Alglucerase (glucocerebrosidase)

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alglucerase may be confused with agalsidase alfa, agalsidase beta, alglucosidase alfa
Ceredase® may be confused with Cerezyme®

U.S. BRAND NAMES — Ceredase®

PHARMACOLOGIC CATEGORY
Enzyme

DOSING: ADULTS — Gaucher's disease: I.V.: Initial: 30-60 units/kg every 2 weeks; dosing is individualized based on disease severity; average dose: 60 units/kg every 2 weeks. Range: 2.5 units/kg 3 times/week to 60 units/kg once weekly to every 4 weeks. Once patient response is well established, dose may be reduced every 3-6 months to determine maintenance therapy.

DOSING: PEDIATRIC — Refer to adult dosing.

(For additional information see "Alglucerase (glucocerebrosidase): Pediatric drug information")

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL) [contains human albumin 1%]

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL)

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — I.V.: Infuse I.V. over 1-2 hours. Use of an in-line filter is recommended. Do not shake solution as it denatures the enzyme.

COMPATIBILITY — Stable in NS; do not mix with any other additives.

USE — Replacement therapy for Gaucher's disease (type 1)

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Cardiovascular: Peripheral edema

Central nervous system: Chills, fatigue, fever, headache, lightheadedness

Endocrine & metabolic: Hot flashes, menstrual abnormalities

Gastrointestinal: Abdominal discomfort, diarrhea, nausea, oral ulcerations, vomiting

Local: Injection site: Abscess, burning, discomfort, pruritus, swelling

Neuromuscular & skeletal: Backache, weakness

Miscellaneous: Dysosmia; hypersensitivity reactions (abdominal cramping, angioedema, chest discomfort, flushing, hypotension, nausea, pruritus, respiratory symptoms, urticaria); IgG antibody formation (~13%)

CONTRAINDICATIONS — Hypersensitivity to any component of the formulation

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypersensitivity reactions: Patients who develop IgG antibodies may be at a higher risk for developing hypersensitivity. Use with caution in patients with prior allergies to hCG.

Disease-related concerns: Androgen-sensitive malignancies: Use with caution in patients with androgen-sensitive malignancies.

Special populations: Pediatrics: Safety and efficacy have not been established in children <2 years of age (limited experience). May cause early virilization in males <10 years of age.

Dosage form specific issues: Placental tissue: Prepared from pooled human placental tissue that may contain the causative agents of some viral diseases.

DRUG INTERACTIONS — There are no known significant interactions.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Animal studies have not been conducted.

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS — CBC, platelets, liver function tests, IgG antibody formation, acid phosphatase (AP); MRI or CT of liver and spleen, skeletal x-rays, physical exam every 6-12 months

INTERNATIONAL BRAND NAMES — Ceredase (DE, ES, GB, NL)

MECHANISM OF ACTION — Alglucerase is a modified form of glucocerebrosidase; it is prepared from human placental tissue. Glucocerebrosidase is an enzyme deficient in Gaucher's disease. It is needed to catalyze the hydrolysis of glucocerebroside to glucose and ceramide.

PHARMACODYNAMICS / KINETICS — Half-life elimination: ~3-11 minutes

Alglucerase (glucocerebrosidase)

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Alglucerase may be confused with agalsidase alfa, agalsidase beta, alglucosidase alfa
Ceredase® may be confused with Cerezyme®

U.S. BRAND NAMES — Ceredase®

PHARMACOLOGIC CATEGORY
Enzyme

DOSING: ADULTS — Gaucher's disease: I.V.: Initial: 30-60 units/kg every 2 weeks; dosing is individualized based on disease severity; average dose: 60 units/kg every 2 weeks. Range: 2.5 units/kg 3 times/week to 60 units/kg once weekly to every 4 weeks. Once patient response is well established, dose may be reduced every 3-6 months to determine maintenance therapy.

DOSING: PEDIATRIC — Refer to adult dosing.

(For additional information see "Alglucerase (glucocerebrosidase): Pediatric drug information")

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL) [contains human albumin 1%]

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
Ceredase®: 80 units/mL (5 mL)

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — I.V.: Infuse I.V. over 1-2 hours. Use of an in-line filter is recommended. Do not shake solution as it denatures the enzyme.

COMPATIBILITY — Stable in NS; do not mix with any other additives.

USE — Replacement therapy for Gaucher's disease (type 1)

ADVERSE REACTIONS SIGNIFICANT — Frequency not defined.

Cardiovascular: Peripheral edema

Central nervous system: Chills, fatigue, fever, headache, lightheadedness

Endocrine & metabolic: Hot flashes, menstrual abnormalities

Gastrointestinal: Abdominal discomfort, diarrhea, nausea, oral ulcerations, vomiting

Local: Injection site: Abscess, burning, discomfort, pruritus, swelling

Neuromuscular & skeletal: Backache, weakness

Miscellaneous: Dysosmia; hypersensitivity reactions (abdominal cramping, angioedema, chest discomfort, flushing, hypotension, nausea, pruritus, respiratory symptoms, urticaria); IgG antibody formation (~13%)

CONTRAINDICATIONS — Hypersensitivity to any component of the formulation

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Hypersensitivity reactions: Patients who develop IgG antibodies may be at a higher risk for developing hypersensitivity. Use with caution in patients with prior allergies to hCG.

Disease-related concerns: Androgen-sensitive malignancies: Use with caution in patients with androgen-sensitive malignancies.

Special populations: Pediatrics: Safety and efficacy have not been established in children <2 years of age (limited experience). May cause early virilization in males <10 years of age.

Dosage form specific issues: Placental tissue: Prepared from pooled human placental tissue that may contain the causative agents of some viral diseases.

DRUG INTERACTIONS — There are no known significant interactions.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Animal studies have not been conducted.

LACTATION — Excretion in breast milk unknown/use caution

MONITORING PARAMETERS — CBC, platelets, liver function tests, IgG antibody formation, acid phosphatase (AP); MRI or CT of liver and spleen, skeletal x-rays, physical exam every 6-12 months

INTERNATIONAL BRAND NAMES — Ceredase (DE, ES, GB, NL)

MECHANISM OF ACTION — Alglucerase is a modified form of glucocerebrosidase; it is prepared from human placental tissue. Glucocerebrosidase is an enzyme deficient in Gaucher's disease. It is needed to catalyze the hydrolysis of glucocerebroside to glucose and ceramide.

PHARMACODYNAMICS / KINETICS — Half-life elimination: ~3-11 minutes

Food Allergies

Introduction

Background

Adverse food reactions can be broadly classified into 2 categories. The first category consists of immunologically-mediated adverse reactions to foods that are termed food allergies. Food allergies can result in disorders with an acute onset of symptoms following ingestion of the triggering food allergen (eg, anaphylaxis) and in chronic disorders (eg, atopic dermatitis).

The second category is composed of adverse reactions that are not immune-mediated. An example is lactose intolerance caused by a deficiency of lactase. Adverse reactions to foods can also occur from toxic (eg, bacterial food poisoning) or pharmacologic (eg, caffeine) effects.

Pathophysiology

Food allergies are primarily the result of immune responses to food proteins.Normally, noninflammatory immune responses develop to ingested foods in a process called oral tolerance.³ For reasons that remain unclear, but likely include environmental and genetic factors, tolerance may be abrogated, leading to adverse immune responses. While sensitization (eg, development of an immunoglobulin E [IgE] immune response) to an allergen has been primarily assumed to occur from ingestion, this may not always be the case. For example, oral allergy syndrome (pollen-food related syndrome) describes an allergic response to specific raw fruits or vegetables that share homologous proteins with pollens; the initial route of sensitization is respiratory exposure to pollen proteins rather than oral exposure to food proteins. The skin may be another potential route of sensitization.

