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Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson syndrome is characterized by keratinocyte Keratinocyte Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Erythema Multiforme necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage and separation of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions from the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will present with a flu-like prodrome Prodrome Symptoms that appear 24–48 hours prior to migraine onset. Migraine Headache, followed by cutaneous bullae Bullae Erythema Multiforme and sloughing on the face, thorax, and mucous membranes. Stevens-Johnson syndrome is considered a medical emergency, and management is largely supportive. Withdrawal of the causative agent is required. Monitoring for, and treating, superinfection is essential due to the high risk of associated death in these patients.

Last updated: 8 Jan, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Classification

  • Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe mucocutaneous reactions. 
  • Considered a continuum of the same disease
  • Classified based on the percentage of body surface affected by blisters, erosions Erosions Corneal Abrasions, Erosion, and Ulcers, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions detachment:
Subtype Involved BSA

Stevens-Johnson syndrome

10% of BSA

Overlapping SJS/TEN

10%‒30% of BSA

Toxic epidermal necrolysis

30% of BSA

BSA: body surface area
SJS: Stevens-Johnson syndrome
TEN: toxic epidermal necrolysis

Epidemiology

  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency
    • 1–7 cases per million people per year
    • Higher in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HIV HIV Anti-HIV Drugs and active cancer
    • SJS is more common.
  • Mortality Mortality All deaths reported in a given population. Measures of Health Status rate: 
    • SJS: 10%
    • TEN: 50%
  • More common in women than men, with a ratio of 2:1
  • Can occur at any age

Etiology

  • Medications 
    • Approximately 70% of cases
    • Occurs within 8 weeks of medication onset
  • Infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 
  • Idiopathic Idiopathic Dermatomyositis
    • > 1/3 of cases
  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics
    • Some HLA types are associated with an increased risk.
  • Other risk factors 
    • Malignancy Malignancy Hemothorax 
    • Lupus 
    • Ultraviolet light Ultraviolet light That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-uv or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-uv or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants. Bullous Pemphigoid and Pemphigus Vulgaris stimulus 
    • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy

The following table lists the major common medication and infectious Infectious Febrile Infant causes of SJS/TEN:

Types Examples

Medications

Antiepileptics

Lamotrigine Lamotrigine A phenyltriazine compound, sodium and calcium channel blocker that is used for the treatment of seizures and bipolar disorder. Second-Generation Anticonvulsant Drugs, phenobarbital Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates gamma-aminobutyric acid action on gaba-a receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. First-Generation Anticonvulsant Drugs, carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs, valproate Valproate A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs, phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs

Sulfa

Cotrimoxazole, sulfasalazine Sulfasalazine A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid released in the colon. Sulfonamides and Trimethoprim

Other antibiotics

Aminopenicillins Aminopenicillins Penicillins, fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones, cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with “cef-” or “ceph-.” Cephalosporins

NSAIDs NSAIDS Primary vs Secondary Headaches

Meloxicam Meloxicam A benzothiazine and thiazole derivative that acts as a nsaid and cyclooxygenase-2 (cox-2) inhibitor. It is used in the treatment of rheumatoid arthritis; osteoarthritis; and ankylosing spondylitis. Nonsteroidal Antiinflammatory Drugs (NSAIDs), piroxicam Piroxicam A cyclooxygenase inhibiting, non-steroidal anti-inflammatory agent (nsaid) that is well established in treating rheumatoid arthritis and osteoarthritis and used for musculoskeletal disorders, dysmenorrhea, and postoperative pain. Its long half-life enables it to be administered once daily. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Antiretrovirals

Nevirapine Nevirapine A potent, non-nucleoside reverse transcriptase inhibitor used in combination with nucleoside analogues for treatment of HIV infections and aids. Anti-HIV Drugs

Miscellaneous

Allopurinol Allopurinol A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms. Gout Drugs, chlormezanone

Infectious

Viral

Herpes simplex virus Herpes Simplex Virus A group of acute infections caused by herpes simplex virus type 1 or type 2 that is characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane. It occurs as a primary infection or recurs due to a reactivation of a latent infection. Encephalitis, HIV HIV Anti-HIV Drugs, coxsackievirus Coxsackievirus Coxsackievirus is a member of a family of viruses called Picornaviridae and the genus Enterovirus. Coxsackieviruses are single-stranded, positive-sense RNA viruses, and are divided into coxsackie group A and B viruses. Both groups of viruses cause upper respiratory infections, rashes, aseptic meningitis, or encephalitis. Coxsackievirus, hepatitis, influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza, mumps Mumps Mumps is caused by a single-stranded, linear, negative-sense RNA virus of the family Paramyxoviridae. Mumps is typically a disease of childhood, which manifests initially with fever, muscle pain, headache, poor appetite, and a general feeling of malaise, and is classically followed by parotitis. Mumps Virus/Mumps, Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus, enteroviruses

