The wheel and flare of urticaria is the pathognomonic feature of histamine-mediated cutaneous lesions. In fact, urticaria is one of the most common chief complaints encountered by dermatologists. Fortunately, their life-threatening sequelae, namely anaphylaxis and shock, are exceedingly rare. Understanding the mechanisms through which histamine release occurs and its subsequent physiologic and potentially pathologic impact is vital to our ability to triage and treat appropriately. All dermatologists should be proficient at recognizing and diagnosing both common and unusual histamine-mediated emergencies in order to implement timely and directed therapy that could be potentially lifesaving.
In this chapter, we will review the pathophysiology of histamine-mediated disease, the clinical manifestations, and targeted therapies. Subjects that will be discussed in detail include urticaria, angioedema, anaphylaxis and their many etiologies including foods, medications, blood products, latex, arthropod assaults, as well as the many physical urticarias and their triggers. We will conclude with a brief review of cutaneous and systemic mastocytosis and their potential to be life-threatening.
Histamine
Histamine is an organic nitrogen compound that has potent physiologic activity. Several life-threatening emergencies are mediated by histamine, most of which have associated dermatologic manifestations.
Histamine was first discovered in 1910 as a critical mediator of hypersensitivity. About twenty years later, it was identified as a mediator of life-threatening anaphylactic reactions. Histamine belongs to a group of biogenic amines and is synthesized from the amino acid histidine. This process occurs most notably in mast cells and basophils, but also in platelets, histaminergic neurons, and enterochromaffin cells. Histamine is stored intracellularly within vesicles and released upon stimulation. Histamine has a rapid onset of action, able to achieve its maximum productivity quite efficiently. Notably, once released into circulation, histamine is elevated for only 30-60 minutes, making it a poor marker for mast cell and basophil activation. However, a metabolite of histamine, methylhistamine, is present in the urine for up to 24 hours after peak plasma histamine levels, and may be used as a diagnostic tool.
Histamine exerts specific actions by binding to one of four known human histamine receptors designated H1-H4. Its effects, however, are potentiated mainly through the H1 and H2 receptors and include vasodilatation (seen as erythema, flushing, and hypotension), increased vascular permeability by separation of endothelial cells (seen as angioedema), smooth muscle contraction (seen as stomach cramps and diarrhea), increased cardiac contraction (leading to tachycardia and arrhythmias), and increased glandular secretion (allergic rhinitis, dyspnea, and bronchoconstriction). Finally, histamine stimulates the release of cyclic adenine monophosphate (cAMP), leading to increased production of mast cells in the bone marrow. Activation of the H3 receptor in the peripheral and central nervous system leads to increased neurotransmitter release causing vertigo, nausea, and vomiting. The numerous effects of histamine explain why the clinical signs and symptoms of urticaria, angioedema, bronchospasm, hypotension, and gastrointestinal symptoms can occur rapidly after mast cell and basophil activation.
Though histamine is the principle mediator of hypersensitivity reactions and anaphylaxis, it is not the only one. Research has shown that other granule-associated preformed mediators (tryptase, chymase, and heparin), newly formed mediators (prostaglandins, leukotrienes, and platelet activating factor), and numerous cytokines and chemokines are released during the degranulation cascade.
Release of mediators can occur within several minutes of the inciting event. The release of inflammatory cytokines, however, can take several hours, thereby mainly contributing to late phase reactions. Late phase reactions occur within 2-24 hours of exposure to the inciting event and are due to the migration of leukocytes to the skin, respiratory tract, or gastrointestinal tract. Cytokines may also contribute to protracted reactions that can last hours to days without a clear resolution of symptoms. This is not to be confused with biphasic reactions. Biphasic reactions are characterized by initial symptoms of a uniphasic anaphylactic response that resolve spontaneously or with treatment, followed by an asymptomatic period (1 to 72 hours), and then a recurrence of symptoms without further exposure to antigen. The second response in biphasic reactions may be less severe, similar to, or more severe than the original episode, and can be fatal. Biphasic reactions can occur in patients of any age. The mechanism of biphasic reactions is not completely understood. There are also no consistently reported risk factors, which creates a clinical dilemma for clinicians treating patients for anaphylaxis.
Hypersensitivity Reactions
Hypersensitivity, or allergic, reactions are “overreactions” of the immune system to innocuous environmental antigens in susceptible, pre-sensitized individuals. These reactions can range from localized tissue injury to death. The most common classification of hypersensitivity reactions is that of Gel and Coombs. Histamine release from mast cells and basophil activation occurs mainly through IgE-mediated immune reactions, which are type I hypersensitivity reactions. In brief, soluble antigen and IgE activation of mast cells and basophils causes degranulation and release of mediators leading to vasodilatation, vascular leakage, smooth muscle spasm and the recruitment of inflammatory cells. These physiological mechanisms result clinically in urticaria, asthma, allergic rhinitis, angioedema, and anaphylaxis.
URTICARIA, ANGIOEDEMA, and ANAPHYLAXIS
Definitions
Urticaria has been recognized since the beginning of medicine during the times of Hippocrates. The name dates back to the 18th century, when the burning and swelling of skin was likened to that caused by contact with nettles (Urtica dioica). Urticaria, or “hives,” is a vascular inflammatory reaction of the papillary dermis. The lesions appear as superficial wheals typically surrounded by an erythematous, often pruritic, ring, or flare with central clearing. Mast cells and basophils are the primary effectors of urticarial reactions. They release inflammatory mediators that cause an increase in capillary permeability, the most important of which is histamine.
Acute urticaria, by definition, occurs over a period of less than 6 weeks. It typically involves isolated, self-limited lesions that rarely last longer than 24 hours, are often migratory, and can recur for indefinite periods of time. Rarely, postinflammatory pigment alteration is noted following resolution. Contact urticaria is defined as the development of acute urticarial lesions at the site where an external agent contacts the skin or mucosa; these lesions are not migratory. In contrast, chronic urticaria requires episodes at least 2 days per week lasting more than 6 weeks duration. While patients with chronic urticaria are observed for IgE-mediated causes, only 10% to 20% of patients with chronic urticaria have an identifiable trigger.
Angioedema is caused by the same pathophysiologic mechanism as urticaria but occurs deeper, typically in the subcutaneous, and submucosal tissues. Thus, although swelling is appreciated in angioedema, erythema is typically absent.
Anaphylaxis is commonly defined as a life-threatening IgE-mediated type I hypersensitivity reaction that is rapid in onset and involves multiple organ systems. It occurs when an immunologic reaction to an allergen in a sensitized individual causes a life-threatening event. Anaphylactic reactions usually occur within 30 minutes of exposure to the antigen and rarely last beyond 2 hours. Delayed presentations as well as biphasic anaphylactic reactions have been described in patients up to 72 hours after exposure. Histamine is the principal mediator of allergic hypersensitivity reactions, including anaphylaxis. Manifestations of anaphylaxis include diffuse erythema, urticaria, and angioedema initially, followed by bronchospasm, laryngeal edema, increased gastrointestinal motility, increased mucosal secretions, hypotension, and cardiac arrhythmias.