IgE antibody – mediated responses are the most widely recognized form of food allergy and account for acute reactions. Patients with atopy produce IgE antibodies to specific epitopes (areas of the protein) of one or more food allergens. These antibodies bind to high-affinity IgE receptors on circulating basophils and tissue mast cells present throughout the body, including the skin, gastrointestinal tract, and respiratory tract.

Subsequent allergen exposure binds and cross links IgE antibodies on the cell surface, resulting in receptor activation and intracellular signaling that initiates the release of inflammatory mediators (eg, histamine) and synthesis of additional factors (eg, chemotactic factors, cytokines) that promote allergic inflammation. The effects of these mediators on surrounding tissues result in vasodilatation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during acute allergic reactions to food.

Cell-mediated responses to food allergens may also mediate allergic responses, particularly in disorders with delayed or chronic symptoms. For example, food protein – induced enterocolitis syndrome (FPIES), a gastrointestinal food allergy, appears to be mediated by T-cell elaboration of the cytokine tumor necrosis factor (TNF)-alpha. Persons with atopic dermatitis that flares with ingestion of milk have been noted to have T cells that, in vitro, express the homing receptor cutaneous lymphocyte antigen, which is thought to home the cell to the skin and mediate the response.⁶ Celiac disease is the result of an immune response to gluten proteins in grains; this disorder is reviewed in the eMedicine Pediatrics article Celiac Disease.

Food allergens are typically water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10-70 kd. These characteristics facilitate the absorption of these allergens across mucosal surfaces. Numerous food allergens are purified and well-characterized, such as peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly m1; fish-Gad c1; and shrimp-Pen a1. Closely related foods frequently contain allergens that crossreact immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently crossreact clinically Recently, delayed allergic reactions to meat proteins have been attributed to reactions to carbohydrate moieties

Frequency

General surveys report that as many as 25-30% of households consider at least 1 family member to have a food allergy.This high rate is not supported by controlled studies in which oral food challenges (a medically supervised, gradual test feeding) are used to confirm patient histories. The actual prevalence of food allergies is estimated to be 5-6% in infants and children and 3.7 % in adults.

However, comprehensive studies that include oral food challenges are few in number. Considering allergy to milk, egg, peanut, and seafood in a meta-analysis of 6 international studies using oral food challenges, estimated rates of 1-10.8% were obtained.In a meta-analysis including allergy to fruits and vegetables (excluding peanut), only 6 international studies included oral food challenges, and estimates of allergy varied widely from 0.1-4.3% for fruits and tree nuts to 0.1-1.4% for vegetables to under 1% for wheat, soy, and sesame.

Studies in the United States and the United Kingdom indicate a rise in peanut allergy among young children in the past decade. One study showed an increase of peanut allergy in children from 0.4% in 1997 to 0.8% in 2002. Recent studies from Canada and the United Kingdom indicate allergy rates to peanut of over 1% in children.

Based upon available studies, estimations of the rate of food allergies in children have been summarized as follows for common food allergens: cow milk, 2.5%; eggs, 1.3%; peanuts, 0.8%; wheat, 0.4%; and soy, 0.4%. Allergic reactions to non-protein food additives are uncommon.

United States

A recent report from the Centers for Disease Control and Prevention (CDC) indicated an 18% rise in food allergy among children in the past decade.

Mortality/Morbidity

• Severe anaphylactic reactions, including death, can occur following the ingestion of food.Symptoms observed in a food-induced anaphylactic reaction may involve the skin, gastrointestinal tract, and respiratory tract. Frequently observed symptoms include oropharyngeal pruritus, angioedema (eg, laryngeal edema), stridor, dysphonia, cough, dyspnea, wheezing, nausea, vomiting, diarrhea, flushing, urticaria, and angioedema. Fatalities result from severe laryngeal edema, irreversible bronchospasm, refractory hypotension, or a combination thereof.
• Peanuts, tree nuts, fish, and shellfish are the foods most often implicated in severe food-induced anaphylactic reactions, though anaphylactic reactions have been reported to a wide variety of foods. Fatalities caused by reactions to milk are increasingly noted.
• Risk factors or associations for fatal food-induced anaphylaxis include: (1) the presence of asthma, especially in patients with poorly controlled disease; (2) previous episodes of anaphylaxis with the incriminated food; (3) a failure to recognize early symptoms of anaphylaxis; and (4) a delay or lack of immediate use of epinephrine to treat the allergic reaction. Teenagers and young adults appear to be overrepresented in registries of food allergy fatalities and present a special risk group.

Race

• No predilection is known.

Sex

• Among children, males appear to be more affected; among adults, females are more frequently affected.

Age

• In infants and children younger than 3 years, the prevalence of food allergy is approximately 5-6%.
• The estimated prevalence in adults is approximately 3.7%.

Clinical

History

• Necessary elements of a thorough medical history
  • Develop a complete list of all foods suspected to cause symptoms.
  • Discuss the manner of preparation of the food (cooked, raw, added spices or other ingredients).
  • Determine the minimum quantity of food exposure required to cause the symptoms.
  • Determine the reproducibility of symptoms upon exposure to the food.
  • Obtain a thorough description of each reaction, including the following:
    • The route of exposure (ingestion, skin contact, inhalation) and dose
    • The timing of the onset of symptoms in relation to food exposure
    • All observed symptoms and each one’s severity
    • The duration of the reaction
    • The treatment provided and the clinical response to treatment
    • The most recent reaction
  • Inquire about a personal or family history of other allergic disease.
  • Inquire about eliciting factors that can potentiate a food-allergic reaction (eg, exercise , nonsteroidal anti-inflammatory drugs [NSAIDs], alcohol)