Bacterial

Group A beta-hemolytic streptococci, brucellosis Brucellosis Brucellosis (also known as undulant fever, Mediterranean fever, or Malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Brucella/Brucellosis, mycobacteria Mycobacteria Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium, Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or “walking” pneumonia. Mycoplasma pneumoniae, rickettsia Rickettsia Rickettsiae are a diverse collection of obligate intracellular, gram-negative bacteria that have a tropism for vascular endothelial cells. The vectors for transmission vary by species but include ticks, fleas, mites, and lice. Rickettsia, tularemia
NSAIDs NSAIDS Primary vs Secondary Headaches: Nonsteroidal anti-inflammatory drugs

Pathogenesis

The exact mechanism is unknown, but there are several theories:

  1. Drug, or infectious Infectious Febrile Infant, antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions tissue → stimulates cytotoxic Cytotoxic Parvovirus B19 T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions, natural killer T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions (NKT), and natural killer (NK) cells → granulysin release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology keratinocyte Keratinocyte Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Erythema Multiforme death
  2. Apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage of keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions → epidermal separation from the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions → characteristic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions detachment of SJS/TEN
  3. Dying cells and necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage → ↑ antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination load → triggers Triggers Hereditary Angioedema (C1 Esterase Inhibitor Deficiency) T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions to continue the inflammatory response → development of fluid-filled blisters 

This impaired skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions integrity can lead to:

  • Water loss
  • Secondary bacterial infections and sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
Pathophysiology in stevens-johnson syndrome and toxic epidermal necrolysis

Schematic showing how a peptide antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination (in this case, from a drug) presented on keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions can lead to a cytotoxic Cytotoxic Parvovirus B19 inflammatory response resulting in granulysin release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology, keratinocyte Keratinocyte Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Erythema Multiforme apoptosis and necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage, detachment of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions, and blister Blister Bullous Pemphigoid and Pemphigus Vulgaris formation in SJS and TEN.

Image by Lecturio.

Clinical Presentation

Clinical manifestations

Prodrome Prodrome Symptoms that appear 24–48 hours prior to migraine onset. Migraine Headache

  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever (often > 39°C)
  • Myalgia Myalgia Painful sensation in the muscles. Ion Channel Myopathy and arthralgia Arthralgia Pain in the joint. Rheumatic Fever
  • Keratoconjunctivitis ( inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy and conjunctiva Conjunctiva The mucous membrane that covers the posterior surface of the eyelids and the anterior pericorneal surface of the eyeball. Eye: Anatomy)
  • Sore throat Sore throat Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis
  • Headache
  • Malaise Malaise Tick-borne Encephalitis Virus

Acute phase Acute phase Short Bowel Syndrome

  • 1‒3 days after the prodrome
  • Lasts 8‒12 days
  • Cutaneous lesions
    • Begin as ill-defined, coalescing macules with purpuric centers or diffuse erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion
      • Start on the face and thorax, then spread symmetrically
      • Typically spare scalp, palms, and soles
      • Tender to touch
    • Vesicles and bullae Bullae Erythema Multiforme form as the disease progresses
    • Skin begins to slough within days
    • Nikolsky’s sign: extension Extension Examination of the Upper Limbs of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions sloughing by applying pressure
  • Mucosal lesions 

Complications

  • Significant fluid loss 
  • Bacterial infection 
    • Sepsis and septic shock Sepsis and Septic shock Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Septic shock is diagnosed during treatment when vasopressors are necessary to control hypotension. Sepsis and septic shock are medical emergencies and antibiotics are given within an hour of diagnosis. Sepsis and Septic Shock are the main cause of death in SJS/TEN patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.
    • Most often caused by Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess and Pseudomonas aeruginosa Pseudomonas aeruginosa A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. Aeruginosa is a major agent of nosocomial infection. Pseudomonas
  • Tracheobronchial epithelial involvement  
    • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia 
    • Interstitial pneumonitis Pneumonitis Human Herpesvirus 6 and 7 
    • Acute respiratory distress syndrome Acute Respiratory Distress Syndrome Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome (ARDS) 
  • Protein loss: edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
  • Electrolyte imbalances
  • Epithelial necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage of the gastrointestinal tract  
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea 
    • Melena Melena The black, tarry, foul-smelling feces that contain degraded blood. Gastrointestinal Bleeding 
    • Colonic perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis 
    • Small bowel Small bowel The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy intussusception Intussusception Intussusception occurs when a part of the intestine (intussusceptum) telescopes into another part (intussuscipiens) of the intestine. The condition can cause obstruction and, if untreated, progress to bowel ischemia. Intussusception is most common in the pediatric population, but is occasionally encountered in adults. Intussusception

Diagnosis

The diagnosis is clinical, based on history and physical exam findings.

