sloughing. Lung sounds were clear, after thick yellow secretions were suctioned from the endotracheal tube. Bowel sounds were present; the abdomen was soft and not distended. The skin of the trunk was denuded, with the appearance of a second-degree burn, and intact vesicles covered much of the skin of the arms and legs; there was involvement of 97 percent of the epidermis, sparing only the vertex of the scalp. A catheter drained cloudy, dark-yellow urine. The results of other laboratory tests are shown in Table 1 and Table 2.
During the patient's first 24 hours after admission, the temperature increased to 40.2°C. The mean arterial pressure decreased to 45 mm Hg; a dopamine infusion was begun, and 1 unit of red cells was transfused. The urine output ranged between 8 and 18 ml per hour; 5 percent albumin solution was added to the intravenous therapy and the infusion rate of lactated Ringer's solution increased gradually, with improvement in urinary output and mean arterial pressure. Oxygen saturation decreased from 100 percent to 88 percent while she was receiving 40 percent inspired oxygen, scattered ronchi were heard, and patchy infiltrates were seen on chest radiography. Albuterol and beta-agonist agents were delivered by nebulizer, and intravenous morphine and midazolam were administered. Tube feedings were begun but were discontinued because of ileus and incomplete gastric emptying, and total parenteral nutrition was initiated on the third hospital day.
Sloughing of the corneas and respiratory and gastrointestinal mucosae occurred over the course of the first three days of hospitalization, with blood loss into the bowel and airway; thrombocytopenia persisted and neutropenia and anemia developed (Table 1). Fever, hypotension, and cardiac and respiratory failure with acidosis and hypoxemia persisted. Sequential chest radiographs during the second and third weeks revealed worsening air-space opacities and bilateral pleural effusions. Treatment with nitric oxide resulted in no improvement. Permissive hypercapnia was instituted. Echocardiography on the 24th hospital day revealed a dilated left atrium and ventricle, with an estimated ejection fraction of 66 percent. Blood cultures were positive at various times for gram-positive (Staphylococcus aureus) and gram-negative (Stenotrophomonas maltophilia) bacteria, as well as fungi (Candida parapsilosis), and antibiotic and antifungal therapy was administered.
Throughout the period when the patient's skin was denuded, frequent fluid replacement and electrolyte repletion were required. During the fourth week, the skin wounds began to heal, followed gradually by healing of the corneal and oral mucosal lesions.
The patient's respiratory function gradually improved, and the trachea was extubated on the 35th day. The hematocrit and results of renal-function tests returned to normal, and she became afebrile. Pain medications were tapered slowly. She was discharged to her home on the 91st hospital day.
Differential Diagnosis
Dr. Vincent Liu: Although I am aware of the diagnosis in this case, a generalized blistering skin eruption in a child has a broad differential diagnosis (Table 3).1 Most of these diagnoses can be readily ruled out by the history and clinical features in this case. The fact that therapy with carbamazepine had been recently initiated focuses the differential diagnosis on cutaneous reactions to drugs.2 The most important consideration is the staphylococcal scalded skin syndrome, which is mediated by the exotoxin (phage group II, type 71) produced by S. aureus; it produces diffuse ill-defined erythema and flaccid bullae, with a positive Nikolsky's sign. However, this disorder affects primarily newborns and infants under two years of age and patients with renal failure.
Table 3. Differential Diagnosis of Bullous Exfoliative Erythroderma in a Child.
Erythema multiforme3 is a hypersensitivity response that usually follows infection with either herpes simplex virus or mycoplasma; it is characterized by the sudden, symmetric onset of raised, targetoid erythematous macules and thin plaques, predominantly on the arms and legs and hands and feet; mucosal involvement, formation of bullae, and sloughing occur rarely (for instance, in bullous erythema multiforme, erythema multiforme major — conditions that may be more closely related to the Stevens–Johnson syndrome and toxic epidermal necrolysis).4 Erythema multiforme usually resolves spontaneously without life-threatening complications. The Stevens–Johnson syndrome and toxic epidermal necrolysis are thought to represent a single disease with a spectrum of severity.5 Generalized tender erythematous macules that progress to blisters and denudation are often preceded by photophobia, symptoms of upper respiratory infection, and fever. The Stevens–Johnson syndrome and toxic epidermal necrolysis are typically distinguished from each other according to the extent of cutaneous involvement6,7,8 (Table 4). This patient had generalized denudation of skin and mucous membranes after exposure to carbamazepine, a drug commonly associated with toxic epidermal necrolysis9 (Table 5). The extent of involvement and the clinical history in this patient are virtually diagnostic of this disorder.
Table 4. Distinguishing Features of Erythema Multiforme, Stevens–Johnson Syndrome, and Toxic Epidermal Necrolysis.
Table 5. Most Common Drugs Associated with Toxic Epidermal Necrolysis.