Clinical manifestations and disorders

• Cutaneous reactions
  • These are the most common clinical manifestations of an allergic reaction to a food or food additive.
  • Symptoms range from acute urticaria (most common) to flushing to angioedema to exacerbations of atopic dermatitis.
  • Food allergy is rarely the cause of chronic urticaria or angioedema.
• Atopic dermatitis
  • Controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis. Studies show that of patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated food allergy.
  • Both food-specific IgE-mediated and cellular mechanisms appear responsible for chronic eczematous inflammation.
  • Removal of a specific food allergen leads to reduction or resolution of clinical symptoms in affected patients; reintroduction of the food exacerbates the atopic dermatitis. Reintroduction of a suspected food allergen should be performed under medical supervision because, in some instances, initial reintroduction of the food after a period of dietary elimination has resulted in more significant symptoms than were observed when the food was regularly ingested.
  • Prophylactic studies show that avoiding particular foods (eg, cow milk, eggs, peanuts) helps delay the onset of atopic dermatitis.
• Celiac disease: Celiac disease is the result of an immune response to gluten proteins in grain. This disorder is reviewed in the eMedicine Pediatrics article Celiac Disease.
• Dermatitis herpetiformis
  • This is a form of non-IgE cell-mediated hypersensitivity related to celiac disease. It is a blistering skin disorder that manifests clinically with a chronic and intensely pruritic rash with a symmetrical distribution.
  • Elimination of gluten from the diet usually leads to resolution of skin symptoms.
• IgE-mediated gastrointestinal food allergy
  • These food allergy reactions include immediate hypersensitivity reactions and the pollen-food allergy syndrome (oral allergy syndrome).
  • Specific gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhea is found less frequently.
• Pollen-food allergy syndrome (oral allergy syndrome)
  • Patients with this syndrome develop itching or tingling of the lips, tongue, palate, and throat following the ingestion of certain foods. In addition, edema of the lips, tongue, and uvula and a sensation of tightness in the throat may be observed. In fewer than 3% of cases, symptoms progress to more systemic reactions, such as laryngeal edema or hypotension.
  • This syndrome is caused by cross-reactivity between certain pollen and food allergens. For example, individuals with ragweed allergy may experience oropharyngeal symptoms following the ingestion of bananas or melons, and patients with birch pollen allergy may experience these symptoms following the ingestion of raw carrots, celery, potato, apple, peach or hazelnut.
• Mixed IgE/non-IgE gastrointestinal food allergy (eosinophilic esophagitis and gastroenteritis)
  • Symptoms vary according to location of eosinophilia. Typical symptoms include postprandial nausea, abdominal pain, and a sensation of early satiety. Eosinophilic esophagitis may manifest as reflux symptoms and dysphagia; food impaction can occur as well.
  • Children may experience weight loss or failure to thrive.
  • CBC count and differential findings may show eosinophilia in approximately 50% of patients; however, this is not diagnostic. Typically, endoscopy and biopsy must be performed in order to establish the presence of eosinophils in the affected segment of the gut. While a dense eosinophil infiltrate may be seen anywhere from the lower esophagus through the large bowel, involvement is patchy and variable.
  • An elemental (no potential allergens) or oligoantigenic diet (a diet that removes common allergenic foods) and trials of food elimination may be required to determine the role of foods in a patient's condition. Eosinophilic esophagitis does not respond to acid blockade therapy.
  • In addition to diet therapy (or in place of diet therapy), treatment with anti-inflammatory medications (eg, corticosteroids) may be needed.
• Non–IgE-mediated gastrointestinal food allergy
  • Food protein – induced enterocolitis syndrome typically manifests in the first few months of life with severe projectile vomiting, diarrhea, and failure to thrive.
  • Cow milk and soy protein formulas are usually responsible for these reactions. However, solid foods may also trigger these reactions, especially rice and oats.
  • When the allergen is removed from the diet, symptoms resolve. Re-exposure prior to resolution results in a delayed (2 h) onset of vomiting, lethargy, increase in the peripheral blood polymorphonuclear leukocyte count, and, later, diarrhea. Hypotension and methemoglobinemia may occur.
  • Infants who are chronically ingesting the allergen typically appear lethargic, wasted, and dehydrated. The presentation may mimic sepsis. An oral food challenge may establish the diagnosis but is not always needed if the history is clear. No other definitive diagnostic tests are available.
  • Breastfed infants may have mucus and blood in their stool, attributed to food allergens ingested by the mother, primarily cow milk. This allergic proctocolitis does not typically lead to anemia and is not associated with vomiting or poor growth. Maternal exclusion of the allergen resolves the bleeding. Eosinophilic inflammation of the rectum is noted if a biopsy is performed.Additional causes of bleeding (eg, infection, fissures) should be considered.
• Upper and lower respiratory tract reactions
  • Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal symptoms.
  • IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or bronchospasm.
• Asthma
  • The role of food allergy in the pathogenesis of asthma is a controversial area of investigation.
  • At the National Jewish Center for Immunology and Respiratory Medicine, 67 (24%) of the 279 children with a history of food-induced asthma were documented to have a positive result after a blinded food challenge, which included wheezing. Interestingly, only 5 (2%) of these patients had wheezing as their only objective adverse symptom.
  • In a related report, 320 children with atopic dermatitis undergoing blinded food challenges at Johns Hopkins Hospital were monitored for respiratory reactions. Overall, 34 (17%) of 205 children with positive results from food challenges developed wheezing as part of their reaction. Therefore, a conservative estimate is that 5-10% of patients with asthma have food-induced allergy symptoms.
  • In a pediatric case-controlled study comparing 19 children who required ventilation for an exacerbation of asthma and 38 control subjects matched by sex, age, and ethnicity, coincident food allergy was found to be independently associated with life-threatening asthma.
  • Wheezing as the only manifestation of an allergic reaction to food is rare.
• Food-induced pulmonary hemosiderosis (Heiner syndrome)
  • This is a rare disorder characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, hemosiderosis, gastrointestinal blood loss, iron deficiency anemia, and failure to thrive in infants.
  • While the precise immunologic mechanism is unknown, it is thought to be secondary to a non-IgE hypersensitivity process.
• Food-induced anaphylaxis
  • Following the ingestion of food, severe anaphylactic reactions (ie, systemic allergic reactions), including death, can occur.
  • Symptoms may include the following:
    • Oropharyngeal pruritus
    • Angioedema (eg, laryngeal edema)
    • Urticaria
    • Ocular injection, ocular pruritus, conjunctival edema, periocular swelling
    • Nasal congestion, nasal pruritus, rhinorrhea, and sneezing
    • Stridor
    • Dysphonia
    • Cough
    • Dyspnea
    • Wheezing, bronchospasm
    • Nausea
    • Emesis
    • Abdominal pain
    • Diarrhea
    • A feeling of impending doom
    • Cardiovascular collapse
  • Anaphylaxis can occur without skin symptoms
  • Food-associated, exercise-induced anaphylaxis describes a disorder in which exercise is tolerated and a food or foods are tolerated, but when exercise follows ingestion of a specific food or foods, anaphylaxis results

Physical

• The physical examination findings are most useful for assessing overall nutritional status, growth parameters, and signs of other allergic disease, such as atopic dermatitis, allergic rhinitis, or asthma.
• Findings from a comprehensive physical examination can help rule out other conditions that may mimic food allergy.

Causes

• Any food protein can trigger an allergic response, and allergic reactions to a large number of foods have been documented; however, only a small group of foods account for most of these reactions.
• Eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often implicated in allergic reactions that have been confirmed in well-controlled blinded food challenges. Sesame appears to be an emerging allergen.
• Investigations of near-fatal or fatal anaphylactic reactions following food ingestion reveal that most are caused by peanuts, tree nuts, and shellfish, although milk has been increasingly reported

Food Allergies

Introduction

Background

Adverse food reactions can be broadly classified into 2 categories. The first category consists of immunologically-mediated adverse reactions to foods that are termed food allergies. Food allergies can result in disorders with an acute onset of symptoms following ingestion of the triggering food allergen (eg, anaphylaxis) and in chronic disorders (eg, atopic dermatitis).

The second category is composed of adverse reactions that are not immune-mediated. An example is lactose intolerance caused by a deficiency of lactase. Adverse reactions to foods can also occur from toxic (eg, bacterial food poisoning) or pharmacologic (eg, caffeine) effects.

Pathophysiology

Food allergies are primarily the result of immune responses to food proteins.Normally, noninflammatory immune responses develop to ingested foods in a process called oral tolerance.³ For reasons that remain unclear, but likely include environmental and genetic factors, tolerance may be abrogated, leading to adverse immune responses. While sensitization (eg, development of an immunoglobulin E [IgE] immune response) to an allergen has been primarily assumed to occur from ingestion, this may not always be the case. For example, oral allergy syndrome (pollen-food related syndrome) describes an allergic response to specific raw fruits or vegetables that share homologous proteins with pollens; the initial route of sensitization is respiratory exposure to pollen proteins rather than oral exposure to food proteins. The skin may be another potential route of sensitization.

IgE antibody – mediated responses are the most widely recognized form of food allergy and account for acute reactions. Patients with atopy produce IgE antibodies to specific epitopes (areas of the protein) of one or more food allergens. These antibodies bind to high-affinity IgE receptors on circulating basophils and tissue mast cells present throughout the body, including the skin, gastrointestinal tract, and respiratory tract.