  • Skin biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma 
    • Not required for diagnosis, but can confirm and rule out other conditions
    • Keratinocyte necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage is the hallmark finding.
      • Can be partial or full-thickness
      • Apoptotic keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions are scattered in the basal layer of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions in early lesions.
      • Full-thickness epidermal necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage and subepidermal bullae Bullae Erythema Multiforme later in the disease
    • Lymphocytic inflammatory infiltration
    • Direct immunofluorescence is negative.
  • Supporting workup 
Curcumin in stevens-johnsons syndrome culprit or bystander1

Histopathology of a skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma taken from a patient with SJS/TEN showing characteristic epidermal detachment and lymphocyte infiltration in the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions

Image: “Curcumin in stevens-johnsons syndrome: culprit or bystander?” by Irani C, Haddad F, Maalouly G, Nemnoum R. License: CC BY 2.0

Treatment

  • Immediate hospital admission
    • Patients typically require intensive care or a burn unit Burn unit Specialized hospital facilities which provide intensive care for burn patients. Staphylococcal Scalded Skin Syndrome (SSSS).
    • SCORTEN score (score of toxic epidermal necrolysis) is calculated to determine severity, prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas, and appropriate setting for management (see table below).
  • Withdrawal of causative agent is required.
  • Supportive care:
    • Wound care 
    • Fluid and electrolyte management
    • Nutritional support 
      • Parenteral nutrition Parenteral nutrition The administering of nutrients for assimilation and utilization by a patient who cannot maintain adequate nutrition by enteral feeding alone. Nutrients are administered by a route other than the alimentary canal (e.g., intravenously, subcutaneously). Central Venous Catheter for those with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia and odynophagia Odynophagia Epiglottitis 
      • Transition to oral feeds when tolerated
    • Ocular care 
      • Ophthalmology consultation
      • Corticosteroid and antibiotic eye drops 
      • Artificial tears for lubrication 
    • Temperature management
    • Pain control 
      • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen and ibuprofen Ibuprofen A nonsteroidal anti-inflammatory agent with analgesic properties used in the treatment of rheumatism and arthritis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) for mild pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways 
      • Opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics for severe pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Monitoring and treatment of superinfections 
    • Education on future drug avoidance, including closely related agents
  • Controversial treatments:
Table: SCORTEN score
Prognostic factorsScore

Age ≥ 40 years

1

Malignancy Malignancy Hemothorax present

1

Body surface area detached ≥ 10%

1

Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children ≥ 120/min

1

Serum urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle > 10 mmol/L

1

Serum glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance > 14 mmol/L

1

Serum bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes < 20 mmol/L

1

The SCORTEN score is used to help determine the severity, prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas, and appropriate setting for management in SJS/TEN patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.

  • Score 0‒1: 94% survival, may be treated in non-specialized wards
  • Score 2: 87% survival, should be transferred to an intensive care unit, burn unit Burn unit Specialized hospital facilities which provide intensive care for burn patients. Staphylococcal Scalded Skin Syndrome (SSSS), or specialized dermatology unit
  • Score 3: 53% survival, should be transferred to an intensive care unit, burn unit Burn unit Specialized hospital facilities which provide intensive care for burn patients. Staphylococcal Scalded Skin Syndrome (SSSS), or specialized dermatology unit
  • Score 4: 25% survival, should be transferred to an intensive care unit, burn unit Burn unit Specialized hospital facilities which provide intensive care for burn patients. Staphylococcal Scalded Skin Syndrome (SSSS), or specialized dermatology unit
  • Score 5‒7: 17% survival, should be transferred to an intensive care unit, burn unit Burn unit Specialized hospital facilities which provide intensive care for burn patients. Staphylococcal Scalded Skin Syndrome (SSSS), or specialized dermatology unit