Dr. Vincent Liu's Diagnosis
Toxic epidermal necrolysis, due to carbamazepine.
Pathological Discussion
Dr. Liu: The diagnosis of toxic epidermal necrolysis can be confirmed by a skin biopsy, although one was not performed in this case. When obtained, skin-biopsy specimens show that the epidermis is necrotic and detached from the underlying dermis (Figure 1). The dermis shows a mild superficial perivascular lymphocytic infiltrate. The staphylococcal scalded skin syndrome and toxic epidermal necrolysis both involve necrosis of the epidermis: the key distinguishing feature is the extent of epidermal necrosis, which involves only the superficial corneal layer in the staphylococcal scalded skin syndrome or acute exanthematous pustulosis, and the full thickness of the epidermis in the Stevens–Johnson syndrome and toxic epidermal necrolysis. This aspect of toxic epidermal necrolysis lends itself to a rapid means of identification: when the epidermis is "peeled off" in toxic epidermal necrolysis, rolled around a cotton-swab stick like a jelly roll, and examined in a frozen section, full-thickness epidermal necrosis can be recognized (shown in Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Figure 1. Skin-Biopsy Specimens from Another Case of Toxic Epidermal Necrolysis.
The epidermis is separated from the underlying dermis, which contains a scant inflammatory infiltrate. The inset, at higher magnification, reveals necrosis and dyskeratosis of the epidermis.
Toxic epidermal necrolysis is thought to be a cell-mediated immunologic reaction to drug metabolites, which may accumulate because of abnormal metabolism of the drug, resulting in the persistence of immunogenic metabolites. There is a reported association with the HLA-B12 haplotype; a genetic association is suggested in this case by the father's history of a sloughing skin reaction to a sulfa drug in childhood. The necrosis appears to be mediated by CD8+ T cells by way of Fas-mediated apoptosis.10
Discussion of Management
Dr. Robert L. Sheridan: This child was admitted to the burn unit with a diagnosis of toxic epidermal necrolysis, with massive necrosis of the skin, rapidly progressive multiple-organ failure, and polymicrobial sepsis. Patients with toxic epidermal necrolysis are increasingly referred to burn units for care because the resources needed for management, intensive care, and wound expertise are similar to those required by patients with large burns.11,12,13
The syndrome generally begins, as it did in this child, with a diffuse macular rash (Figure 2A) that spreads and becomes confluent, with separation of the epidermis, fluid loss, and bleeding (Figure 2A of the Supplementary Appendix). Involvement of the ocular mucous membranes (Figure 2B of the Supplementary Appendix) and the oral mucous membranes (Figure 2B) is usually prominent in toxic epidermal necrolysis, as occurred in this child. The latter often compromises airway patency and protective reflexes, mandating endotracheal intubation, as happened in this case. Cutaneous and visceral wounds progress in a variable and unpredictable way. In those who survive, cutaneous reepithelialization usually occurs at four to eight weeks. Frequently, healing of the conjunctival and visceral wounds lags behind healing of the cutaneous wounds.
Figure 2. Clinical Images of Patients with Toxic Epidermal Necrolysis.
The process begins with a diffuse macular rash (Panel A, from another patient), which becomes confluent. Sloughing of the lips and oropharynx (Panel B, this patient) compromised the child's ability to guard her airway, and intubation was required. Eventually, the skin was almost completely denuded (Panel C). Two years later, recovery was virtually complete (Panel D).
As is in this child, it is very common for the diagnosis of toxic epidermal necrolysis to be delayed, probably because of the rarity of the syndrome and its relatively nonspecific early signs. However, in its full-blown form, the diagnosis is straightforward, since no other entity is characterized by such extensive sloughing of cutaneous, ocular, oropharyngeal, rectal, and genitourinary surfaces, along with the high degree of systemic toxicity. There are no specific laboratory or radiographic findings. Management of this condition requires strategies for wound care and for control of organ failure.
Management of the Wound
This child's most obvious presenting problem was a rapidly enlarging, painful cutaneous wound (Figure 2C). The principal problems associated with this are extreme pain, loss of protein-rich fluid, bleeding, hypothermia, and infection.14 Less obvious, but in many ways more problematic, are visceral wounds of variable extent that involved all epithelium-lined structures: the mouth, nares, oropharynx, esophagus and gastrointestinal tract, biliary and pancreatic ducts, bladder, vagina, rectum, and conjunctiva. The principal problems associated with these wounds are organ dysfunction, blood loss, and infection.15
The objectives of cutaneous-wound management are the prevention of desiccation and superinfection and the control of pain. When surface infection is present, topical antimicrobial agents are ideal.16 When wounds are clean, membrane dressings are more appropriate.17,18 In this child, the principal topical preparation used was 0.5 percent aqueous silver nitrate, and the principal membranes were porcine xenograft and a silver-containing synthetic material. It is essential that such wounds be managed in an environment that can minimize evaporative heat loss, if hypothermia and dangerous electrolyte disturbances are to be avoided. This child was placed in a bacteria-controlled nursing unit in the burn intensive care unit, engineered for this purpose.19 Management of the visceral wounds was essentially supportive, treating infections as they arose, replacing blood losses, and supporting failing organ systems, while awaiting reepithelialization of these inaccessible surfaces.
