Angioedema,By:Dr. Sajid Mumtaz Sodhar

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Dr. Sajid Mumtaz Sodhar , Internist, Dr. Mumtaz Sodhar Medical Center, Mehar , Sind, Pakistan

Angioedema:

Angioedema Angioedema is a subcutaneous extension of urticaria , resulting in deep swelling within subcutaneous sites. In contrast, urticaria results from transient extravasation of plasma into the dermis, causing a wheal characterized by tense edema with or without redness.

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Angioedema can occur with generalized urticaria if the tissue swelling has indistinct borders around the eyelids and lips. In addition, when the swelling of urticaria extends to the face, hands, feet, and genitalia, the clinical manifestation may be called angioedema. As many as 50% of children who have urticaria exhibit angioedema with swelling of the hands and feet.

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Angioedema involves swelling of the deep dermal and subcutaneous/submucosal tissues. Approximately 50% of patients have both urticaria and angioedema. Angioedema is non-pitting and non-hot.

Types of angioedema:

Types of angioedema Based on the current clinical understanding of angioedema, dividing cases into the following types is useful: Hereditary type 1 (HAE1) Hereditary type 2 (HAE2) Hereditary type 3 (HAE3) Acquired type 1 (AAE1) (very rare; only a few reported cases) Acquired type 2 (AAE2) (very rare; only a few reported cases) Nonhistaminergic angioedema (INAE) (may occur in approximately 1 of 20 angioedema cases) Idiopathic angioedema Allergic angioedema (most common form) ACE inhibitor–induced angioedema (4-8% of cases)

History:

History Hereditary angioedema (HAE) accounts for only 0.4% of angioedema cases; however, the specific diagnostic tests and high mortality rate associated with hereditary angioedema deserve special attention. In 1876, Milton described the first case. Six years later, Quincke introduced the term angioneurotic edema to describe this disease. Later, Osler described the disease as episodic bouts of well-circumscribed nonpitting subepithelial edema that primarily involved the extremities, larynx, face, and abdomen.  Hereditary angioedema is an autosomal dominant disease usually associated with a positive family history of angioedema. However, numerous cases are due to a new mutation of the gene.

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In approximately 80-85% of hereditary angioedema cases, serum levels of C1 inhibitor (C1INH) are decreased to approximately 30% of reference range values. In contrast, about 15% of patients with hereditary angioedema have reference range levels of antigenic C1NIH but mostly nonfunctional C1INH. Missing or nonfunctional C1INH leads to failure in controlling the enzymatic activity of C1,  resulting in lower levels of the early acting complement components C4 and C2 because of overconsumption. HAE1 (low levels of functional C1INH) may be due to a wide range of gene mutations. In HAE2 (reference range or even increased levels of antigenic but nonfunctional C1INH), different point mutations have been described within or nearby the reactive center of the C1INH gene.

Pathophysiology :

Pathophysiology Bradykinin is the important mediator behind the symptoms of angioedema. Bradykinin is a potent vasodilator, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily.

Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema::

Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema: 1. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. 2. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase inhibitor (C1INH), and continuous production of kallikrein, another process inhibited by C1INH. This serine protease inhibitor normally inhibits the conversion of C1 to C1r and C1s, which - in turn - activate other proteins of the complement system.

The mechanism of angioedema resulting from C1-esterase inhibitor deficiency. :

The mechanism of angioedema resulting from C1-esterase inhibitor deficiency.

AAE1:

AAE1 AAE1 is related to the immune complex and is usually linked to an underlying lymphoproliferative disorder. During the disease process, it destroys the function of C1INH . The onset of angioedema can precede other symptoms of a lymphoproliferative disease; thus, exploring the possibility of underlying malignancy in cases of AAE1 is vital.

AAE2:

AAE2 AAE2 is associated with autoantibodies that directly inhibit C1INH functions. No underlying disorder is apparent. AAE1 and AAE2 are very rare in the pediatric population.

HAE3:

HAE3 Recently, a new form of hereditary angioedema, hereditary angioedema type 3 (HAE3), has been described. In HAE3, C1INH function and complement components are normal. Essential features of HAE3 include (1) a long history of recurrent skin swelling, attacks of abdominal pain, or episodes of upper airway obstruction; (2) familial occurrence, exclusively in female members of the family; (3) no history of urticaria in the patient or other family members; (4) normal C1INH and C4 concentrations in the plasma; and (5) a failure to respond to antihistamines, corticosteroids, or C1INH concentrate.

Nonhistaminergic angioedema (INAE) :

Nonhistaminergic angioedema (INAE) INAE angioedema is angioedema without urticaria.  Patients usually do not respond to H1 blockers (antihistamines). Parasites, infections, and autoimmune diseases are not present.