Epidemiology
Approximately 15% to 25% of individuals will experience at least 1 episode of urticaria at some point during their lives. Many people suffer from mild symptoms and fail to recognize it as urticaria. This leads to tremendous under reporting. The majority of these cases are acute urticarial episodes that do not recur; however, up to 30% of cases can advance to chronic urticaria. Urticaria is present in higher proportions in patients with atopic dermatitis. One study found that of patients with acute urticaria, half also suffered from hay fever, allergic asthma, or atopic dermatitis. Acute urticaria is also more common in children and adolescents, while chronic urticaria is seen more frequently in adults.
The epidemiology of anaphylaxis is difficult to quantify, but it is estimated that there are around 84,000 cases of anaphylaxis each year in the United States. Anywhere from 500-1000 of these cases are fatal. Based on reports by the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group in 2006, the estimated lifetime prevalence is approximately 0.05% to 2.0% with the largest number of incident cases among children and adolescents. However, accurate reporting is complicated by factors such as under diagnosis, under reporting, and a prior lack of a universal definition for anaphylaxis, making a true estimate of exact cases difficult to measure.
Pathophysiology
Acute urticaria and angioedema are caused by allergic immunoglobulin E (IgE)-mediated, non-IgE-mediated, and nonimmunologic mechanisms. In allergic IgE-mediated urticaria, the body views an antigen and produces specific IgE antibodies against this antigen. The Fc portion of IgE has a strong affinity for the Fcε (epsilon) receptor-1 (Fcε (epsilon) R1) proteins on the surface of mast cells and basophils. Once the IgE binds to these receptors, a person is considered ‘sensitized’ to the IgE-specific antigen. As many as half a million molecules of IgE can fix to a single mast cell or basophil. The body can be exposed to an antigen through the skin, mucous membranes, respiratory tract, or the GI tract.
Upon reintroduction, the antigen binds to several IgE antibodies already bound to mast cells or basophils, causing cross-linking of the IgE antibodies, thus activating the inflammatory cascade that clinically presents as urticaria and/or angioedema. Cross-linkage of IgE antibodies may also occur from anti-IgE antibodies or other capable allergens. While up to 50% of chronic urticaria cases are thought to be idiopathic, recent studies show that approximately 35% to 45% of patients with idiopathic chronic urticaria in fact have an IgG autoantibody directed against mast cell or basophil surface-bound IgE. Thus, an autoimmune process may actually cause many cases of chronic urticaria.
Mast cells reside in connective tissue near blood vessels, in the lower respiratory tract, in bronchial lumen, central nervous system, bone marrow, and gastrointestinal tract mucosa, and the skin. Basophils are polymorphonuclear leukocytes found circulating in the blood and constitute 0.1% to 2.0% of peripheral blood leukocytes and are rarely found in tissues. When these cells are activated, preformed and newly formed mediators are released; the most important is histamine.
Similar to urticaria and angioedema described above, anaphylaxis is caused by allergic IgE-mediated, non-IgE-mediated, and nonimmunologic mechanisms. It, too, is a result of mast cell and basophil activation and subsequent release of histamine and other small molecules. The wide and variable distribution of mast cells and basophils throughout the body may explain why systemic features seen in anaphylaxis are not present during the activation of cutaneous mast cells in patients who present with urticaria or angioedema. The effects of the released chemical mediators include smooth muscle contraction, especially in the pulmonary and gastrointestinal systems, coronary artery vasoconstriction, increased vascular permeability and capillary leakage. Extravasation of fluid and protein from blood vessels leads to a decrease in plasma volume, reduction in venous return, and ultimate circulatory collapse.
Anaphylactic shock is reserved for cases of circulatory collapse that occur during anaphylactic reactions. There are four broad classifications of shock (hypovolemic, cardiogenic, distributive, and obstructive). Anaphylactic shock may be a combination of hypovolemic shock due to capillary leakage, distributive shock secondary to vasodilation, and cardiogenic shock because of decreased cardiac contractility. Half of all deaths due to anaphylaxis result from circulatory collapse and shock. The other half is from airway obstruction.
Aside from the classic immunologic IgE-mediated hypersensitivity reactions, clinically identical presentations can occur via immunologic non-IgE mediated or nonimmunologic mechanisms. Immunologic non-IgE mediated reactions occur through activation of the complement system via immune complexes, and generation of kallikrein and bradykinin. Certain byproducts of the complement cascade, including plasma-activated complement 3 (C3a), plasma-activated complement 4 (C4a), and plasma-activated complement 5 (C5a), are called anaphylotoxins and can cause mast cell or basophil activation without IgE involvement. Nonimmunologic reactions are a result of physical factors or antigens acting directly on mast cells and basophils to cause degranulation and histamine release, and not via an antigen-antibody interaction. The pathophysiology of immunologic contact urticaria is similar to what was described above for allergic IgE-mediated urticaria. In contrast, nonimmunologic contact urticaria is thought to occur independent of histamine and rather through prostaglandin release from the epidermis, based on the beneficial response in such cases to acetylsalicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) versus antihistamines.
Thus, IgE-dependent reactions occur only after the patient has been previously exposed at least once to the antigen and is sensitized. Conversely, non-IgE mediated reactions can occur following a single, first time exposure to certain agents in non-sensitized individuals. Because these reactions produce the same clinical manifestations, regardless of the method of histamine release, treatment is uniform. Nonimmunologic triggers induce mast cell and basophil activation without evidence of involvement of IgE, IgG, or immune complexes, and will be elaborated later in this chapter.
Clinical Features
The lesions of acute urticaria appear as erythematous wheals. They are pruritic and blanching and generally resolve within 12-24 hours without complication or residual skin findings. Wheals may be small or large, single or multiple. In the case of physical urticaria, the distribution pattern and morphology can be helpful in separating the different clinical types. Allergens that are only locally absorbed, as in contact urticaria, usually result in confined symptoms of burning, itching, or tingling, and wheals developing at the site of exposure. Angioedema is also often present. In cases of immunologic contact urticaria, however, skin or mucosal contact with an inciting antigen in a sensitized patient can also lead to extracutaneous symptoms such as rhinoconjunctivitis, orolaryngeal and gastrointestinal dysfunction, or even progress to anaphylaxis. Allergens that disseminate systemically through ingestants or inhalants can result in diffuse urticaria.