Special mention should be made of the management of conjunctival sloughing.20 This condition affects most children with this illness to a variable degree and is often quite severe. The denuded cornea and globe are very painful and prone to desiccation, corneal ulceration, and destructive local infection.21 The palpebral and globular conjunctivae can form adhesions. This condition is best managed with frequent ocular lubrication, the use of topical corticosteroids, frequent culturing, and administration of focused topical antibiotics. The lids should be regularly separated from the globes to prevent adhesions. Biologic dressings are useful in some children for temporary coverage of the cornea, but they were not required in this case.
Corneal and cutaneous wounds are exquisitely painful, and control of pain and anxiety is an important component of management. Pain and anxiety were managed in this patient by intravenous infusions of escalating doses of morphine sulfate and midazolam, with additional doses when dressings needed to be changed, wounds cleansed or manipulated, or vascular-access or other procedures performed.22
Management of Multiple-Organ Failure
Multiple-organ failure is common in children with toxic epidermal necrolysis, although the intensity, duration, and sequence are quite variable. This child had perhaps the most common sequence of organ dysfunction. As her cutaneous and oropharyngeal wounds progressed, intubation was required for airway protection.23,24 By the 15th hospital day, her respiratory status began to deteriorate. Pulmonary hypertension and intrapulmonary shunting developed and did not improve with inhaled nitric oxide, which was discontinued on the 20th hospital day.25 Could we review the chest radiographs?
Dr. Sudha Anupindi: The chest radiograph obtained on the second hospital day showed mild interstitial edema but no pleural effusions (Figure 3A). A radiograph taken on the 11th day showed peripheral alveolar opacities with consolidation in the left upper lobe (Figure 3A of the Supplementary Appendix), which progressively worsened, as seen on a radiograph from the 20th day (Figure 3B). The findings on chest radiography stabilized at that point and then started to improve (Figure 3B of the Supplementary Appendix). The differential diagnosis of the alveolar opacities includes pulmonary hemorrhage, pneumonia, or pulmonary edema; in this clinical setting, the progressive changes seen on the films best fit the pattern of the acute respiratory distress syndrome.
Figure 3. Chest Radiography.
An anteroposterior radiograph of the chest on the first hospital day (Panel A) shows mild interstitial edema (arrows). A chest radiograph obtained on the 20th hospital day (Panel B) shows alveolar opacities, predominantly peripheral, with areas of consolidation in the left upper lobe (arrow).
Dr. Sheridan: The acute respiratory distress syndrome in this patient was managed with neuromuscular blockade, pressure-controlled ventilation, and permissive hypercapnia.26 Despite severe respiratory failure, this approach succeeded, and she was extubated on the 37th day after admission.
Large free-water and electrolyte losses occurred through this child's wounds, resulting in electrolyte disturbances. Diligent monitoring and replacement were required to maintain electrolytes in the physiologic range. Central venous and arterial access was required throughout the period of critical illness; systemic arterial pressure was maintained through the use of adequate fluid replacement and inotropic and vasopressor agents. Gastrointestinal failure developed, with a protracted period of ileus, hepatic dysfunction, and pancreatitis that prevented effective enteral nutrition. She was supported nutritionally for several weeks by means of a combination of enteral and parenteral formulations. Parenteral support is well tolerated by critically ill children and will prevent excessive catabolism and facilitate wound healing.27,28
Profound pancytopenia, which developed in this child, as it does in many patients with toxic epidermal necrolysis, is minimally responsive to granulocyte colony-stimulating factor. By hospital day 5, her absolute neutrophil count was less than 400 per cubic millimeter. Neutropenia posed a particular problem in the face of a denuded skin and gut, and the situation required the administration of prophylactic antibiotics, including vancomycin, gentamicin, and ceftriaxone. Thrombocytopenia also occurred, with platelet counts in the range of 60,000 per cubic millimeter for several days after admission, and it exacerbated blood loss into the denuded gut, genitourinary tract, and airway. Transfusions of red cells were administered, and coagulation proteins were supported with infusions of fresh-frozen plasma. Neutropenia in this patient resolved by the 10th hospital day. Anemia persisted and was thought to be due to blood loss from the intestinal and bronchial mucosae. Transfusions of a total of 8 units of packed red cells were given over the course of three weeks.