Subsequent allergen exposure binds and cross links IgE antibodies on the cell surface, resulting in receptor activation and intracellular signaling that initiates the release of inflammatory mediators (eg, histamine) and synthesis of additional factors (eg, chemotactic factors, cytokines) that promote allergic inflammation. The effects of these mediators on surrounding tissues result in vasodilatation, smooth muscle contraction, and mucus secretion, which, in turn, are responsible for the spectrum of clinical symptoms observed during acute allergic reactions to food.

Cell-mediated responses to food allergens may also mediate allergic responses, particularly in disorders with delayed or chronic symptoms. For example, food protein – induced enterocolitis syndrome (FPIES), a gastrointestinal food allergy, appears to be mediated by T-cell elaboration of the cytokine tumor necrosis factor (TNF)-alpha. Persons with atopic dermatitis that flares with ingestion of milk have been noted to have T cells that, in vitro, express the homing receptor cutaneous lymphocyte antigen, which is thought to home the cell to the skin and mediate the response.⁶ Celiac disease is the result of an immune response to gluten proteins in grains; this disorder is reviewed in the eMedicine Pediatrics article Celiac Disease.

Food allergens are typically water-soluble glycoproteins resistant to heating and proteolysis with molecular weights of 10-70 kd. These characteristics facilitate the absorption of these allergens across mucosal surfaces. Numerous food allergens are purified and well-characterized, such as peanut Ara h1, Ara h2, and Ara h3; chicken egg white Gal d1, Gal d2, and Gal d3; soybean-Gly m1; fish-Gad c1; and shrimp-Pen a1. Closely related foods frequently contain allergens that crossreact immunologically (ie, lead to the generation of specific IgE antibodies detectable by skin prick or in vitro testing) but less frequently crossreact clinically Recently, delayed allergic reactions to meat proteins have been attributed to reactions to carbohydrate moieties

Frequency

General surveys report that as many as 25-30% of households consider at least 1 family member to have a food allergy.This high rate is not supported by controlled studies in which oral food challenges (a medically supervised, gradual test feeding) are used to confirm patient histories. The actual prevalence of food allergies is estimated to be 5-6% in infants and children and 3.7 % in adults.

However, comprehensive studies that include oral food challenges are few in number. Considering allergy to milk, egg, peanut, and seafood in a meta-analysis of 6 international studies using oral food challenges, estimated rates of 1-10.8% were obtained.In a meta-analysis including allergy to fruits and vegetables (excluding peanut), only 6 international studies included oral food challenges, and estimates of allergy varied widely from 0.1-4.3% for fruits and tree nuts to 0.1-1.4% for vegetables to under 1% for wheat, soy, and sesame.

Studies in the United States and the United Kingdom indicate a rise in peanut allergy among young children in the past decade. One study showed an increase of peanut allergy in children from 0.4% in 1997 to 0.8% in 2002. Recent studies from Canada and the United Kingdom indicate allergy rates to peanut of over 1% in children.

Based upon available studies, estimations of the rate of food allergies in children have been summarized as follows for common food allergens: cow milk, 2.5%; eggs, 1.3%; peanuts, 0.8%; wheat, 0.4%; and soy, 0.4%. Allergic reactions to non-protein food additives are uncommon.

United States

A recent report from the Centers for Disease Control and Prevention (CDC) indicated an 18% rise in food allergy among children in the past decade.

Mortality/Morbidity

• Severe anaphylactic reactions, including death, can occur following the ingestion of food.Symptoms observed in a food-induced anaphylactic reaction may involve the skin, gastrointestinal tract, and respiratory tract. Frequently observed symptoms include oropharyngeal pruritus, angioedema (eg, laryngeal edema), stridor, dysphonia, cough, dyspnea, wheezing, nausea, vomiting, diarrhea, flushing, urticaria, and angioedema. Fatalities result from severe laryngeal edema, irreversible bronchospasm, refractory hypotension, or a combination thereof.
• Peanuts, tree nuts, fish, and shellfish are the foods most often implicated in severe food-induced anaphylactic reactions, though anaphylactic reactions have been reported to a wide variety of foods. Fatalities caused by reactions to milk are increasingly noted.
• Risk factors or associations for fatal food-induced anaphylaxis include: (1) the presence of asthma, especially in patients with poorly controlled disease; (2) previous episodes of anaphylaxis with the incriminated food; (3) a failure to recognize early symptoms of anaphylaxis; and (4) a delay or lack of immediate use of epinephrine to treat the allergic reaction. Teenagers and young adults appear to be overrepresented in registries of food allergy fatalities and present a special risk group.

Race

• No predilection is known.

Sex

• Among children, males appear to be more affected; among adults, females are more frequently affected.

Age

• In infants and children younger than 3 years, the prevalence of food allergy is approximately 5-6%.
• The estimated prevalence in adults is approximately 3.7%.

Clinical

History

• Necessary elements of a thorough medical history
  • Develop a complete list of all foods suspected to cause symptoms.
  • Discuss the manner of preparation of the food (cooked, raw, added spices or other ingredients).
  • Determine the minimum quantity of food exposure required to cause the symptoms.
  • Determine the reproducibility of symptoms upon exposure to the food.
  • Obtain a thorough description of each reaction, including the following:
    • The route of exposure (ingestion, skin contact, inhalation) and dose
    • The timing of the onset of symptoms in relation to food exposure
    • All observed symptoms and each one’s severity
    • The duration of the reaction
    • The treatment provided and the clinical response to treatment
    • The most recent reaction
  • Inquire about a personal or family history of other allergic disease.
  • Inquire about eliciting factors that can potentiate a food-allergic reaction (eg, exercise , nonsteroidal anti-inflammatory drugs [NSAIDs], alcohol)