In contrast to the erythematous pruritic lesions of urticaria, patients with angioedema typically do not exhibit visible erythema but complain of pain at the involved site. Angioedema typically involves the extremities, head, neck, face, and, in men, the genitalia, and may last for several days. Most importantly, if it occurs in the soft tissues of the larynx and upper airway it can lead to life-threatening airway compromise and death. Urticaria and angioedema may occur in any location together or separately. Urticaria occurs in association with angioedema in up to 50% of patients. Approximately 10% of cases will exhibit angioedema in the absence of urticaria and 40% involve urticaria alone.
The classic clinical picture of anaphylaxis begins with scalp pruritus, urticaria, and angioedema and ends with bronchospasm, hypotension, and gastrointestinal symptoms. Urticaria and angioedema are the most common symptoms in anaphylaxis and are seen in 88% of patients. In non-lethal cases, hypotension often causes symptoms of nausea, vomiting, dyspnea, dizziness, diaphoresis, and falls. However, systemic hypotension and profound shock are clinical emergencies and may rapidly lead to cardiopulmonary arrest within 5 to 15 minutes after reaction onset. Of note, patients who experience severe anaphylaxis should be observed for an extended timeframe of up to 72 hours to eliminate the risk of a severe biphasic reaction occurring without medical attention. Finally, it is important to remember that anaphylactic reactions can occur without any dermatologic manifestations.
Risk factors for severe hypersensitivity reactions
Several important factors can increase the likelihood of a severe hypersensitivity reaction. These include very young or old age, pregnancy, comorbidities (e.g., asthma, atopy, cardiovascular, or respiratory disease), and use of certain concurrent medications like angiotensin converting enzyme (ACE) inhibitors or β-blockers, which sometimes hinder the treatment of anaphylaxis.
Small retrospective case series and large patient databases have demonstrated that an underlying history of asthma is a major risk factor for fatal or near fatal anaphylactic reactions to food with up to a 3.3 relative risk of anaphylaxis in patients with severe asthma. In addition, severe allergic rhinitis and severe eczema increase the risk of life-threatening anaphylaxis. Atopy also appears to be a risk factor. However, it is not as specific for food-induced anaphylaxis, as patients with atopy may also have an increased incidence of anaphylactic reactions to latex, exercise, and radiocontrast media but not to medications or insect stings.
More severe and immediate reactions to medications occur when drugs are delivered parenterally versus orally. In patients with allergies to hymenoptera stings, elevated baseline tryptase levels demonstrate a higher risk for severe systemic reactions. Therefore baseline tryptase levels in patients with systemic reactions should be measured.
Finally, patients with subclinical or clinical mastocytosis who have a history of a serious hypersensitivity reaction to a known allergen, have a significantly increased risk for future life-threatening reactions.
Etiologies
Many of the same causes of urticaria and angioedema can lead to anaphylaxis. Triggers can function via three different mechanisms: immunologic IgE-mediated, immunologic non-IgE-mediated, and nonimmunologic. This section will focus on life-threatening causes of hypersensitivity reactions.
Food
Food allergy is still considered the most common cause of anaphylaxis. It is also one of the most common causes of immunologic IgE-mediated contact urticaria. Up to 2% of the US population may be affected by food allergies with 4% to 8% of children and 1% to 3% of adults with food allergy confirmed by skin prick testing. The contribution of foods differ by age with children most often affected by peanuts, tree nuts, milk, and eggs, and adults with increased rates of allergy to shellfish, fish and peanuts. Food additives (e.g. spices, vegetable gums, colorants (e.g. carmine), sodium benzoate, nitrates, and papain), food contaminants, and food parasites (e.g. Anisakis simplex) have also rarely been associated with anaphylaxis.
Cow’s milk protein is often the first allergen to which infants react, with symptoms presenting in the first week that formula feeds are introduced into the diet. The majority of children will outgrow their allergy. This reaction can be either IgE- or non-IgE-mediated with slightly better recovery rates for children with non-IgE-mediated allergies. While fewer studies have been conducted in children with allergies to egg and wheat, a significant percentage of these allergies are also lost by school age.
Shellfish allergy is typically an IgE-mediated process with shrimp, crab, and lobster responsible for the majority of reported allergic reactions. Allergy in these patients is typically thought to be lifelong.
Scombroid poisoning or histamine fish poisoning can mimic food-induced anaphylaxis, but results from the consumption of mishandled scombridae fish including tuna, mackerel, and bonito as well as other (non-scombroid) fish species such as mahi mahi or sardines. Bacteria in spoiled fish produces enzymes capable of decarboxylating histadine to produce biogenic amines like histamine and cis-urocanic acid, which are also capable of mast cell degranulation and further histamine release. While there are numerous other proposed mechanisms of toxicity, scombroid poisoning caused by elevated histamine levels in seafood is the most widely accepted. Common symptoms are similar to those seen in patients with food allergies. Rarely are serious cardiac and respiratory complications reported and even more infrequently do patients require hospitalization. One way to help differentiate between fish poisoning and a seafood allergy is that most people eating the same meal will demonstrate a response to scombrotoxic fish versus only those with a specific fish allergy are expected to experience symptoms. Regardless of the mechanism of toxicity, scombroid poisoning is treated in a similar manner to food allergy.
Peanut allergy remains the most common cause of food-induced anaphylaxis. It typically starts in early childhood but a late-onset cohort of patients can also be seen. The incidence of childhood peanut allergy is increasing and exceeds a prevalence of 1% in the US. In contrast to children with milk, egg, and wheat allergies, only a small proportion outgrow peanut allergy, and vigilant lifelong avoidance is necessary.
Signs and symptoms of anaphylaxis typically develop within 30 minutes of food ingestion but can also occur within five minutes and rarely up to two hours later. The skin and respiratory systems are involved in up to 76% and 80% of patients, respectively, and gastrointestinal symptoms are seen more frequently in cases of food-induced versus food-independent anaphylaxis. Respiratory collapse is the cause of death in most fatal cases of food-induced anaphylaxis. Shock is a rare physiologic component and almost never seen without respiratory compromise.
Several recent studies have assessed the efficacy, safety and feasibility of oral immunotherapy (OIT) for high-risk patients with severe peanut allergies. One study was conducted in 23 children, ages 3-14 years, with confirmed IgE-mediated peanut allergies. They received OIT following a rush protocol with roasted peanut for 7 days or, if protective doses of 0.5 g (0.16 teaspoons) of peanut were not achieved during the rush protocol, long-term buildup with biweekly dose increases up to 0.5 g of peanut was performed. Twenty-two of 23 patients continued with the long-term protocol and 14 reached the 0.5 g protective dose after a median of 7 months. Subsequently, these patients were able to tolerate a median of 1 g of peanut, in comparison to 0.19 g of peanut before OIT. Therefore, it was determined that for long-term buildup, but not rush, OIT was safe and effective in reaching clinically relevant protective doses, which may protect many high-risk patients against accidental ingestion reactions. However, until larger randomized trials are conducted to further evaluate the benefit-risk ratio of OIT versus avoidance, the current mainstay of management, OIT cannot be considered for routine clinical practice.