Most deaths in patients with toxic epidermal necrolysis are a result of sepsis-induced organ failure. In this child, blood cultures at various times grew S. aureus, C. albicans, and S. maltophilia. These episodes were associated with hypothermia and hypotension and worsening multiple-organ failure. S. maltophilia is a difficult, multidrug-resistant gram-negative organism, which was sensitive to trimethoprim–sulfamethoxazole, a sulfa-derived drug. Since sulfa drugs have a known potential for causing toxic epidermal necrolysis, this risk was discussed with the family before therapy. Fortunately, no reaction occurred, and the infection was controlled.
This child received intravenous immune globulin early on, and severe diffuse toxic epidermal necrolysis continued to evolve. It has been theorized that intravenous immune globulin may improve outcomes, given its salutary effect in another inflammatory condition, Kawasaki's disease. This contention has been supported by small, uncontrolled clinical trials.29 However, other data do not support its use, and intravenous immune globulin is not now part of the standard of care for toxic epidermal necrolysis.30 Corticosteroid drugs have also been advocated for toxic epidermal necrolysis, but most clinicians do not support their routine use, given the risk of increased infection and the absence of data demonstrating benefit. Plasma exchange has also been proposed but not shown to be efficacious. These interventions were not used in this case.
Survival and Long-Term Outcome
Published mortality rates for patients with toxic epidermal necrolysis vary widely and are between 40 and 70 percent.15,31,32 In this child, as in most survivors, cutaneous reepithelialization became evident four to eight weeks after admission and was followed by healing of the mucous membranes and conjunctivae. Presumably, resurfacing of viscera was also occurring at this time, when there was rapid clinical improvement in cardiovascular and pulmonary function. The patient was discharged to her home after three months; she eventually returned to school and resumed normal activities.
Ophthalmic complications, seen in about 30 percent of surviving children,20 include impaired tear production and drainage, aberrant lashes, dry eye syndrome, photophobia, metaplasia of the conjunctiva, and corneal scarring with blindness. This patient had mild photophobia for several months, which gradually resolved. Variegated skin pigment changes have persisted in this patient, but the quality of the skin has become otherwise essentially normal (Figure 2D). Fingernail and toenail deformities are common; this patient lost all of her fingernails and toenails. Most of her nails have subsequently regrown, but they remain deformed, as they do in about 40 percent of children who survive this condition.
Other than the minor residual deformities of her fingernails and toenails, this patient is normal. She has recovered virtually completely.
Final Diagnosis
Toxic epidermal necrolysis.
Source Information
From the Burn Surgical Service, Shriners Hospital for Children (R.L.S.); the Division of Burns, Department of Surgery (R.L.S.), and the Departments of Pathology (V.L.) and Radiology (S.A.), Massachusetts General Hospital; and the Departments of Surgery (R.L.S.), Pathology (V.L.), and Radiology (S.A.), Harvard Medical School — all in Boston.
References
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A 10-year-old girl was transferred to the Shriners Hospital for Children because of a bullous skin eruption, with sloughing of the skin and respiratory failure.
The patient had been well until two months before admission, when she had a generalized tonic–clonic seizure. She was examined at another hospital and treated with diazepam. An electroencephalogram obtained the next day revealed no abnormalities. A neurologist believed that the risk of a recurrent seizure was low, and therefore, no antiseizure medication was prescribed. Two weeks later, magnetic resonance imaging (MRI) of the brain showed a cyst, 7 mm in diameter, in the left choroidal fissure and several small nonspecific foci of increased T2-weighted signal in the right centrum semiovale.
One month before admission, during an episode of gastroenteritis in which the patient's body temperature rose to 39.2°C, intermittent twitching occurred in both legs. A diagnosis of seizure was made, and a neurologist prescribed carbamazepine, 100 mg twice daily for two weeks, after which the dose was increased to 150 mg twice daily. On examination by the neurologist two days after the seizure, the patient was alert and her behavior was appropriate, the weight was 28.8 kg, the height 132.5 cm, and the physical and neurologic examinations showed no abnormalities.
Nine days later, the temperature rose to 40.6°C, and a rash appeared on the patient's trunk. The next day her pediatrician noted an elevated temperature and petechiae and sent her to the emergency room of the hospital where she had been examined previously. The blood pressure was 101/62 mm Hg, the pulse 125 beats per minute, the temperature 39.0°C, the respiratory rate 28 breaths per minute, and the weight 28.8 kg. A diffuse, erythematous morbilliform rash with extensive confluence was present, most intensely visible on the trunk, back, and upper arms and thighs, with blanching. The skin was warm and dry, there was no palm or sole involvement, and approximately 5 to 10 isolated petechiae were seen on the abdomen, without purpura. The remainder of the examination was normal. A diagnosis of hypersensitivity reaction was made. The carbamazepine was discontinued, and lorazepam was begun. Specimens of blood and urine were sent for cultures, and a dose of ceftriaxone was administered. The patient was discharged to her home.