Differential Diagnosis

  • Erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme: an acute, immune-mediated skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions eruption with typical targetoid lesions; may be accompanied by systemic symptoms and mucosal involvement. Etiology is usually due to infection from the herpes simplex virus, unlike SJS/TEN, which is usually caused by a medication. Diagnosis is clinical and will differentiate this condition from SJS. Treatment includes supportive care.
  • Staphylococcal scalded skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions syndrome ( SSSS SSSS Staphylococcal scalded skin syndrome (SSSS), also known as Ritter disease and staphylococcal epidermal necrolysis, is a toxin-mediated condition caused by Staphylococcus aureus. The exfoliative toxin produced disseminates and cleaves desmoglein 1 in the epidermis, causing separation and detachment of the skin. Staphylococcal Scalded Skin Syndrome (SSSS)): presents with a painful, desquamative skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions rash Rash Rocky Mountain Spotted Fever, especially around the nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose and Nasal Cavity: Anatomy, mouth, and anus. The condition results from a staphylococcal toxin, and is usually seen in children. Unlike SJS/TEN, there is no mucosal involvement. Diagnosis is clinical and confirmed with bacterial cultures Cultures Klebsiella. A biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma will show noninflammatory, superficial splitting Splitting Defense Mechanisms of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions. Treatment includes antibiotics, wound care, and supportive care.
  • Exfoliative dermatitis Dermatitis Any inflammation of the skin. Atopic Dermatitis (Eczema): a generalized, symmetric, erythematous rash Rash Rocky Mountain Spotted Fever caused by an underlying cutaneous disease ( psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis, atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema)), medications, and malignancy ( lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum). The condition can mimic the early stages of SJS; however, there is no mucosal involvement (which will differentiate the condition from SJS). Diagnosis is made clinically, and treatment focuses on treating the underlying cause, withdrawal of implicated medications, and supportive care.
  • Toxic shock syndrome Toxic Shock Syndrome Toxic shock syndrome (TSS) is an acute, multi-systemic disease caused by the toxin-producing bacteria, Staphylococcus aureus and Streptococcus pyogenes. Staphylococcal TSS is more common and associated with tampons and nasal packing. Toxic Shock Syndrome: a systemic syndrome caused by staphylococcus or streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus endotoxins Endotoxins Toxins closely associated with the living cytoplasm or cell wall of certain microorganisms, which do not readily diffuse into the culture medium, but are released upon lysis of the cells. Bacteriology. Patients present with fever, shock, and multisystem organ dysfunction. Cutaneous manifestations include a diffuse, erythematous rash Rash Rocky Mountain Spotted Fever and desquamation Desquamation Staphylococcal Scalded Skin Syndrome (SSSS). Diagnosis is based on blood culture results, clinical history, and exam, which will differentiate this condition from SJS. Treatment includes hemodynamic support, fluid resuscitation Resuscitation The restoration to life or consciousness of one apparently dead. . Neonatal Respiratory Distress Syndrome, and antibiotics.
  • Pemphigus vulgaris Pemphigus vulgaris Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In pemphigus vulgaris, autoantibodies attack the desmosomal proteins, which connect the keratinocytes to one another. This attack results in a more severe, potentially fatal condition with fragile, flaccid blisters, usually with significant mucosal involvement. Bullous Pemphigoid and Pemphigus Vulgaris: an autoimmune disorder Autoimmune Disorder Septic Arthritis causing intraepidermal blistering and erosions Erosions Corneal Abrasions, Erosion, and Ulcers of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and mucous membranes. Patients will have cutaneous bullae Bullae Erythema Multiforme appearing on normal-appearing skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and painful mucocutaneous erosions Erosions Corneal Abrasions, Erosion, and Ulcers. Diagnosis involves a biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma with immunofluorescence testing showing immunoglobulin G ( IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis) antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions against keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions, differentiating this condition from SJS. Treatment includes corticosteroids Corticosteroids Chorioretinitis, immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants, and IVIG IVIG Dermatomyositis.
  • Bullous pemphigoid Bullous pemphigoid Bullous pemphigoid and pemphigus vulgaris are two different blistering autoimmune diseases. In bullous pemphigoid, autoantibodies attack the hemidesmosomes, which connect epidermal keratinocytes to the basement membrane. This attack results in large, tense subepidermal blisters. Bullous Pemphigoid and Pemphigus Vulgaris: an autoimmune skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions disorder causing pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema), erythematous plaques, and tense, bullous lesions. Mucous membrane involvement is rare. Triggers include medications, trauma, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions conditions, and systemic disease. Biopsy with immunofluorescence shows IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis and complement deposits along the basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN), which differentiates the condition from SJS. Treatment includes steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors, immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants, and anti-inflammatory medications.

References

  1. High, W.A. (2019). Stevens-Johsnon syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis. In Corona, R. (Ed.), Uptodate. Retrieved November 7, 2020, from https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-pathogenesis-clinical-manifestations-and-diagnosis
  2. High, W.A. (2020). Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae. In Corona, R. (Ed.), Uptodate. Retrieved November 7, 2020, from https://www.uptodate.com/contents/stevens-johnson-syndrome-and-toxic-epidermal-necrolysis-management-prognosis-and-long-term-sequelae
  3. Benedetti, J. (2020). Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). MSD Manual Professional Edition. Retrieved November 7, 2020, from https://www.msdmanuals.com/professional/dermatologic-disorders/hypersensitivity-and-inflammatory-skin-disorders/stevens-johnson-syndrome-sjs-and-toxic-epidermal-necrolysis-ten
  4. Foster, C.S, Ba-Abbad, R., Letko, E., and Parillo, S.J. (2019). Stevens-Johnson syndrome. In Dahl, A.A. (Ed.), Medscape. Retrieved November 7, 2020, from https://emedicine.medscape.com/article/1197450-overview

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