Medications and Blood Products
Drug allergy is considered a type of adverse drug reaction and there is tremendous overlap between drugs that lead to urticaria, angioedema, and life-threatening anaphylaxis. Medications can trigger anaphylaxis through immunologic IgE-dependent mechanisms, immunologic non-IgE-mediated mechanisms, or nonimmunologic mechanisms. Several medications can also act through multiple different mechanisms. Antibiotics are the most common cause of IgE-dependent, immunologic based reactions, especially beta-lactams such as penicillins and cephalosporins, and less frequently, sulfonamides and tetracyclines. Biologic agents including vaccines and hormones, as well as radiocontrast dye and certain monoclonal antibodies also act through IgE-dependent pathways; however, the majority of hypersensitivity reactions to radiocontrast media are non-immunologic. Radiocontrast media may also act via complement activation that subsequently leads to mast cell activation. As the use of monoclonal antibodies in the various clinical settings continues to increase, there is a rise in incidence of hypersensitivity reactions. Many of these reactions are seen with the first dose of therapy, implicating a nonimmunologic mechanism of action. However, many patients also experience IgE-dependent reactions or even delayed reactions, with symptoms developing after several future doses. Systemic infusion reactions related to the rate of monoclonal antibody drug infusion also occur.
Opioids cause mainly nonimmunologic hypersensitivity reactions while ASA classically acts via a non-IgE-mediated immunologic pathway. NSAIDs produce mainly nonimmunologic and rarely IgE-dependent immunologic reactions and are responsible for up to 25% of all adverse drug reactions. After taking ASA or other NSAIDs, one-third of patients with controlled underlying chronic urticaria and up to two-thirds of patients with active chronic urticaria will have exacerbations of urticaria or angioedema.
Vancomycin, a glycopeptide antibiotic, can cause two different hypersensitivity reactions: 1) nonimmunologic mast cell and basophil degranulation causing ‘Red Man Syndrome’ and 2) IgE-mediated anaphylaxis. ‘Red Man Syndrome’ is far more common and is caused by a rapid infusion of vancomycin. It typically presents with flushing, erythema, and pruritus of the face and upper torso but can also progress to angioedema, hypotension, and, rarely, cardiovascular depression. While there is a correlation with the peak plasma histamine concentration during infusion and severity of the reaction, elevated histamine levels may also be seen in patients treated with slower infusion rates who do not experience ‘Red Man Syndrome’. Other antibiotics have rarely been associated with ‘Red Man Syndrome’.
Urticaria and angioedema can occur together or independent of each other. In the case of angioedema without urticaria, it is important to consider an underlying complement system enzyme deficiency, such as hereditary or acquired C1-esterase inhibitor deficiency. On the other hand, all patients treated with ACE inhibitors, a type of antihypertensive, can experience side effects related to increased bradykinin, including angioedema without urticaria. Therefore, special consideration should be taken when prescribing ACE inhibitors in patients who may have an underlying enzyme deficiency due to their predisposition for angioedema. Furthermore, it should be noted that symptoms of angioedema secondary to an underlying enzyme deficiency may be delayed up to a year after beginning treatment with ACE inhibitors and may be mistaken as a side effect of the drug only.
Life-threatening reactions to the administration of human IgG are rare in clinical practice. The most common blood transfusion related anaphylactic reaction occurs in patients with IgA deficiency. Up to 40% of patients with IgA deficiency produce IgG or IgE anti-IgA antibodies. During blood transfusions, the IgG or IgE anti-IgA antibodies attack the IgA proteins in the donor blood. Two ways to prevent or minimize a serious anaphylactic reaction could be to use washed red blood cells or blood from another IgA deficient individual. In cases when IgA levels are not readily available, patients may be pretreated with antihistamines prior to emergent therapy.
The most severe cases of drug allergies can occur immediately or hours to days following drug administration. Factors including prior sensitization, route of administration, drug metabolism, drug interactions and concomitant food intake play a modifying role and affect the rate of symptom development. Anaphylaxis secondary to cutaneous injections or topical applications has only rarely been reported.
Latex
Food and latex (natural rubber) are two of the most common causes of immunologic IgE-mediated contact urticaria. In the 1980s, when universal precautions were implemented and the use of latex gloves increased, so too did the incidence of type-I hypersensitivity reactions predominantly in healthcare settings. Typically, reactions from a latex allergy occur within thirty minutes of exposure and include the development of pruritus and urticaria to the localized area of contact. Generalized urticaria can occur and often results from dissemination of the allergy (antigen) after direct contact with mucosal surfaces. Serious, life-threatening latex induced anaphylactic reactions can also occur.
Latex allergy may be a source of morbidity for patients in their work place, in particular medical workers and people in occupations where they are regularly exposed to or use latex gloves. Individuals can also be exposed in their homes with common latex items including balloons, latex contraceptives, rubber bands, and much more. The latex-fruit syndrome refers to the cross-reaction of latex allergens with many plant-derived food allergens, which results from structural similarities between several latex and plant antigenic proteins. The most commonly involved fruits include kiwi, banana, avocado, passion fruit, and chestnut. In this situation, it is difficult to determine if the patients were first sensitized to latex or to fruit, which would help provide more evidence-based prophylaxis. It is highly advised that when visiting a doctor patients make their latex allergy known in order to help prevent life-threatening reactions.
Hymenoptera Stings
Venom from insects of the order Hymenoptera, which includes ants, bees, hornets, wasps, and yellow jackets, or saliva from biting insects such as flies, mosquitoes, ticks, kissing bugs, and caterpillars, can cause severe anaphylactic reactions. Insect stings as a cause of anaphylaxis can be seen all around the world with varying geographic areas affected more commonly by different families of Hymenoptera. Similarly, occupational hazards lend to increased risks of specific allergies. An obvious example is seen with the bee venom allergy, which is found in higher proportions in beekeepers. Population-based studies have difficulty calculating the overall prevalence of Hymenoptera sting allergies, which may be responsible for up to 34.1% of all-cause anaphylaxis. Severe systemic reactions are seen more frequently in adults and may present with all the same features of anaphylaxis with hypotension being the most dominant feature. Baseline serum tryptase levels are the best predictor of the severity of anaphylaxis in insect sting-allergic patients. Understanding the classification of the various insect stings and bites that can lead to life-threatening hypersensitivity reactions is helpful in patient management and future preventive therapy. Specific venom immunotherapy (VIT) can prevent morbidity and mortality in patients with severe hymenoptera sting allergies. A 3-5 year course of subcutaneous injections significantly reduces the risk of anaphylaxis in up to 98% of children and is even effective and safe in high-risk patients with mastocytosis. Indications and recommendations for VIT differ by country and are based on clinical history of systemic reactions, positive skin test, and knowledge of the history and risk factors for a severe reaction to treatment.