The next day, the temperature remained elevated, the rash had spread to involve most of her body, and vesicles had developed. The patient vomited twice. She returned to the emergency room of the first hospital. There was no history of diarrhea. Methylprednisolone (2 mg per kg of body weight), lorazepam, and ranitidine were administered intravenously, and she was admitted.
On examination, diffuse, erythematous, raised lesions involved the face, trunk, back, arms and legs, and lips. Nikolsky's sign (ready removal of the epidermis with slight tangential pressure) was present. There were multiple vesicles and ulcers on the oral and lingual mucosa, with desquamation of the lingual mucosa. The lungs were clear, and the heart sounds were normal. The abdomen was diffusely tender, a finding that was thought to be due to the skin lesions. A rectal examination revealed no abnormalities, and a guaiac stool test was negative. The results of laboratory tests are shown in Table 1 and Table 2.
Table 1. Hematologic Laboratory Data.
Table 2. Blood Chemical Values.
Over the course of the next 24 hours, increased pain in the mouth, pain on urination, and additional vesicular skin lesions developed. Ceftriaxone and morphine were administered intravenously. On the second hospital day, the patient was transferred to the intensive care unit. Sloughing of the skin and oral mucosa occurred; the trachea was intubated, and mechanical ventilation was instituted; a right femoral triple-lumen catheter was placed, and an infusion of lactated Ringer's solution was begun. The wounds were blistered and productive of a moderate amount of clear drainage fluid; bland petroleum dressings were applied. Acetaminophen, midazolam, morphine, immune globulin, ranitidine, cefazolin, oxacillin, and lorazepam were administered. The results of blood and urine cultures were pending. Later that day, the patient was transferred to the Shriners Hospital for Children, which is affiliated with this hospital.
The patient had no other medical problems, no known allergies, and her immunizations were up to date. Her father had had sloughing of the skin after taking a sulfa drug when he was five years of age, which had required hospitalization. He had had a tonic–clonic seizure when he was 10 years of age for which phenytoin was administered for nine months; no further seizures occurred. Other family members were well.
On examination, the patient was intubated and sedated, but she responded to tactile stimuli. The axillary temperature was 39.4°C, the pulse 158 beats per minute, the respiratory rate 22 breaths per minute, and the blood pressure 95/46 mm Hg. The weight was 30.15 kg. Her tongue was swollen, and the oral mucosa was sloughing. Lung sounds were clear, after thick yellow secretions were suctioned from the endotracheal tube. Bowel sounds were present; the abdomen was soft and not distended. The skin of the trunk was denuded, with the appearance of a second-degree burn, and intact vesicles covered much of the skin of the arms and legs; there was involvement of 97 percent of the epidermis, sparing only the vertex of the scalp. A catheter drained cloudy, dark-yellow urine. The results of other laboratory tests are shown in Table 1 and Table 2.
During the patient's first 24 hours after admission, the temperature increased to 40.2°C. The mean arterial pressure decreased to 45 mm Hg; a dopamine infusion was begun, and 1 unit of red cells was transfused. The urine output ranged between 8 and 18 ml per hour; 5 percent albumin solution was added to the intravenous therapy and the infusion rate of lactated Ringer's solution increased gradually, with improvement in urinary output and mean arterial pressure. Oxygen saturation decreased from 100 percent to 88 percent while she was receiving 40 percent inspired oxygen, scattered ronchi were heard, and patchy infiltrates were seen on chest radiography. Albuterol and beta-agonist agents were delivered by nebulizer, and intravenous morphine and midazolam were administered. Tube feedings were begun but were discontinued because of ileus and incomplete gastric emptying, and total parenteral nutrition was initiated on the third hospital day.
Sloughing of the corneas and respiratory and gastrointestinal mucosae occurred over the course of the first three days of hospitalization, with blood loss into the bowel and airway; thrombocytopenia persisted and neutropenia and anemia developed (Table 1). Fever, hypotension, and cardiac and respiratory failure with acidosis and hypoxemia persisted. Sequential chest radiographs during the second and third weeks revealed worsening air-space opacities and bilateral pleural effusions. Treatment with nitric oxide resulted in no improvement. Permissive hypercapnia was instituted. Echocardiography on the 24th hospital day revealed a dilated left atrium and ventricle, with an estimated ejection fraction of 66 percent. Blood cultures were positive at various times for gram-positive (Staphylococcus aureus) and gram-negative (Stenotrophomonas maltophilia) bacteria, as well as fungi (Candida parapsilosis), and antibiotic and antifungal therapy was administered.
Throughout the period when the patient's skin was denuded, frequent fluid replacement and electrolyte repletion were required. During the fourth week, the skin wounds began to heal, followed gradually by healing of the corneal and oral mucosal lesions.
The patient's respiratory function gradually improved, and the trachea was extubated on the 35th day. The hematocrit and results of renal-function tests returned to normal, and she became afebrile. Pain medications were tapered slowly. She was discharged to her home on the 91st hospital day.