Clinical manifestations and disorders

• Cutaneous reactions
  • These are the most common clinical manifestations of an allergic reaction to a food or food additive.
  • Symptoms range from acute urticaria (most common) to flushing to angioedema to exacerbations of atopic dermatitis.
  • Food allergy is rarely the cause of chronic urticaria or angioedema.
• Atopic dermatitis
  • Controversy surrounds the role of food allergy in the pathogenesis of atopic dermatitis. Studies show that of patients with moderate chronic atopic dermatitis, 35-40% have IgE-mediated food allergy.
  • Both food-specific IgE-mediated and cellular mechanisms appear responsible for chronic eczematous inflammation.
  • Removal of a specific food allergen leads to reduction or resolution of clinical symptoms in affected patients; reintroduction of the food exacerbates the atopic dermatitis. Reintroduction of a suspected food allergen should be performed under medical supervision because, in some instances, initial reintroduction of the food after a period of dietary elimination has resulted in more significant symptoms than were observed when the food was regularly ingested.
  • Prophylactic studies show that avoiding particular foods (eg, cow milk, eggs, peanuts) helps delay the onset of atopic dermatitis.
• Celiac disease: Celiac disease is the result of an immune response to gluten proteins in grain. This disorder is reviewed in the eMedicine Pediatrics article Celiac Disease.
• Dermatitis herpetiformis
  • This is a form of non-IgE cell-mediated hypersensitivity related to celiac disease. It is a blistering skin disorder that manifests clinically with a chronic and intensely pruritic rash with a symmetrical distribution.
  • Elimination of gluten from the diet usually leads to resolution of skin symptoms.
• IgE-mediated gastrointestinal food allergy
  • These food allergy reactions include immediate hypersensitivity reactions and the pollen-food allergy syndrome (oral allergy syndrome).
  • Specific gastrointestinal symptoms include nausea, vomiting, abdominal pain, and cramping. Diarrhea is found less frequently.
• Pollen-food allergy syndrome (oral allergy syndrome)
  • Patients with this syndrome develop itching or tingling of the lips, tongue, palate, and throat following the ingestion of certain foods. In addition, edema of the lips, tongue, and uvula and a sensation of tightness in the throat may be observed. In fewer than 3% of cases, symptoms progress to more systemic reactions, such as laryngeal edema or hypotension.
  • This syndrome is caused by cross-reactivity between certain pollen and food allergens. For example, individuals with ragweed allergy may experience oropharyngeal symptoms following the ingestion of bananas or melons, and patients with birch pollen allergy may experience these symptoms following the ingestion of raw carrots, celery, potato, apple, peach or hazelnut.
• Mixed IgE/non-IgE gastrointestinal food allergy (eosinophilic esophagitis and gastroenteritis)
  • Symptoms vary according to location of eosinophilia. Typical symptoms include postprandial nausea, abdominal pain, and a sensation of early satiety. Eosinophilic esophagitis may manifest as reflux symptoms and dysphagia; food impaction can occur as well.
  • Children may experience weight loss or failure to thrive.
  • CBC count and differential findings may show eosinophilia in approximately 50% of patients; however, this is not diagnostic. Typically, endoscopy and biopsy must be performed in order to establish the presence of eosinophils in the affected segment of the gut. While a dense eosinophil infiltrate may be seen anywhere from the lower esophagus through the large bowel, involvement is patchy and variable.
  • An elemental (no potential allergens) or oligoantigenic diet (a diet that removes common allergenic foods) and trials of food elimination may be required to determine the role of foods in a patient's condition. Eosinophilic esophagitis does not respond to acid blockade therapy.
  • In addition to diet therapy (or in place of diet therapy), treatment with anti-inflammatory medications (eg, corticosteroids) may be needed.
• Non–IgE-mediated gastrointestinal food allergy
  • Food protein – induced enterocolitis syndrome typically manifests in the first few months of life with severe projectile vomiting, diarrhea, and failure to thrive.
  • Cow milk and soy protein formulas are usually responsible for these reactions. However, solid foods may also trigger these reactions, especially rice and oats.
  • When the allergen is removed from the diet, symptoms resolve. Re-exposure prior to resolution results in a delayed (2 h) onset of vomiting, lethargy, increase in the peripheral blood polymorphonuclear leukocyte count, and, later, diarrhea. Hypotension and methemoglobinemia may occur.
  • Infants who are chronically ingesting the allergen typically appear lethargic, wasted, and dehydrated. The presentation may mimic sepsis. An oral food challenge may establish the diagnosis but is not always needed if the history is clear. No other definitive diagnostic tests are available.
  • Breastfed infants may have mucus and blood in their stool, attributed to food allergens ingested by the mother, primarily cow milk. This allergic proctocolitis does not typically lead to anemia and is not associated with vomiting or poor growth. Maternal exclusion of the allergen resolves the bleeding. Eosinophilic inflammation of the rectum is noted if a biopsy is performed.Additional causes of bleeding (eg, infection, fissures) should be considered.
• Upper and lower respiratory tract reactions
  • Upper respiratory reactions typically include nasal congestion, sneezing, nasal pruritus, or rhinorrhea. They are usually observed in conjunction with ocular, skin, or gastrointestinal symptoms.
  • IgE-mediated pulmonary symptoms may include laryngeal edema, cough, or bronchospasm.
• Asthma
  • The role of food allergy in the pathogenesis of asthma is a controversial area of investigation.
  • At the National Jewish Center for Immunology and Respiratory Medicine, 67 (24%) of the 279 children with a history of food-induced asthma were documented to have a positive result after a blinded food challenge, which included wheezing. Interestingly, only 5 (2%) of these patients had wheezing as their only objective adverse symptom.
  • In a related report, 320 children with atopic dermatitis undergoing blinded food challenges at Johns Hopkins Hospital were monitored for respiratory reactions. Overall, 34 (17%) of 205 children with positive results from food challenges developed wheezing as part of their reaction. Therefore, a conservative estimate is that 5-10% of patients with asthma have food-induced allergy symptoms.
  • In a pediatric case-controlled study comparing 19 children who required ventilation for an exacerbation of asthma and 38 control subjects matched by sex, age, and ethnicity, coincident food allergy was found to be independently associated with life-threatening asthma.
  • Wheezing as the only manifestation of an allergic reaction to food is rare.
• Food-induced pulmonary hemosiderosis (Heiner syndrome)
  • This is a rare disorder characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates, hemosiderosis, gastrointestinal blood loss, iron deficiency anemia, and failure to thrive in infants.
  • While the precise immunologic mechanism is unknown, it is thought to be secondary to a non-IgE hypersensitivity process.
• Food-induced anaphylaxis
  • Following the ingestion of food, severe anaphylactic reactions (ie, systemic allergic reactions), including death, can occur.
  • Symptoms may include the following:
    • Oropharyngeal pruritus
    • Angioedema (eg, laryngeal edema)
    • Urticaria
    • Ocular injection, ocular pruritus, conjunctival edema, periocular swelling
    • Nasal congestion, nasal pruritus, rhinorrhea, and sneezing
    • Stridor
    • Dysphonia
    • Cough
    • Dyspnea
    • Wheezing, bronchospasm
    • Nausea
    • Emesis
    • Abdominal pain
    • Diarrhea
    • A feeling of impending doom
    • Cardiovascular collapse
  • Anaphylaxis can occur without skin symptoms
  • Food-associated, exercise-induced anaphylaxis describes a disorder in which exercise is tolerated and a food or foods are tolerated, but when exercise follows ingestion of a specific food or foods, anaphylaxis results

Physical

• The physical examination findings are most useful for assessing overall nutritional status, growth parameters, and signs of other allergic disease, such as atopic dermatitis, allergic rhinitis, or asthma.
• Findings from a comprehensive physical examination can help rule out other conditions that may mimic food allergy.

Causes

• Any food protein can trigger an allergic response, and allergic reactions to a large number of foods have been documented; however, only a small group of foods account for most of these reactions.
• Eggs, milk, peanuts, soy, fish, shellfish, tree nuts, and wheat are the foods most often implicated in allergic reactions that have been confirmed in well-controlled blinded food challenges. Sesame appears to be an emerging allergen.
• Investigations of near-fatal or fatal anaphylactic reactions following food ingestion reveal that most are caused by peanuts, tree nuts, and shellfish, although milk has been increasingly reported

Transparency at the Food and Drug Administration

Afia K. Asamoah, J.D., and Joshua M. Sharfstein, M.D.

On his first full day in office, President Barack Obama issued a memorandum calling for “creating an unprecedented level of openness in Government.” The Department of Health and Human Services embraced this goal, and in June 2009, the new commissioner of the Food and Drug Administration (FDA), Dr. Margaret Hamburg, announced a major transparency initiative. The goal of this initiative was to better explain the FDA’s actions by providing information that supports clinical medicine, biomedical innovation, and public health.

The FDA already makes substantial amounts of information about the regulatory process for medical products publicly available. For example, extensive summary data on drugs and devices are released for public advisory committee meetings before approval, and detailed reviews of drugs are released after approval. However, many aspects of the FDA’s work remain unknown to the public. Few people understand the basic processes followed within the FDA, such as how the agency monitors medical products for safety after they have been approved or how the device-approval process works for products in various risk categories.