Idiopathic
Idiopathic reactions are responsible for up to one third of all type I hypersensitivity reactions. The diagnosis is one of exclusion, after a complete medical history, skin prick testing, serum specific IgE levels, radioallergosorbent test (RAST), and other lab testing reveal no recognizable external trigger. Similarly, any other diseases that could mimic the anaphylactic hypersensitivity reaction picture should be ruled out. Patients should also be evaluated for mastocytosis or clonal mast cell disorders. Serum tryptase can be very useful in differentiating anaphylaxis from many conditions that can masquerade as anaphylaxis. The attack rate is variable and fatalities can occur. Patients typically present with symptoms identical to those of other type I hypersensitivity reactions and individual patients tend to have the same physical manifestations on repeated episodes.
Less common etiologies
Physical urticaria is an eruption in response to physical stimuli. Several defined subtypes of this phenomenon include dermatographic, cold, heat, adrenergic, cholinergic, aquagenic, solar, pressure, vibratory, and exercise-induced/food and exercise-induced. Severe, life-threatening responses to physical stimuli are exceedingly rare. Of all the physical urticarias, exercise-induced and food-exercise-induced urticaria/anaphylaxis and primary cold urticaria have the highest incidence of associated anaphylaxis.
Viral infections, while not a primary cause of urticaria, have also been known to exacerbate urticarial reactions. It is thought that the up-regulation of cytokines during acute phases of illness may lead to an enhanced state of mediator release from mast cells.
Differential Diagnosis
The differential diagnosis of histamine-mediated emergencies in dermatology is extensive. Because cutaneous signs such as urticaria are frequently the earliest signs of life-threatening events, conditions with an urticarial component must be ruled out. These include insect bite reactions, Sweets’ syndrome (acute febrile neutrophilic dermatosis), the urticarial stage of bullous pemphigoid, acute contact dermatitis of the face, urticarial drug reactions, and urtication caused by rubbing of the lesions of urticaria pigmentosa. The prolonged duration of the individual urticarial lesions in these conditions helps to differentiate them from true urticaria, lesions of which typically last for less than 24 hours.
Diagnosis
Urticaria and Angioedema
A comprehensive history and physical examination are essential in the diagnosis of a suspected histamine-mediated emergency. The sequential exposure of an agent with the development of signs and symptoms, along with details of disease duration, known allergens, occupation, history and frequency of similar episodes, duration of previous episodes and any previously successful or unsuccessful therapies should be reviewed. A thorough physical exam assessing morphology, location, and duration of cutaneous signs of histamine release, in particular urticaria and angioedema, should also be undertaken. Specific testing should be based on information provided in the history and physical and may include blood tests, skin biopsies of notable lesions in patients with lesions lasting more than 24 hours, food challenges, skin testing for allergens, and tests designed to look for functional autoantibodies against IgE or the high-affinity receptor (Fcε (epsilon) R1) of dermal mast cells and basophils.
A measurement of serum and urine histamine and histamine metabolites and the serum tryptase level can be done to demonstrate mast cell or basophil activation. Serum histamine levels remain elevated for only 30-60 minutes after the onset of symptoms; therefore normal serum histamine levels cannot rule out a serious histamine-mediated reaction. A 24-hour urine study of methylhistamine is more accurate and should be initiated as soon as possible after symptoms begin. Tryptase is a proteinase specific to mast cells and levels remain elevated for up to 5 hours after mast cell activation. In cases of anaphylaxis, levels are expected to exceed 10 ng/mL and can increase greater than 100 ng/mL in anaphylaxis from hymenoptera stings or medications.
Allergen-specific skin testing or radioallergosorbent (RAST) testing can be used to identify certain causes of immunologic IgE-mediated reactions to food, latex, stinging insects, and other environmental allergens. These reactions can manifest as acute urticaria, angioedema, contact urticaria, or anaphylaxis. The recent National Institute for Health and Clinical Excellence guidelines recommend that all children with a clinically suspected immediate-type hypersensitivity reaction, based on an allergy focused clinical history, undergo skin prick testing or specific IgE blood tests, in order to confirm the diagnosis. Additionally, these tests should only be performed where facilities are available to quickly manage and treat an anaphylactic reaction. Patients with severe chronic urticaria should be tested for thyroid autoantibodies as well as have thyroid function tests performed if clinically relevant. Patients with chronic urticaria have a higher incidence of thyroid autoantibodies and may indicate an autoimmune etiology of the patient’s urticaria. Limitations exist in confirming the presence of functional serum autoantibodies. Immunoassays for anti-Fcε (epsilon) RI and anti-IgE may not be completely accurate as patients may have non-functional as well as functional autoantibodies. Autologous serum skin tests (ASSTs) can be a helpful screening tool. They involve intradermal injections of autologous serum versus a saline controls with positive results demonstrated by a pink wheal response at 30 minutes that is 1.5 mm greater in diameter. Further research is necessary to find accurate means to diagnose patients with functional autoantibodies and an autoimmune etiology of anaphylaxis.
Physical Urticaria
Several different standards have been proposed to aid in the diagnosis of the numerous physical urticarias. Table 4 provides a basic elicitation strategy for each physical urticaria. Eliciting for a physical urticaria along with antihistamine-responsive symptoms may be all that is required for diagnosis. However, some patients may prove more difficult to accurately diagnose. Important to remember is that patients may have severe reactions upon eliciting a physical urticaria and testing must be performed in a safe, controlled setting.
Anaphylaxis
Although anaphylaxis was first described over 100 years ago, and is broadly understood as described above (see Urticaria, Angioedema, and Anaphylaxis: Definition), there is still no universally accepted definition. In 2006 the second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium on the definition and management of anaphylaxis was held to determine the necessary clinical criteria for diagnosing anaphylaxis. Anaphylaxis is considered highly likely when there is acute onset of illness (within minutes to hours) with involvement of the skin, mucosal tissue, or both AND either respiratory compromise or evidence of end organ dysfunction (i.e., decreased blood pressure, incontinence, syncope). After exposure to a likely allergen, anaphylaxis is also highly likely if at least two of the following signs and symptoms are present: involvement of the skin or mucosa; respiratory compromise; hypotension; or persistent gastrointestinal symptoms. Finally, criteria for diagnosing anaphylaxis can be completely based on a patient’s reduced blood pressure after exposure to a known allergen. In adults, a systolic blood pressure of less than 90 mm Hg or a 30% or greater decrease from baseline is considered significant.
Treatment
Urticaria and Angioedema
Urticaria is often idiopathic, infrequently associated with a known allergen, and rarely results in life-threatening conditions. The treatment is not a clear-cut science and often requires a patient specific regimen. All patients who suffer from urticaria should be given information on common precipitants. Antihistamines, topical antipruritic preparations, and the avoidance of known triggers are often a successful initial approach. Some patients, however, will need additional interventions, including systemic steroids.