Differential Diagnosis
Dr. Vincent Liu: Although I am aware of the diagnosis in this case, a generalized blistering skin eruption in a child has a broad differential diagnosis (Table 3).1 Most of these diagnoses can be readily ruled out by the history and clinical features in this case. The fact that therapy with carbamazepine had been recently initiated focuses the differential diagnosis on cutaneous reactions to drugs.2 The most important consideration is the staphylococcal scalded skin syndrome, which is mediated by the exotoxin (phage group II, type 71) produced by S. aureus; it produces diffuse ill-defined erythema and flaccid bullae, with a positive Nikolsky's sign. However, this disorder affects primarily newborns and infants under two years of age and patients with renal failure.
Table 3. Differential Diagnosis of Bullous Exfoliative Erythroderma in a Child.
Erythema multiforme3 is a hypersensitivity response that usually follows infection with either herpes simplex virus or mycoplasma; it is characterized by the sudden, symmetric onset of raised, targetoid erythematous macules and thin plaques, predominantly on the arms and legs and hands and feet; mucosal involvement, formation of bullae, and sloughing occur rarely (for instance, in bullous erythema multiforme, erythema multiforme major — conditions that may be more closely related to the Stevens–Johnson syndrome and toxic epidermal necrolysis).4 Erythema multiforme usually resolves spontaneously without life-threatening complications. The Stevens–Johnson syndrome and toxic epidermal necrolysis are thought to represent a single disease with a spectrum of severity.5 Generalized tender erythematous macules that progress to blisters and denudation are often preceded by photophobia, symptoms of upper respiratory infection, and fever. The Stevens–Johnson syndrome and toxic epidermal necrolysis are typically distinguished from each other according to the extent of cutaneous involvement6,7,8 (Table 4). This patient had generalized denudation of skin and mucous membranes after exposure to carbamazepine, a drug commonly associated with toxic epidermal necrolysis9 (Table 5). The extent of involvement and the clinical history in this patient are virtually diagnostic of this disorder.
Table 4. Distinguishing Features of Erythema Multiforme, Stevens–Johnson Syndrome, and Toxic Epidermal Necrolysis.
Table 5. Most Common Drugs Associated with Toxic Epidermal Necrolysis.
Dr. Vincent Liu's Diagnosis
Toxic epidermal necrolysis, due to carbamazepine.
Pathological Discussion
Dr. Liu: The diagnosis of toxic epidermal necrolysis can be confirmed by a skin biopsy, although one was not performed in this case. When obtained, skin-biopsy specimens show that the epidermis is necrotic and detached from the underlying dermis (Figure 1). The dermis shows a mild superficial perivascular lymphocytic infiltrate. The staphylococcal scalded skin syndrome and toxic epidermal necrolysis both involve necrosis of the epidermis: the key distinguishing feature is the extent of epidermal necrosis, which involves only the superficial corneal layer in the staphylococcal scalded skin syndrome or acute exanthematous pustulosis, and the full thickness of the epidermis in the Stevens–Johnson syndrome and toxic epidermal necrolysis. This aspect of toxic epidermal necrolysis lends itself to a rapid means of identification: when the epidermis is "peeled off" in toxic epidermal necrolysis, rolled around a cotton-swab stick like a jelly roll, and examined in a frozen section, full-thickness epidermal necrosis can be recognized (shown in Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org).
Figure 1. Skin-Biopsy Specimens from Another Case of Toxic Epidermal Necrolysis.
The epidermis is separated from the underlying dermis, which contains a scant inflammatory infiltrate. The inset, at higher magnification, reveals necrosis and dyskeratosis of the epidermis.
Toxic epidermal necrolysis is thought to be a cell-mediated immunologic reaction to drug metabolites, which may accumulate because of abnormal metabolism of the drug, resulting in the persistence of immunogenic metabolites. There is a reported association with the HLA-B12 haplotype; a genetic association is suggested in this case by the father's history of a sloughing skin reaction to a sulfa drug in childhood. The necrosis appears to be mediated by CD8+ T cells by way of Fas-mediated apoptosis.10
Discussion of Management
Dr. Robert L. Sheridan: This child was admitted to the burn unit with a diagnosis of toxic epidermal necrolysis, with massive necrosis of the skin, rapidly progressive multiple-organ failure, and polymicrobial sepsis. Patients with toxic epidermal necrolysis are increasingly referred to burn units for care because the resources needed for management, intensive care, and wound expertise are similar to those required by patients with large burns.11,12,13
The syndrome generally begins, as it did in this child, with a diffuse macular rash (Figure 2A) that spreads and becomes confluent, with separation of the epidermis, fluid loss, and bleeding (Figure 2A of the Supplementary Appendix). Involvement of the ocular mucous membranes (Figure 2B of the Supplementary Appendix) and the oral mucous membranes (Figure 2B) is usually prominent in toxic epidermal necrolysis, as occurred in this child. The latter often compromises airway patency and protective reflexes, mandating endotracheal intubation, as happened in this case. Cutaneous and visceral wounds progress in a variable and unpredictable way. In those who survive, cutaneous reepithelialization usually occurs at four to eight weeks. Frequently, healing of the conjunctival and visceral wounds lags behind healing of the cutaneous wounds.