In addition, the FDA generally does not disclose certain information, including whether a drug or device is under development, when an application is withdrawn by a sponsor, whether the agency has placed a hold on clinical studies, whether it agrees with reports published by others about products with pending applications not yet approved by the FDA, and why it does not approve a marketing application. The FDA does not routinely post on its Web site the dates when facilities are inspected or the results of these inspections. Regulated companies have expressed interest in additional transparency about the standards to which their products are held, the process for soliciting guidance from the agency, and the progress of regulatory efforts at the agency.

Through its transparency initiative, the FDA has considered a wide range of options for increasing transparency about these and other aspects of its work. The agency has held two public meetings, participated in multiple listening sessions, launched an online blog, and established a docket (public record) to solicit ideas from the public. The agency has received more than 1500 comments.

A task force that includes senior leaders at the agency has reviewed the public input and discussed how best to balance the important and often dueling considerations of transparency and confidentiality. With the support of Dr. Hamburg, the agency is moving forward to implement a series of changes and propose others for further public dialogue.

The first step came in January 2010, when the FDA released a Web-based resource called FDA Basics (www.fda.gov/fdabasics). This site aims to answer fundamental questions about how the agency does its work, covering such topics as the product-approval process, inspections, and adverse-event reporting. To date, the site has had more than 165,000 unique visitors, who have left more than 4000 comments.

The second step came in April 2010, when, as part of the open-government efforts of the Department of Health and Human Services, the FDA launched a program-performance system called FDA-TRACK (www.fda.gov/fdatrack). This system discloses specific measures of workload and results for more than 100 offices at the FDA. Data on nearly all these measures are calculated on a monthly basis. These include the backlog in reviews of applications for approval of generic drugs, the extent to which approvals are meeting goals for review time, and whether complaints about drug advertising are found to have merit. The agency is also tracking more than 50 key projects, including ones that are fostering the development of medical devices to respond to unmet public health needs, recruiting new advisory committee members, and identifying faster ways to determine whether salmonella is present in food.

The third step begins on May 19, 2010, with the release of a report from the Transparency Task Force containing 21 draft proposals for expanding the disclosure of information by the agency while maintaining confidentiality for trade secrets and individually identifiable patient information (see Examples of Draft Proposals for Public Comment). Not all these proposals will necessarily be implemented. Some may require changes in law or regulation, and some may require substantial amounts of resources. The agency is now accepting public comment on the content of the proposals, as well as on which draft proposals should be given priority.

If the proposals were to be adopted and implemented, the FDA would make substantially more information about the regulatory process available to the public. The agency would disclose, among other things, when a drug or device is being studied and for what indication, when an application for a new drug or device has been submitted or withdrawn by the sponsor, whether there was a significant safety concern associated with the drug or device that caused the sponsor to withdraw an application, and why the agency did not approve an application. If a report that is published by a sponsor were to contain an incomplete picture about the safety or efficacy of a product, the FDA would be able to provide its analysis to contribute to the scientific discussion.

The task force believes that implementing some of the proposals would accelerate the development process for medical products by allowing companies to learn from the successes and failures of other products. One proposal, for example, would allow the FDA to explain that an orphan drug whose application was abandoned or withdrawn by the sponsor for business reasons may nevertheless represent an important therapeutic advance for a rare disease. This information would be of substantial interest to patients with that disease, their families, and their clinicians. It could also encourage additional investment for development of that drug or provide another company with the incentive to purchase and continue with the application.

The task force is also proposing further public discussions on the appropriate release of certain raw data, without patient identifiers, to allow for additional study of, and new insights into, the safety and efficacy of drugs and devices.

Implementing other proposals would illuminate the agency’s enforcement efforts by having the FDA post the classification of every facility inspection it performs. The final inspectional classification is based on the inspectors’ observations and reflects the degree to which the establishment is out of compliance with laws and regulations designed to ensure the safety of FDA-regulated products. Another proposal would have the FDA generate and share with the public information about the most common objectionable conditions or practices found by agency staff during inspections. This information could be very useful to consumers and purchasers of medical products and food.

More than 30 years ago, FDA Commissioner Donald Kennedy noted “a basic principle of our political system [is] that people affected by governmental decisions have a right to know the basis on which they are made.” With the daily practice of medicine routinely affected by the decisions of the FDA, the medical community has a large stake in transparency at the agency. The full set of draft proposals can be found on the FDA’s Web site (www.fda.gov/transparency). The agency is accepting comment on the proposals until July 20, 2010.

Examples of Draft Proposals for Public Comment.

Elaborate on the FDA’s decisions

At the time the FDA issues a refuse-to-file or complete response letter in response to an original new-drug application, biologics-licensing application, or efficacy supplement for such applications, the agency should disclose that it has done so and should simultaneously disclose the refuse-to-file or complete response letter, which contains the reasons for issuing the letter.

Provide increased access to important data

The agency should disclose relevant summary safety and effectiveness information from an investigational application or a pending marketing application, if the agency concludes that disclosure is in the interest of the public health, including when it believes that doing so is necessary to correct misleading information about the product that is the subject of the application.

Illuminate enforcement efforts

The agency should disclose the name and address of the entity inspected, the date or dates of inspection, the type or types of FDA-regulated product involved, and the final inspectional classification — official action indicated, voluntary action indicated, or no action indicated — for inspections conducted of clinical trial investigators, institutional review boards, and facilities that manufacture, process, pack, or hold an FDA-regulated product that is currently marketed. The disclosure of this information should be timed so as not to interfere with planned enforcement actions.

Support innovation

When an application for a designated orphan human drug or a designated minor-use or minor-species animal drug has been withdrawn, terminated, or abandoned, the agency should disclose, if it so determines through its review, that the application was not withdrawn, terminated, or abandoned for safety reasons and that the product, if approved, could represent a significant therapeutic advance for a rare disease or for a minor animal species. A disclaimer should accompany the disclosure of this information, indicating that the agency’s expressed views about the product do not reflect whether a subsequent application involving the product will be accepted for filing or will be approved by the FDA.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

Ms. Asamoah is the director of the FDA’s Transparency Initiative, Silver Spring, MD, and Dr. Sharfstein is the FDA’s principal deputy commissioner and chair of its Transparency Task Force.

This article (10.1056/NEJMp1005202) was published on May 19, 2010, at NEJM.org.

Transparency at the Food and Drug Administration

Afia K. Asamoah, J.D., and Joshua M. Sharfstein, M.D.

On his first full day in office, President Barack Obama issued a memorandum calling for “creating an unprecedented level of openness in Government.” The Department of Health and Human Services embraced this goal, and in June 2009, the new commissioner of the Food and Drug Administration (FDA), Dr. Margaret Hamburg, announced a major transparency initiative. The goal of this initiative was to better explain the FDA’s actions by providing information that supports clinical medicine, biomedical innovation, and public health.

The FDA already makes substantial amounts of information about the regulatory process for medical products publicly available. For example, extensive summary data on drugs and devices are released for public advisory committee meetings before approval, and detailed reviews of drugs are released after approval. However, many aspects of the FDA’s work remain unknown to the public. Few people understand the basic processes followed within the FDA, such as how the agency monitors medical products for safety after they have been approved or how the device-approval process works for products in various risk categories.

In addition, the FDA generally does not disclose certain information, including whether a drug or device is under development, when an application is withdrawn by a sponsor, whether the agency has placed a hold on clinical studies, whether it agrees with reports published by others about products with pending applications not yet approved by the FDA, and why it does not approve a marketing application. The FDA does not routinely post on its Web site the dates when facilities are inspected or the results of these inspections. Regulated companies have expressed interest in additional transparency about the standards to which their products are held, the process for soliciting guidance from the agency, and the progress of regulatory efforts at the agency.