First line therapy for treatment of urticaria is accomplished with antihistamines, which are most effective when taken on a daily basis rather than as-needed symptomatic relief. Classic sedating H1-antihistamines include chlorpheniramine, hydroxyzine, and diphenhydramine. While effective in controlling symptoms of urticaria, their potent sedative effects are a drawback, and they are not more efficient than the modern, non-sedating H1-antihistamines. Additionally, newer H1-antihistamines and their derivatives have less anticholinergic effects; therefore, patients experience less dry mouth, visual disturbances, tachycardia, or urinary retention. Examples include loratadine, desloratadine, cetirizine, levocetirizine, terfenadine, fexofenadine, and mizolastine. H2-antihistamines, such as cimetidine and ranitidine, have no beneficial effect on histamine-induced pruritus, and should therefore not be used as monotherapy for urticaria.
If symptoms are not improved after 2 weeks of treatment with a non-sedating H1-antihistamine, increasing the dosage up to 4 times may provide relief. Patients with chronic urticaria have demonstrated increased symptomatic relief from doses of antihistamines up to 4 times higher than conventional doses without a compromise in safety. Patients with frequent episodes of idiopathic anaphylaxis may also benefit from the use of daily prophylactic H1-antihistamine. Patients should wait between 1-4 weeks before considering switching to alternative therapies to allow for the full effectiveness of antihistamine therapy. Patients should also try switching to a different H1-antihistamine before adding on additional medications.
Second line therapies should be initiated if symptomatic relief is not accomplished with antihistamines alone. The addition of a leukotriene antagonist, such as zafirlukast or montelukast, may provide some patients relief from symptoms, especially patients with symptoms aggravated by NSAIDs and food additives. While evidence is limited for the use of lipoxygenase (zileuton) and cyclooxygenase (rofecoxib) inhibitors, these medications may also be effective for chronic urticaria. Doxepin, a tricyclic antidepressant with potent H1- and H2-antihistamine acitivity, may also be beneficial for patients unresponsive to antihistamine therapy. Dosing begins at 10-25 mg at night, and can be increased to up to 75 mg nightly. Side effets may include sedation and weight gain.
A short course (3-7 days) of high-dose corticosteroids (prednisone or prednisolone 30-60 mg/day) may be effective in antihistamine resistant cases of chronic urticaria or severe episodes of acute urticaria when a rapid clinical response is needed. Longer treatments with steroids beyond 7-14 days are not recommended, but if necessary, should be carried out under the care of a specialty clinic. Long-term use of systemic corticosteroids is associated with substantial adverse effects. Patients may be at increased risk for developing diabetes mellitus, hypertension, osteoporosis, adrenal insufficiency, or gastrointestinal bleeding [64]. Patients who suffer from chronic urticaria or known severe allergies to certain foods, medications or insect bites, should carry a self-injectable epinephrine pen (e.g. EpiPen) and be adequately trained in its use and administration.
If symptomatic relief is still not achieved, the addition of cyclosporine, H2-antihistamines, dapsone, or omalizumab are recommended as fourth level treatment by the current international guidelines for management of urticaria. Low-dose cyclosporine has shown in several randomized and non-randomized trials to be safe and effective in decreasing urticarial symptoms in patients with chronic idiopathic urticaria. Additionally, cyclosporine inhibits the release of preformed histamine and de novo mediators from human skin mast cells and basophils. The combined use of H1- and H2-antihistamines may improve symptoms in some patients with difficult chronic urticaria. Dapsone has been shown to achieve better long-term complete resolution of urticaria when used in combination with antihistamines as compared to treatment with antihistamines alone. However, the efficacy of dapsone longer than three months after withdrawal has not been well studied.
Omalizumab is a recombinant humanized monoclonal antibody (mAb) that binds to the C3 domain of the IgE antibody, the site where IgE binds to the Fcε (epsilon) R1, thereby blocking the binding of IgE to the Fcε (epsilon) R on the surface of mast cells and basophils. Therefore, it can reduce levels of circulating IgE autoantibodies and inhibit binding of IgE to high-affinity Fcε (epsilon) R1 resulting in Fcε (epsilon) R1 down regulation. Studies have demonstrated that a fixed subcutaneous doses of omalizumab added to a stable dose of H1-antihistamine may be effective in patients with refractory chronic idiopathic urticaria or a small subpopulation of chronic urticaria patients who exhibit IgE autoantibodies against thyroperoxidase.
Since the recognition that some patients with chronic urticaria may have an autoimmune component to their disease, research is ongoing in the use of other immunomodulatory therapies. These include low-dose methotrexate, rituximab, mycophenolate mofetil, cyclosporine, cyclophosphamide, plasmapheresis, and intravenous immunoglobulin therapy azathioprine, and oral tacrolimus. Methotrexate is an antimetabolite that has demonstrated efficacy in patients with chronic urticaria non-responsive to conventional therapies. The mechanism of methotrexate in treating chronic urticaria, however, remains unknown. Rituximab is a chimeric murine/human recombinant mAb that binds to CD20, which is found on B-cells. This binding leads to B-cell depletion and possibly decreased production of IgG autoantibodies. Rituximab is being investigated for the treatment of non-IgE autoantibody-mediated forms of chronic autoimmune urticaria, but further research is needed in this patient population.
In summary, the treatment of urticaria and angioedema first requires the avoidance of known allergens such as food, drugs, latex, or other contact allergens. Symptomatic relief is often achieved with oral antihistamines. A short course of oral corticosteroids may be necessary for severe protracted episodes and to prevent a late-phase response, though it takes up to four hours for the effects of oral corticosteroids to be seen. Finally, epinephrine should be considered only in the acute intervention of severe and life-threatening attacks.
Anaphylaxis
Despite efforts to avoid known or common triggers of anaphylaxis, there is still no way to absolutely prevent exposures. Therefore, it is crucial that at-risk patients and caregivers be able to recognize early signs and symptoms of anaphylaxis and have knowledge of emergent, life-saving measures. The treatment of anaphylaxis requires implementing standard principles for emergency resuscitation, including an initial assessment of the patient’s airway, breathing, circulation, and vital signs, before proceeding with any further management.
Epinephrine is considered an essential component of anaphylaxis treatment by the World Health Organization and World Allergy Organization. Epinephrine should be administered at the first sign of anaphylaxis since delayed administration of epinephrine, especially in the pediatric population, leads to an increased risk of biphasic reactions, hypoxic-ischemic encephalopathy, and mortality. The most important life-saving effects of epinephrine occur through the alpha-1 adrenergic receptors. These include vasoconstriction of small arterioles and precapillary sphincters with resultant decreased mucosal edema, reduction in angioedema and hives, and relief of upper airway obstruction, hypotension, and shock. Additional benefit from epinephrine follows from the effects on alpha-2 (decreased insulin release), beta-1 (increased heart rate and force of cardiac contractions), and beta-2 (bronchodilation and decreased release of mediators from mast cells and basophils) adrenergic receptors.