Idiopathic angioedema :

Idiopathic angioedema The idiopathic form of angioedema may be associated with swelling, hives that persist longer than 6 weeks, or both. Thyroid dysfunction should be considered.

Allergic angioedema:

Allergic angioedema Allergic angioedema is characterized by swelling, hives, or both in reaction to environmental factors such as food, an insect sting or bite, cold, heat, latex, or a drug. Usually, these environmental factors provoke histamine release that leads to swelling, hives, or both.

ACE inhibitors Angioedema:

ACE inhibitors Angioedema Angioedema can also be caused by ACE inhibitors (eg, captopril, enalapril, genzapril, quinapril, ramipril) used to treat high blood pressure. Swelling may begin a few hours to years after first starting the medication.

Frequency :

Frequency Urticaria-associated angioedema occurs in nearly 50% of children who have urticaria. Because urticaria occurs in 2-3% of children, urticaria-associated angioedema is estimated to occur in 1-2% of the general population. the frequency rate of hereditary angioedema diseases is currently unknown.

Mortality/Morbidity :

Mortality/Morbidity Mortality may occur because of laryngeal swelling and subsequent asphyxiation. In the past, the mortality rate for attacks involving the upper airways exceeded 25%. SEX Hereditary angioedema is an autosomal dominant disorder and affects both sexes. 

Symptoms :

Symptoms Airway blockage -- involves throat swelling and sudden hoarseness Repeat episodes of abdominal cramping without obvious cause Swelling in the arms, legs, lips, eyes, tongue, or throat Swelling of the intestines -- can be severe and leads to vomiting, dehydration, diarrhea, pain, and occasionally shock

Clinical features::

Clinical features:

ACE-inhibitor-induced angioedema affecting the upper lip :

ACE-inhibitor-induced angioedema affecting the upper lip

Abdominal Attacks:

Abdominal Attacks

Clinical Features:

Clinical Features The initial manifestations of hereditary angioedema in children occurred at a median age of 4.8 years (range, 3-9.7 y). Hereditary angioedema attacks are characterized by episodic angioedema that usually involves the extremities. Swelling is usually brawny and is not associated with urticaria or pruritus. Patients also have episodic attacks of severe abdominal pain that are sometimes associated with vomiting but are not associated with diarrhea ; they persist until the angioedema attacks subside. Abdominal pain may resemble that of acute abdomen.

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Hereditary angioedema attacks generally last 1-4 days. Swelling of the extremities is typically painless. Abdominal attacks due to edema in the submucosa and serosa of the bowel wall are often associated with nausea, vomiting, and severe pain. Edema of the upper airway may result in asphyxiation. Only 25% of patients provide a positive family history.

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Many patients have a family history of sudden death from asphyxia. In the past, the mortality rate for attacks involving the upper airways exceeded 25%. Patients live with the constant threat of life-threatening laryngeal obstruction.

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The location of swelling may be characteristic in some forms of angioedema. For instance, in HAE1 and HAE2, swelling can occur in the extremities, abdomen, throat, and other organs. Airway swelling can be fatal. Abdominal swelling usually involves pain, vomiting, and diarrhea. Symptoms (angioedema attacks) occur by age 13 in most hereditary angioedema cases and may increase in severity after puberty. Angioedema episodes may spontaneously occur or may be triggered by physical trauma or even emotional stress. HAE2 or HAE3 may present like HAE1.

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The acquired form of angioedema (AAE1 or AAE2) may present like classic hereditary angioedema, except for the age of onset. Usually, this type of angioedema occurs in the fourth decade of life or later. Because it is an acquired defect, a family history is negative for angioedema.

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The idiopathic form of angioedema may cause swelling anywhere in or on the body and may be accompanied by urticaria (hives). Swelling due to nonhistaminergic angioedema (INAE) may occur anywhere, including the face, arms, legs, genitalia, throat, and abdomen, although abdominal symptoms are far less common than in those with hereditary angioedema. Furthermore, symptoms do not change with menstrual period or pregnancy.

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In patients with ACE-inhibitor–induced angioedema, swelling may occur just about anywhere, including the throat, face, lips, tongue, hands, feet, genitalia, and intestines. Urticaria (hives) is very rare in this form of angioedema.

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Symptoms last 1-4 days, and most patients have one or more attacks per month, leaving them unable to engage in normal social activities for 20-100 days a year.

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The cause of acquired angioedema in patients using ACE inhibitors is believed to be the accumulation of bradykinin, which is subject to breakdown by ACE. ACE inhibitors help build up bradykinin levels in the tissue. Onset usually follows trauma such as surgery, dental manipulation, an accident, or mental stress. In HAE2, attacks occur more often with sex hormone fluctuation. Onset is usually in adolescence, with more severe symptoms associated with menses.