Figure 2. Clinical Images of Patients with Toxic Epidermal Necrolysis.
The process begins with a diffuse macular rash (Panel A, from another patient), which becomes confluent. Sloughing of the lips and oropharynx (Panel B, this patient) compromised the child's ability to guard her airway, and intubation was required. Eventually, the skin was almost completely denuded (Panel C). Two years later, recovery was virtually complete (Panel D).
As is in this child, it is very common for the diagnosis of toxic epidermal necrolysis to be delayed, probably because of the rarity of the syndrome and its relatively nonspecific early signs. However, in its full-blown form, the diagnosis is straightforward, since no other entity is characterized by such extensive sloughing of cutaneous, ocular, oropharyngeal, rectal, and genitourinary surfaces, along with the high degree of systemic toxicity. There are no specific laboratory or radiographic findings. Management of this condition requires strategies for wound care and for control of organ failure.
Management of the Wound
This child's most obvious presenting problem was a rapidly enlarging, painful cutaneous wound (Figure 2C). The principal problems associated with this are extreme pain, loss of protein-rich fluid, bleeding, hypothermia, and infection.14 Less obvious, but in many ways more problematic, are visceral wounds of variable extent that involved all epithelium-lined structures: the mouth, nares, oropharynx, esophagus and gastrointestinal tract, biliary and pancreatic ducts, bladder, vagina, rectum, and conjunctiva. The principal problems associated with these wounds are organ dysfunction, blood loss, and infection.15
The objectives of cutaneous-wound management are the prevention of desiccation and superinfection and the control of pain. When surface infection is present, topical antimicrobial agents are ideal.16 When wounds are clean, membrane dressings are more appropriate.17,18 In this child, the principal topical preparation used was 0.5 percent aqueous silver nitrate, and the principal membranes were porcine xenograft and a silver-containing synthetic material. It is essential that such wounds be managed in an environment that can minimize evaporative heat loss, if hypothermia and dangerous electrolyte disturbances are to be avoided. This child was placed in a bacteria-controlled nursing unit in the burn intensive care unit, engineered for this purpose.19 Management of the visceral wounds was essentially supportive, treating infections as they arose, replacing blood losses, and supporting failing organ systems, while awaiting reepithelialization of these inaccessible surfaces.
Special mention should be made of the management of conjunctival sloughing.20 This condition affects most children with this illness to a variable degree and is often quite severe. The denuded cornea and globe are very painful and prone to desiccation, corneal ulceration, and destructive local infection.21 The palpebral and globular conjunctivae can form adhesions. This condition is best managed with frequent ocular lubrication, the use of topical corticosteroids, frequent culturing, and administration of focused topical antibiotics. The lids should be regularly separated from the globes to prevent adhesions. Biologic dressings are useful in some children for temporary coverage of the cornea, but they were not required in this case.
Corneal and cutaneous wounds are exquisitely painful, and control of pain and anxiety is an important component of management. Pain and anxiety were managed in this patient by intravenous infusions of escalating doses of morphine sulfate and midazolam, with additional doses when dressings needed to be changed, wounds cleansed or manipulated, or vascular-access or other procedures performed.22
Management of Multiple-Organ Failure
Multiple-organ failure is common in children with toxic epidermal necrolysis, although the intensity, duration, and sequence are quite variable. This child had perhaps the most common sequence of organ dysfunction. As her cutaneous and oropharyngeal wounds progressed, intubation was required for airway protection.23,24 By the 15th hospital day, her respiratory status began to deteriorate. Pulmonary hypertension and intrapulmonary shunting developed and did not improve with inhaled nitric oxide, which was discontinued on the 20th hospital day.25 Could we review the chest radiographs?
Dr. Sudha Anupindi: The chest radiograph obtained on the second hospital day showed mild interstitial edema but no pleural effusions (Figure 3A). A radiograph taken on the 11th day showed peripheral alveolar opacities with consolidation in the left upper lobe (Figure 3A of the Supplementary Appendix), which progressively worsened, as seen on a radiograph from the 20th day (Figure 3B). The findings on chest radiography stabilized at that point and then started to improve (Figure 3B of the Supplementary Appendix). The differential diagnosis of the alveolar opacities includes pulmonary hemorrhage, pneumonia, or pulmonary edema; in this clinical setting, the progressive changes seen on the films best fit the pattern of the acute respiratory distress syndrome.
Figure 3. Chest Radiography.
An anteroposterior radiograph of the chest on the first hospital day (Panel A) shows mild interstitial edema (arrows). A chest radiograph obtained on the 20th hospital day (Panel B) shows alveolar opacities, predominantly peripheral, with areas of consolidation in the left upper lobe (arrow).