In an emergency, epinephrine administered intramuscularly or subcutaneously is the treatment of choice; however, intramuscular injections have been shown to reach peak plasma epinephrine levels more rapidly than subcutaneous injections with an auto-injector in children at risk of anaphylaxis. The first-aid dose of epinephrine is 0.5mg for adults and 0.3mg for children. Autoinjector formulations of epinephrine include the EpiPen (Dey LP, Napa, California, USA), Adrenaclick and Twinject (Sciele, Division of Shionogi, Japan) and the Anapen (Lincoln Medical, Salisbury, Wiltshire, UK; not available in the United States), and in most countries they are available in two fixed epinephrine doses per injection, 0.3mg (e.g. EpiPen) and 0.15mg (e.g. EpiPen Jr.). The Twinject and the Adrenaclick are similar devices but the Twinject contains two doses of epinephrine where the Adrenaclick contains only one. In some countries, the Anapen is also available in a 0.5mg fixed epinephrine dose. The injections should be administered intramuscularly in the lateral thigh to control symptoms and maintain normal blood pressures. The 0.3 mg and the 0.15 mg injectable doses are appropriate for pediatric patients over 30 kg and between 15-30 kg, respectively. However, allergy specialists should be involved in the treatment of children below 15 kg requiring first-aid treatment with epinephrine for anaphylaxis, for which the 0.15 mg dose may be too high.
With increasing rates of obesity in the United States, physicians must be aware that auto-injector needles might not achieve appropriate depths for intramuscular injection, even in pediatric patients. It has been proposed that in such patients, injection into the postero-lateral calf muscle (gastrocnemius/soleus), with little overlying subcutaneous fat and no endangered superficial arteries or nerves, may provide an effective alternative. Otherwise, varying length needles on preloaded syringes provide another option, although with reduced shelf life of the epinephrine.
Up to 20% of patients require a second or multiple injections due to persistent symptoms or a biphasic reaction. Maximum doses may be repeated every 5-15 minutes as needed in the absence of a response to epinephrine. Posture my also affect mortality in anaphylaxis and thus patients should be kept lying down with raised legs to maintain the vena cava as the lowest part of the body. This helps blood flow return to the right side of the heart and ensures adequate myocardial perfusion. Patients and caretakers must be properly instructed on the importance of and how to use emergency epinephrine auto-injectors so as to avoid injury from unintentional injections and to make sure epinephrine is delivered to the individual experiencing an anaphylactic episode.
Epinephrine auto-injectors, or any self-injectable devices when auto-injectors are unavailable, should be prescribed for individuals who have already experienced anaphylaxis involving respiratory symptoms, hypotension, or shock, patients with known triggers that are commonly encountered in the community, including foods, insect stings, or physical urticarias, and patients with a history of idiopathic anaphylaxis. Clinical judgment should be used when prescribing an epinephrine auto-injector for patients with a history of moderate to severe urticarial reactions after exposure to a known inciting allergen but no history of anaphylaxis. There are no contraindications to using epinephrine in anaphylaxis and thus the threshold for prescribing should be low. When multiple repeat intramuscular doses of epinephrine are required, patients may benefit from intravenous epinephrine in the form of bolus epinephrine or a continuous infusion. However, intravenous administration of epinephrine should only be performed by a trained and experienced specialist.
Side effects of epinephrine include tachycardia, anxiety, and headache, and caution should be applied for use in patients with hypertension, ischemic heart disease, cerebrovascular disease, and diabetes mellitus. Additionally, side effects of epinephrine may mimic signs of anaphylaxis and care must be taken not to administer extraneous doses. Oxygen therapy and placing the patient in the supine position with lower extremity elevation should also be maintained. Additional therapies depend on the severity of the anaphylactic episode and include intravenous fluids, antihistamines, vasopressors, corticosteroids, glucagon, atropine, and nebulized albuterol. Monitoring patients for several hours after an anaphylactic episode is extremely important, as is providing instructions on how best to avoid future reactions based on the inciting antigen. The arrhythmogenicity of epinephrine may be augmented by certain medications, including tricyclic antidepressants, drugs such as cocaine, or underlying cardiac arrhythmias. Therefore, the benefits must be weighed against the potential side effects when prescribing epinephrine auto-injectors for patients. Finally, efforts should be made to treat any underlying medical conditions since certain diseases, such as asthma or cardiovascular disease, can increase a patient’s risk for a severe anaphylactic episode.
MASTOCYTOSIS
Definition and Epidemiology
Mastocytosis represents a collection of heterogeneous disorders characterized by the abnormal growth and accumulation of mast cells and the aberrant release of mast cell mediators, predominantly histamine, in various organ systems. Mastocytosis can be broadly divided into cutaneous mastocytosis, characterized by the presence of one or more lesions limited to the skin; and systemic mastocytosis, defined by lesions affecting various internal organs, commonly the bone marrow, gastrointestinal tract, the liver and the spleen. Systemic mastocytosis may or may not involve the skin. Cutaneous involvement is more common in indolent forms and often absent in more advanced forms of systemic disease. Cutaneous mastocytosis is more common in children than in adults, with 55% of patients noted to have onset before 2 years of age and an additional 10% of patients with disease onset before the age of 15. In childhood disease, the skin is almost exclusively involved, and skin lesions typically improve or resolve by late adolescence. In contrast, adult-onset disease occurs between the ages of 20 and 40 years, is more frequently systemic, and disease persists throughout a patient’s lifetime. Although cutaneous mastocytosis is less commonly seen in the adult population, patients with systemic mastocytosis and skin involvement are frequently diagnosed based on their cutaneous lesions.
WHO Categorization
The WHO classification of mastocytosis is an accepted clinical approach to help distinguish cutaneous mastocytosis, systemic mastocytosis, and their subvariants. The major types of cutaneous mastocytosis include urticaria pigmentosa, diffuse cutaneous mastocytosis, solitary mastocytoma, and telangiectasia macularis eruptiva perstans. The majority of pediatric cases of cutaneous mastocytosis show a good prognosis with gradual resolution of both symptoms and skin lesions.
In children, systemic involvement is rare and disease may regress spontaneously in puberty or early adolescence. In adults, disease does not regress but rather has an indolent clinical course. Survival in patients with indolent systemic mastocytosis is not statistically different from the general population. Prognoses for aggressive systemic mastocytosis and mast cell leukemia, however, are poor, and median survival is around 41 months and 2 months, respectively.