Causes :

Causes Hereditary angioedema is an autosomal dominant condition. Risk factors for hereditary angioedema episodes include trauma, such as surgery, dental manipulation, or accidents. Episodes of hereditary angioedema are the result of unopposed complement activation and/or activation of the kinin generating system due to the C1INH deficiency. Acquired forms of angioedema are commonly associated with lymphoproliferative disorders or malignancy. They are relatively uncommon in pediatric patients. Patients who are using ACE inhibitors, which are uncommonly in children, may experience episodic swelling of the tissue due to the accumulation of bradykinin. In HAE3, a fluctuation of sex hormones has been speculated to precipitate hereditary angioedema attacks.

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Hereditary A ngioedema A utosomal dominant - 11 chromosome A ndrogens for prophylaxis 1 C 1 inhibitor is low C 1 q level is normal 11 chromosome 11 years is the mean age of onset 11 years before the diagnosis is made, on average

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Acquired Angioedema A A cquired A ngioedema A CEi-related

Differential Diagnoses :

Differential Diagnoses Cellulitis: Usually, this is caused by gram-positive bacterial infection. Pain and fever are common. Erysipelas: This is caused by group A beta streptococci. Tenderness, fever, and redness are common. Lymphedema: Chronic thickening of tissues occurs in lymphedema, in contrast to the acute stretching of tissue observed in angioedema. Systemic lupus erythematosus (SLE) or other collagen vascular disorders: The patient should have a history of systemic illness, indicating the presence of vasculitis. Laboratory findings reflect features of chronic inflammatory conditions. Acute contact dermatitis : The patient has a history of contact with sensitizing agents. It is always accompanied by intense pruritus.

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Idiopathic scrotal edema in children: The etiology is unknown, but swelling is limited to the scrotal area. Rarely, it causes systemic symptoms. Rosenthal-Melkersson syndrome: Recurrent facial edema, recurrent peripheral facial nerve palsy, and remarkable fissuring of the tongue are characteristic.

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Surgical abdomen: Severe pain caused by hereditary angioedema can be difficult to distinguish from conditions leading to surgical abdomen. Conditions include intestinal obstruction and appendicitis . In addition, Crohn disease may cause chronic pain and diarrhea. History and physical examination should be helpful to distinguish those conditions with the aid of imaging studies.

Laboratory Studies :

Laboratory Studies Plasma levels for the diagnosis of hereditary angioedema (HAE) include the following: C4 level less than 14 mg/L (diagnostic) C1q level greater than 77 mg/L C1INH (antigenic) level less than 199 mg/L (diagnostic) C1INH (functional) level less than 72% of the reference range (diagnostic) Measure C1INH and C3 and C4 levels if the patient has a family history of angioedema.

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Perform immunoglobulin E (IgE) antibody skin test or radioallergosorbent test (RAST) if the history is suggestive of a rash caused by foods, drugs, insect venom, or latex.

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Obtain stool for ova and parasites. Perform antinuclear antibody testing and urinalysis with microscopic examination if the patient may have arthritis, photosensitivity, or other signs or symptoms of collagen vascular disease. Obtain a CBC count with differential, C-reactive protein level, and erythrocyte sedimentation rate if the patient's history indicates underlying vasculitis or inflammatory diseases. In laboratory findings, acquired angioedema (AAE) is characterized by low functional C1INH levels, low C4 levels, and C3 levels within the reference range. Concentration of C1q is often very low. 

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Idiopathic angioedema: The complement profile is normal. Nonhistaminergic angioedema (INAE): The complement profile is normal. Allergic angioedema: The complement profile is normal. ACE inhibitor–induced angioedema: The complement profile is normal.

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Imaging Studies Ultrasonography of the GI tract may help differentiate between hereditary angioedema and conditions of surgical abdomen. In hereditary angioedema, ascites and edema of the intestinal walls are present in more than 80% of patients during acute attacks.

Medication Preventive measures :

Medication Preventive measures Ideally, episodes of swelling should be prevented with long-term or short-term prophylaxis. Successful pharmacologic approaches have included prevention of the activation of kinin-releasing enzymes or increasing the blood level of normal C1INH. Androgens and antifibrinolytic agents are frequently used to achieve this purpose. C1INH concentrate for prophylaxis, especially before surgery,

Treatment of an episode of acute angioedema :

Treatment of an episode of acute angioedema Minor episodes of subepithelial swelling need no treatment, but the patient with edema of the face and neck should be closely observed for spread of edema and signs of airway involvement. When hoarseness or other signs of a compromised airway occur, an otolaryngologist should be consulted for possible tracheostomy. This procedure is usually not needed but is sometimes a life-saving measure. The use of C1INH for an acute attack of hereditary angioedema (HAE)

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Another treatment that may be beneficial is an oropharyngeal spray of a 1:1000 dilution of racemic epinephrine (0.2-0.3 mL). These patients may be frightened when airway symptoms or difficulty in swallowing occurs because they have witnessed affected relatives die during such episodes. When an episode of abdominal colic occurs, symptomatic treatment with narcotics may be required to relieve pain. These patients may become addicted.