Dr. Sheridan: The acute respiratory distress syndrome in this patient was managed with neuromuscular blockade, pressure-controlled ventilation, and permissive hypercapnia.26 Despite severe respiratory failure, this approach succeeded, and she was extubated on the 37th day after admission.
Large free-water and electrolyte losses occurred through this child's wounds, resulting in electrolyte disturbances. Diligent monitoring and replacement were required to maintain electrolytes in the physiologic range. Central venous and arterial access was required throughout the period of critical illness; systemic arterial pressure was maintained through the use of adequate fluid replacement and inotropic and vasopressor agents. Gastrointestinal failure developed, with a protracted period of ileus, hepatic dysfunction, and pancreatitis that prevented effective enteral nutrition. She was supported nutritionally for several weeks by means of a combination of enteral and parenteral formulations. Parenteral support is well tolerated by critically ill children and will prevent excessive catabolism and facilitate wound healing.27,28
Profound pancytopenia, which developed in this child, as it does in many patients with toxic epidermal necrolysis, is minimally responsive to granulocyte colony-stimulating factor. By hospital day 5, her absolute neutrophil count was less than 400 per cubic millimeter. Neutropenia posed a particular problem in the face of a denuded skin and gut, and the situation required the administration of prophylactic antibiotics, including vancomycin, gentamicin, and ceftriaxone. Thrombocytopenia also occurred, with platelet counts in the range of 60,000 per cubic millimeter for several days after admission, and it exacerbated blood loss into the denuded gut, genitourinary tract, and airway. Transfusions of red cells were administered, and coagulation proteins were supported with infusions of fresh-frozen plasma. Neutropenia in this patient resolved by the 10th hospital day. Anemia persisted and was thought to be due to blood loss from the intestinal and bronchial mucosae. Transfusions of a total of 8 units of packed red cells were given over the course of three weeks.
Most deaths in patients with toxic epidermal necrolysis are a result of sepsis-induced organ failure. In this child, blood cultures at various times grew S. aureus, C. albicans, and S. maltophilia. These episodes were associated with hypothermia and hypotension and worsening multiple-organ failure. S. maltophilia is a difficult, multidrug-resistant gram-negative organism, which was sensitive to trimethoprim–sulfamethoxazole, a sulfa-derived drug. Since sulfa drugs have a known potential for causing toxic epidermal necrolysis, this risk was discussed with the family before therapy. Fortunately, no reaction occurred, and the infection was controlled.
This child received intravenous immune globulin early on, and severe diffuse toxic epidermal necrolysis continued to evolve. It has been theorized that intravenous immune globulin may improve outcomes, given its salutary effect in another inflammatory condition, Kawasaki's disease. This contention has been supported by small, uncontrolled clinical trials.29 However, other data do not support its use, and intravenous immune globulin is not now part of the standard of care for toxic epidermal necrolysis.30 Corticosteroid drugs have also been advocated for toxic epidermal necrolysis, but most clinicians do not support their routine use, given the risk of increased infection and the absence of data demonstrating benefit. Plasma exchange has also been proposed but not shown to be efficacious. These interventions were not used in this case.
Survival and Long-Term Outcome
Published mortality rates for patients with toxic epidermal necrolysis vary widely and are between 40 and 70 percent.15,31,32 In this child, as in most survivors, cutaneous reepithelialization became evident four to eight weeks after admission and was followed by healing of the mucous membranes and conjunctivae. Presumably, resurfacing of viscera was also occurring at this time, when there was rapid clinical improvement in cardiovascular and pulmonary function. The patient was discharged to her home after three months; she eventually returned to school and resumed normal activities.
Ophthalmic complications, seen in about 30 percent of surviving children,20 include impaired tear production and drainage, aberrant lashes, dry eye syndrome, photophobia, metaplasia of the conjunctiva, and corneal scarring with blindness. This patient had mild photophobia for several months, which gradually resolved. Variegated skin pigment changes have persisted in this patient, but the quality of the skin has become otherwise essentially normal (Figure 2D). Fingernail and toenail deformities are common; this patient lost all of her fingernails and toenails. Most of her nails have subsequently regrown, but they remain deformed, as they do in about 40 percent of children who survive this condition.
Other than the minor residual deformities of her fingernails and toenails, this patient is normal. She has recovered virtually completely.
Final Diagnosis
Toxic epidermal necrolysis.
Source Information
From the Burn Surgical Service, Shriners Hospital for Children (R.L.S.); the Division of Burns, Department of Surgery (R.L.S.), and the Departments of Pathology (V.L.) and Radiology (S.A.), Massachusetts General Hospital; and the Departments of Surgery (R.L.S.), Pathology (V.L.), and Radiology (S.A.), Harvard Medical School — all in Boston.
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