Through its transparency initiative, the FDA has considered a wide range of options for increasing transparency about these and other aspects of its work. The agency has held two public meetings, participated in multiple listening sessions, launched an online blog, and established a docket (public record) to solicit ideas from the public. The agency has received more than 1500 comments.

A task force that includes senior leaders at the agency has reviewed the public input and discussed how best to balance the important and often dueling considerations of transparency and confidentiality. With the support of Dr. Hamburg, the agency is moving forward to implement a series of changes and propose others for further public dialogue.

The first step came in January 2010, when the FDA released a Web-based resource called FDA Basics (www.fda.gov/fdabasics). This site aims to answer fundamental questions about how the agency does its work, covering such topics as the product-approval process, inspections, and adverse-event reporting. To date, the site has had more than 165,000 unique visitors, who have left more than 4000 comments.

The second step came in April 2010, when, as part of the open-government efforts of the Department of Health and Human Services, the FDA launched a program-performance system called FDA-TRACK (www.fda.gov/fdatrack). This system discloses specific measures of workload and results for more than 100 offices at the FDA. Data on nearly all these measures are calculated on a monthly basis. These include the backlog in reviews of applications for approval of generic drugs, the extent to which approvals are meeting goals for review time, and whether complaints about drug advertising are found to have merit. The agency is also tracking more than 50 key projects, including ones that are fostering the development of medical devices to respond to unmet public health needs, recruiting new advisory committee members, and identifying faster ways to determine whether salmonella is present in food.

The third step begins on May 19, 2010, with the release of a report from the Transparency Task Force containing 21 draft proposals for expanding the disclosure of information by the agency while maintaining confidentiality for trade secrets and individually identifiable patient information (see Examples of Draft Proposals for Public Comment). Not all these proposals will necessarily be implemented. Some may require changes in law or regulation, and some may require substantial amounts of resources. The agency is now accepting public comment on the content of the proposals, as well as on which draft proposals should be given priority.

If the proposals were to be adopted and implemented, the FDA would make substantially more information about the regulatory process available to the public. The agency would disclose, among other things, when a drug or device is being studied and for what indication, when an application for a new drug or device has been submitted or withdrawn by the sponsor, whether there was a significant safety concern associated with the drug or device that caused the sponsor to withdraw an application, and why the agency did not approve an application. If a report that is published by a sponsor were to contain an incomplete picture about the safety or efficacy of a product, the FDA would be able to provide its analysis to contribute to the scientific discussion.

The task force believes that implementing some of the proposals would accelerate the development process for medical products by allowing companies to learn from the successes and failures of other products. One proposal, for example, would allow the FDA to explain that an orphan drug whose application was abandoned or withdrawn by the sponsor for business reasons may nevertheless represent an important therapeutic advance for a rare disease. This information would be of substantial interest to patients with that disease, their families, and their clinicians. It could also encourage additional investment for development of that drug or provide another company with the incentive to purchase and continue with the application.

The task force is also proposing further public discussions on the appropriate release of certain raw data, without patient identifiers, to allow for additional study of, and new insights into, the safety and efficacy of drugs and devices.

Implementing other proposals would illuminate the agency’s enforcement efforts by having the FDA post the classification of every facility inspection it performs. The final inspectional classification is based on the inspectors’ observations and reflects the degree to which the establishment is out of compliance with laws and regulations designed to ensure the safety of FDA-regulated products. Another proposal would have the FDA generate and share with the public information about the most common objectionable conditions or practices found by agency staff during inspections. This information could be very useful to consumers and purchasers of medical products and food.

More than 30 years ago, FDA Commissioner Donald Kennedy noted “a basic principle of our political system [is] that people affected by governmental decisions have a right to know the basis on which they are made.” With the daily practice of medicine routinely affected by the decisions of the FDA, the medical community has a large stake in transparency at the agency. The full set of draft proposals can be found on the FDA’s Web site (www.fda.gov/transparency). The agency is accepting comment on the proposals until July 20, 2010.

Examples of Draft Proposals for Public Comment.

Elaborate on the FDA’s decisions

At the time the FDA issues a refuse-to-file or complete response letter in response to an original new-drug application, biologics-licensing application, or efficacy supplement for such applications, the agency should disclose that it has done so and should simultaneously disclose the refuse-to-file or complete response letter, which contains the reasons for issuing the letter.

Provide increased access to important data

The agency should disclose relevant summary safety and effectiveness information from an investigational application or a pending marketing application, if the agency concludes that disclosure is in the interest of the public health, including when it believes that doing so is necessary to correct misleading information about the product that is the subject of the application.

Illuminate enforcement efforts

The agency should disclose the name and address of the entity inspected, the date or dates of inspection, the type or types of FDA-regulated product involved, and the final inspectional classification — official action indicated, voluntary action indicated, or no action indicated — for inspections conducted of clinical trial investigators, institutional review boards, and facilities that manufacture, process, pack, or hold an FDA-regulated product that is currently marketed. The disclosure of this information should be timed so as not to interfere with planned enforcement actions.

Support innovation

When an application for a designated orphan human drug or a designated minor-use or minor-species animal drug has been withdrawn, terminated, or abandoned, the agency should disclose, if it so determines through its review, that the application was not withdrawn, terminated, or abandoned for safety reasons and that the product, if approved, could represent a significant therapeutic advance for a rare disease or for a minor animal species. A disclaimer should accompany the disclosure of this information, indicating that the agency’s expressed views about the product do not reflect whether a subsequent application involving the product will be accepted for filing or will be approved by the FDA.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

Ms. Asamoah is the director of the FDA’s Transparency Initiative, Silver Spring, MD, and Dr. Sharfstein is the FDA’s principal deputy commissioner and chair of its Transparency Task Force.

This article (10.1056/NEJMp1005202) was published on May 19, 2010, at NEJM.org.

Angioedema

Introduction

Background

Many types of angioedema are described in the literature: hereditary angioedema (HAE) types I, II, and III; acquired angioedema; drug-induced angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]); urticaria-associated angioedema; and idiopathic angioedema. Most forms of angioedema are considered idiopathic. In general, angioedema can be categorized as with urticaria or without urticaria. Urticaria and angioedema are similar in pathogenesis; however, angioedema manifests deeper in mucosal tissue. The reaction is mast cell mediated when both are evident during clinical presentation. In this case, the patient describes subjective pruritus, often associated with hypersensitivity to an offending agent.

Ten percent of angioedema cases occur without urticaria and is considered to be kinin-mediated rather than a hypersensitivity reaction. Hereditary angioedema and acquired angioedema are associated with insufficient or dysfunctional C1 esterase inhibitor, resulting in increased circulation of vasoactive substances. This type of angioedema can be induced spontaneously, or it can be due to stress or medications; this type is highly associated with ACE inhibitors.

In general, angioedema is described as deep, subcutaneous, submucosal edema due to increased vascular permeability. It can manifest as an episodic or self-limiting event but can often be described as recurrent. Acute episodes may involve the skin, larynx, and buccal and gastrointestinal (GI) mucosa.

Pathophysiology

Angioedema without urticaria can be classified as hereditary angioedema (HAE) or acquired C1 inhibitory deficiency (AAE/ACID). Hereditary angioedema results from a quantitative or qualitative deficiency of the C1 esterase inhibitor (C1-INH) due to a defective C1NH gene.³ Type I is described as C1 esterase inhibitor deficiency. Type II is believed to be a dysfunction of C1 esterase inhibitor with normal-to-high circulating levels of the molecule. These two forms are not distinguishable clinically.

An additional type III HAE, occurring only in females, has also been described. In this case, there is also an abnormal functioning protein. Abdominal attacks are seen less frequently in this variant. Orofacial involvement seems to be the most common presentation of the type III sensitivity, making it very difficult to distinguish from types I and II. This type has also been associated with exogenous estrogen administration and pregnancy.