Treatment strategies for angioedema :

Treatment strategies for angioedema HAE1 and HAE2: C1INH concentrate administration is preferred for acute treatment and has recently received US Food and Drug Administration (FDA) approval in the United States. Androgens such as danazol and oxandrolone are used for possible prevention of episodes. Hypotension accompanied by abdominal symptoms may require fluid replacement therapy . The combination of meperidine (Demerol) and prochlorperazine (Compazine) suppositories (and possibly dicyclomine to relieve abdominal pain and vomiting) is useful.

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C1 inhibitor purified from plasma (Cinryze and Berinert P) Recombinant C1 inhibitor Kallikrein inhibitor (Ecallantide) Bradykinin type 2 receptor antagonist (Icatibant), can be given SQ

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Currently, numerous products for the treatment of hereditary angioedema are in trial, including genetically engineered a recombinant C1 esterase inhibitor, a kallikrein inhibitor (Dx-88), and a bradykinin B2-receptor antagonist. Icatibant is a potent, specific, and selective peptidomimetic bradykinin B2-receptor antagonist.

Androgens Danazol (Danocrine) Stanozolol (Winstrol) Oxandrolone (Oxandrin) :

Androgens Danazol (Danocrine) Stanozolol (Winstrol) Oxandrolone (Oxandrin) Oral androgens have provided the most successful preventive therapy. Synthetic attenuated androgens (eg, danazol, stanozolol) taken prophylactically increase the serum concentration of C1INH, presumably by enhancing the function of the C1INH gene. When danazol is used prophylactically in adolescents or preadolescents, the concentration of C1INH and C4 are increased in the plasma.

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Adult 200 mg/d PO initially; if abdominal discomfort recurs, increase to 400 mg/d PO for 1-2 mo; once symptoms are controlled, reduce dose to 200 mg/d PO; continue attempt to titrate downward to minimum effective dose. Many patients ultimately take only 50-100 mg PO qd or qod; may double the daily dose for anticipated surgery or dental procedures 4-5 d prior to and for several d afterward Pediatric Presurgical prophylaxis for adolescents or preadolescents: 200 mg PO qd initiated 1 wk prior to surgery

Antifibrinolytic agents:

Antifibrinolytic agents These agents have been successfully used as preventive therapy. The effect may depend on physiologic or pathologic enhancement of plasminogen activation in blood, which may promote activation of C1INH. Aminocaproic acid (Amicar) Used for immediate short-term treatment. Thought to prevent extensive edema formation after onset of an attack. Even if the patient has bouts of intestinal edema, symptoms are markedly ameliorated. Adult 4-5 g IV over 1 h initially, followed by 1 g/h IV for 8 h; dilute IV solution to obtain concentration of 1 g/50 mL

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Tranexamic acid (Cyklokapron) Used for immediate short-term treatment. Also prevents extensive edema formation and helps amelioration of intestinal symptoms. 2 g/d IV until patient improve

Complement replacement agents:

Complement replacement agents Fresh frozen plasma (FFP) is used for treatment of acute attacks. Replacement therapy is logical in the case of an ongoing attack. Numerous reports indicate that FFP may relieve an episode of edema. When patient arrives at the emergency department (ED), the attack has probably been underway for a number of hours or more than a day. Some believe that early administration of FFP may worsen edema.

C1 esterase inhibitor, human (Berinert):

C1 esterase inhibitor, human (Berinert) 20 U/kg IV infused slowly; not to exceed 4 mL/min C1 inhibitor, human (Cinryze) 1000 U IV infused over 10 min; repeat every 3-4 d Investigational use for acute treatment and presurgical continue to be explored: Prophylaxis: 500-1000 U IV for 2h prior to surgery Acute treatment: 500-1000 U IV

Sympathomimetic agents :

Sympathomimetic agents These agents directly or indirectly stimulate adrenergic receptors. They are used as supportive emergency treatment for airway edema. Epinephrine (Adrenaline) Oropharyngeal spray of 1:1000 racemic epinephrine helps reduce edema, especially in the upper airway (eg, laryngeal edema). 0.2-0.3 mL (1:1000 dilution) SC q20min for a total of 3 doses