Pathophysiology
In most patients with mastocytosis, disease is caused by a gain of function mutation in KIT, the mast/stem cell growth factor receptor that is responsible for the differentiation and growth of mast cells. Mutation results in activation with subsequent accumulation and increased survival of mast cells, although a second “hit” is necessary in the pathogenesis, as the same mutations have been found independent of mastocytosis. Specifically, the D816V point mutation is found in 95% of adult patients with systemic mastocytosis. As the pathogenesis of mastocytosis has become better understood it is known that the mechanisms of disease in the pediatric and adult populations may differ, and the frequency and significance of mutations in pediatric cases of mastocytosis is controversial.
Clinical Features
For some patients, the cosmesis of urticaria pigmentosa lesions is the only complaint and the majority of patients with mastocytosis are completely asymptomatic. When present, cutaneous and systemic symptoms are caused by IgE-dependent and non-IgE-mediated degranulation of mast cells and release of histamine and other mediators from the pathogenic mast cells, including tryptase. The pathophysiology of symptom development in mastocytosis is identical to that described for urticaria, angioedema, and anaphylaxis, and can be precipitated by the same mast cell stimulators as detailed above and outlined in Table 4.3. Symptoms of mastocytosis may be exacerbated by physical stimuli, alcohol, narcotics, salicylates and other NSAIDs, polymyxin B, or anticholinergic medications.
Childhood cutaneous mastocytosis often presents with a solitary tan or pink to brown plaque or nodule (mastocytoma) or anywhere from 10-1,000 tan to brown macules or papules (urticaria pigmentosa). Mast cell mediator-related symptoms are present in over 60% of all pediatric cases. Erythema, swelling, and blister formation can occur after stroking or rubbing the lesions. Darier’s sign, the development of urticaria after stroking the lesions of mastocytosis, is not always present and correlates with the concentration of mast cells in the lesion. The trunk and extremities are the most common sites involved, but lesions can also occur on the face, palms, soles, and scalp. Of note, the extent of cutaneous involvement is not directly associated with symptoms and is also not predictive of systemic disease. Diffuse cutaneous mastocytosis (DCM) is a rare severe form seen predominantly in infants. The skin is infiltrated by mast cells in a generalized and diffuse pattern. The skin is thickened and appears doughy with a yellow discoloration and accentuated folds. In areas of increased mast cell accumulation, nodules or plaques are present. Additionally, edema may results from the mast cell infiltration and degranulation in the skin. Life-threatening hypotensive episodes are common complications of DCM and occur due to the extent of lesions, which can involve the entire skin, and the large amount of mast cell mediator release locally and systemically during severe episodes. Bullous eruptions with hemorrhage is a subvariant of DCM seen predominantly in neonates with blisters erupting spontaneously or from a stimulus. Patients may present at birth (congenital) or in early infancy but blistering typically resolving by 3-5 years of age. Mild symptoms such as cutaneous flushing, blistering, or pruritus, or more severe symptoms, such as shortness of breath, asthma exacerbations, hypotension, and GI symptoms, occur more commonly in patients with systemic disease, but may also be seen in patents with severe cutaneous disease, in particular DCM, due to the higher concentrations of mast cells.
When cutaneous lesions are present in adults they appear different from the typical lesions seen in children. They are 2-5 mm brown-reddish macules or papules. Telangiectasia macularis eruptiva perstans is seen in
<1% of patients and exclusively in adults. The lesions appear as tan-to-brown macules with patchy erythema and telangiectasias.
Evolution of a childhood cutaneous form of mastocytosis to a systemic form is seen infrequently. The signs and symptoms of systemic mastocytosis reflect the infiltration of mast cells into the involved tissues. Patients may present with constitutional signs, skin lesions, mediator-related findings (flushing, syncope, diarrhea, hypotension, headache, and/or abdominal pain), and musculoskeletal disease, with an increased risk of severe osteoporosis.
The cumulative prevalence of anaphylaxis in children with mastocytosis is between 6% and 9% and in adults is between 22% and 49%. Patients with systemic disease are at increased risk of anaphylaxis compared to patients with solely cutaneous disease. Severe anaphylactic reactions with shock or cardiopulmonary arrest are more common in patients with mastocytosis, especially individuals with hymenoptera allergies. Deaths associated with extensive mast cell mediator release are rare but have been documented in both the pediatric and adult populations. Overall, the spectrum of cutaneous subtypes of mastocytosis has a good prognosis in comparison to systemic disease.
Diagnosis
The diagnosis of cutaneous mastocytosis requires a high index of suspicion in patients with skin lesions with or without mast cell mediator-related symptoms. These include flushing spells, pruritus, redness, swelling, respiratory symptoms, including asthma exacerbations and shortness of breath, and GI symptoms, including peptic ulcer disease and diarrhea. The lesions of childhood and adult mastocytosis are very characteristic and may rarely be confused with other skin disorders. Demonstration of a positive Darier’s sign, seen most commonly in patients with mastocytomas, is helpful in the diagnosis. A negative sign; however, does not rule out mastocytosis. Most diagnoses are based on clinical findings and results of skin biopsies. Demonstration of increased mast cells in either the blister fluid or skin biopsy of the mastocytosis patient may establish the correct diagnosis. Special stains that recognize tryptase and KIT (CD117) aid in the identification of tissue mast cells. Analysis of KIT-receptor mutations, specifically the D816V mutation, within skin mast cells is recommended. Serum tryptase levels can also be an indicator of mast cell load, but are more likely to be increased in patients with systemic mastocytosis.
Systemic mastocytosis often requires more invasive diagnostic measures. A workup should be performed in children when there is suspicion of progression to a systemic adult form, severe recurrent systemic mast cell mediator-related symptoms, organomegaly, or skin lesions that fail to resolve. Similarly, in adults a careful workup is necessary to accurately diagnose and stage patients with systemic disease. Initial laboratory testing includes a complete blood count with differentials, a chemistry panel, liver enzymes, and tryptase levels. Bone marrow examination with biopsies is also often indicated in adult patients.
In most patients, histologic evaluation of bone marrow biopsies and mast cell identification allow for the most efficient diagnosis of systemic mastocytosis, as the bone marrow is almost always involved. Just as molecular detection of KIT mutations are performed in skin biopsies, they can be performed on fresh bone marrow aspirate, clot sections, bone marrow biopsy sesections and even peripheral blood, if there are circulating mast cells. An immunohistochemistry panel consisting of CD117, tryptase, and CD25, with the latter not present in normal or reactive mast cells, can also detect neoplastic mast cells.
Additional laboratory and radiographic studies may be indicated for patients with additional signs of systemic involvement. Patients with complaints of bone pain should have an X-ray evaluation to look for skeletal involvement. However, in children with cutaneous mastocytosis and no evidence of systemic disease, positive X-ray findings may falsely convey signs of systemic disease. The liver, spleen, lymph nodes, GI tract, and any other organ may also be involved, and require further imaging or workup for diagnosis.
Ultimately, the diagnosis of systemic mastocytosis is based on World Health Organization criteria, with one major and one minor, o