C1 esterase is a serine protease that is involved in the regulation of bradykinin, a potent vasoactive substance. Low levels of this protease results in the activation of the kallikrein-kinin system, the complement cascade, and the fibrinolytic system and results in the release of vasoactive peptides such as bradykinin, considered to be the most important regulatory complement involved in many molecular cascades.Release of vasoactive substances causes vasodilatation of endothelial cells as well as smooth muscle bowel contraction. This ultimately manifests in the common clinical presentation of the disease.

In the setting of hereditary angioedema, AAE, and ACE inhibitor – induced angioedema, bradykinin levels are directly elevated in the blood. ACE is naturally one of the inhibitors of bradykinin. With ACE inhibition, bradykinin levels are increased.

Acquired angioedema (ACID) is classified as type I or type II. It is a result of autoantibodies that act on the protease, thus increasing consumption of C1-INH. Clinically, it presents like hereditary angioedema.

The type I variant of acquired angioedema is associated with B-cell proliferative disorders. In this disease, there is hypercatabolization of C1-INH. Immunocomplexes are formed between antibodies and abnormal immunoglobulins on the cell surface of B cells. The complement cascade hyperreacts, producing large amounts of C1. C1-INH is then consumed on attempts to prevent the activation of the continuously activated C1. The relative deficiency of C1 inhibitor causes increased activation of the kallikrein-kinin system.Enzymatic cleavage by kallikrein is increased with consumption of kininogen and subsequently the production of bradykinin increases. The end result of this intricate molecular cascade is vasodilatation meditated by the interaction of kinins with endothelial cell receptors, B1R and B2R.

The type II variant of acquired angioedema is associated with autoantibodies (immunoglobulin G [IgG] and less often immunoglobulin M [IgM]) directed against the C1-INH molecule.Depletion of C1-INH results in the production of large amounts of bradykinin and other vasoactive substances, which causes the signs and symptoms of angioedema.

Angioedema associated with urticaria is a hypersensitivity to an offending agent. Histamine is released into the bloodstream, resulting in an increase in endothelial cell permeability. Angioedema, generalized urticaria, and, in severe cases, anaphylaxis will occur. The allergen binds to the mast cell, causing degranulation and histamine and tryptase release. Degranulations of mast cells have also been shown to be a direct result of anesthetics, contrast mediums, and opiates.

Autoantibodies against the mast cell IgE receptor or mast cell-bound IgE (or basophils) is another common cause of histamine release. Additionally, proteases may activate the complement cascade associated with c3a, c4a, and c5a, which are considered anaphylactoids, and result in increased capillary permeability and extravasation of fluid.⁷

Frequency

United States

Eighty-five percent of patients who experience angioedema not associated with urticaria have type I HAE. Approximately 1 out of 10,000 patients have recurrent angioedema classified as type I. Type II HAE occurs in 1 out of 50,000 people. Angioedema induced by ACE inhibitors occurs at a frequency of 0.1-0.7%.

Mortality/Morbidity

Morbidity and mortality are directly related to the severity of airway obstruction. Asphyxiation due to laryngeal edema yields a 3-40% mortality rate.

Race

No specific racial predilection exists for angioedema.

Sex

Women tend to have more occurrences of angioedema than men.

Age

Persons who are predisposed to angioedema have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

Clinical

History

• Hereditary angioedema (HAE), idiopathic angioedema, and drug-induced angioedema^1,2
  • Episodes consist of relapsing, self-limiting edema. All edema episodes are self-limiting, last for 1-7 days and are followed by a disease-free interval.
  • Edema may occur in the subcutaneous tissue, wall of the intestine, and larynx.
  • Abdominal pain attacks may present with or without nausea, vomiting, and ascites.
  • Skin swelling most frequently affects the lips, face, hands, feet, and genitalia.
  • Urticaria is generally not a clinical symptom.
  • Rare symptoms include episodes of tongue edema and swelling of the soft palate.
  • Local trauma (eg, dental procedure, tonsillectomy) or stress may be present in the patient's history.
  • The frequency and severity of the clinical symptoms are highly variable from patient to patient and even in the same patient with recurrent episodes.
  • The patient's history may include use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Most of these edema episodes occur spontaneously without a recognizable external trigger.
• Urticaria-associated edema
  • Urticarial eruptions usually appear at intervals and are intensely pruritic.
  • Patients with angioedema or urticaria should be questioned in detail to identify the offending antigen (in cases of allergic angioedema).
  • History of atopy such as allergic rhinitis, asthma, and aspirin allergy should be sought, as these increase the risk of hypersensitivities.
  • Drugs associated with urticaria and angioedema include the following:
    • Radiocontrast agents
    • Opiates
    • Dextran
    • Aspirin
    • Nonsteroidal anti-inflammatory drugs
  • Common sources of antigens that cause urticaria and angioedema include the following:
    • Hymenoptera envenomations
    • Food allergies such as fresh berries, shellfish, fish, nuts, tomatoes, eggs, milk, chocolate, food additives, and preservatives, and exposure to water, sunlight, cold, or heat
    • Animal dander (from scales of shed skin)
  • Chronic urticaria (increasingly associated with Helicobacter pylori bacteria)

Physical

• General examination
  • Patients usually present with acute onset of well-demarcated cutaneous edema of distensible tissues (eg, lips, eyes, earlobes, tongue, uvula).
  • The face, extremities, and genitalia are most commonly affected.
• Airway assessment
  • First, determine airway patency.
  • Severe attacks can herald the onset of systemic anaphylaxis, characterized initially by dyspnea.
• Gastrointestinal (GI): Massive edema of the subcutaneous tissue in the abdominal region may present with abdominal distention and signs consistent with bowel obstruction.

Causes

• Mast cell–mediated angioedema/urticaria : This type of angioedema may be associated with antigen (allergy), food, drug, animal bites, stings (ie, Hymenoptera), preservatives, or food coloring. Note: Food coloring and preservatives may cause angioedema with or without urticaria.
• Hereditary angioedema
  • Hereditary angioedema (HAE) has an autosomal dominant pattern.
  • Types I and II are characterized by C1 esterase deficiency. The gene encoding for C1-INH is located in chromosome band 11q13.1.
  • Approximately 20–25% of cases are the result of spontaneous mutations without a family history of disease. In this disease, the gene is either nonfunctional and thus C1 esterase is not transcribed in adequate quantities, as in type I, or there is synthesis of normal quantities of an abnormally functioning C1-INH protein, as in type II.
  • Type III is characterized by C1 esterase dysfunction. Symptoms occur during the first 2 decades of life.
• Acquired angioedema
  • This type of angioedema usually occurs in the fourth decade of life.
  • Acquired angioedema is often associated with autoimmune diseases and lymphoproliferative disorders.
• Drug-induced angioedema
  • ACE inhibitors precipitate attacks by directly interfering with the degradation of bradykinin, thereby potentiating its biological effect.
  • Other drugs may precipitate attacks by effects on arachidonic acid metabolism (eg, aspirin, NSAIDs, ARBs, opiates, antibiotic, any compound that is a cyclooxygenase inhibitor).
• Physically induced angioedem
  • Physical agents, such as cold, heat pressure, vibration, and ultraviolet radiation, can cause angioedema. This manifestation may occur with or without urticaria.
  • Cold-induced angioedema and urticaria have been reported in association with cryoglobulins, cold agglutinin disease, cryofibrinogenemia, and paroxysmal cold hemoglobinuria.
• Idiopathic angioedema: Most commonly, the cause is idiopathic.