07 - 364 Anaphylaxis

364 Anaphylaxis

PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Anaphylaxis David Hong, Joshua A. Boyce

■ ■BACKGROUND Anaphylaxis is a potentially life-threatening systemic allergic reac­ tion involving one or more organ systems that typically occurs within seconds to minutes of exposure to the anaphylactic trigger, most often a drug, food, or Hymenoptera sting. The term anaphylaxis was first described in 1902 by Charles Richet and Paul Portier who attempted to immunize dogs against sea anemone toxin in the same way Pasteur was able to vaccinate individuals against the smallpox virus. To their surprise, repeated administration of small, sublethal doses of sea anem­ one toxin reliably induced acute-onset death when readministered 2–3 weeks after initial “vaccination” to the toxin. The phenomenon was termed ana (anti)-phylaxis (“protection or guarding”) because vaccination with anemone toxin resulted in the opposite intended immune effect. Charles Richet was awarded the Nobel Prize in Physiol­ ogy or Medicine in 1913 for this work which led to further insights into hypersensitivity and mast cell biology. ■ ■CLINICAL MANIFESTATIONS While 80–90% of anaphylactic episodes are uniphasic, about 10–20% of cases are biphasic, in which anaphylactic symptoms return about an hour or longer after resolution of initial symptoms. Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs, leading potentially to cardiovascular collapse or respiratory failure, respectively. There may be upper or lower airway obstruc­ tion or both. Laryngeal edema may be experienced as a “lump” in the throat, hoarseness, or stridor, whereas bronchial obstruction is associ­ ated with a feeling of tightness in the chest and/or audible wheezing. Patients with underlying asthma are predisposed to severe involvement of the lower airways and increased mortality associated with anaphy­ laxis. In fatal cases with clinical bronchial obstruction, the lungs show marked hyperinflation on gross and microscopic examination. The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosino­ philic infiltration, and the acute emphysema is attributed to intractable bronchospasm that subsides with death. Angioedema resulting in death by mechanical obstruction occurs in the epiglottis and larynx. This process can also be evident in the hypopharynx and trachea. On microscopic examination, there is wide separation of the collagen fibers and the glandular elements. Vascular congestion and eosino­ philic infiltration may also be present. Patients dying of vascular col­ lapse without antecedent hypoxia from respiratory insufficiency have visceral congestion with a presumed loss of intravascular fluid volume. The associated electrocardiographic abnormalities in some patients, with or without infarction, may reflect a primary cardiac event medi­ ated by mast cells (which are prominent near the coronary vessels) or may be secondary to a critical reduction in intravascular volume. Gastrointestinal manifestations represent another severe presenta­ tion of anaphylaxis and include nausea, vomiting, crampy abdominal pain, and/or fecal incontinence. Angioedema of the bowel wall may also cause sufficient intravascular volume depletion to precipitate car­ diovascular collapse. Cutaneous manifestations are among the most common presenta­ tions of anaphylaxis (>90% of cases). Symptoms include urticarial eruptions, flushing with diffuse erythema, and/or a feeling of general­ ized warmth. Urticarial eruptions are intensely pruritic and may be localized or disseminated. They may coalesce to form large urticarial plaques but seldom persist beyond 48 h. ■ ■PATHOPHYSIOLOGY Many of the important early mediators of anaphylaxis are derived from mast cells, basophils, and eosinophils. Mast cells contain preformed granules comprised of histamine, proteases (tryptase, chymase), pro­ teoglycans (heparin, chondroitin sulfate), and tumor necrosis factor-α, which are rapidly released into surrounding tissue upon cell activation, a process known as degranulation. Basophils, like mast cells, contain and release histamine. Mast cells, basophils, and eosinophils are also sources of arachidonic acid–derived products, which include cysteinyl leukotrienes, prostaglandins, and platelet-activating factor (PAF). Histamine release results in flushing, urticaria, pruritus, and, in high concentrations, hypotension and tachycardia. Cysteinyl leukotrienes and prostaglandin D2 cause bronchoconstriction and increased micro­ vascular permeability. Prostaglandin D2 causes cutaneous flushing and attracts eosinophils and basophils to the site of mast cell activation. Serum PAF levels correlate with anaphylaxis severity and are inversely proportional to the constitutive level of PAF acetylhydrolase, which is necessary for PAF inactivation. Tryptase and chymase can activate complement and coagulation pathways. Activation of these pathways results in production of the anaphylatoxins, C3a and C5a, and activa­ tion of the kallikrein-kinin system, which regulates blood pressure and vascular permeability. The actions of these anaphylactic mediators are likely additive or synergistic at the target tissues. ■ ■PREDISPOSING FACTORS AND MECHANISMS Because the most dangerous manifestations of anaphylaxis involve the cardiovascular and/or respiratory systems, preexisting asthma and underlying cardiovascular disease could lead to more rapid decompen­ sation from anaphylaxis. Atopy is not generally thought to be a risk fac­ tor for anaphylaxis from drug reactions or Hymenoptera stings, but it is associated with radiocontrast sensitivity, exercise-induced anaphylaxis, idiopathic anaphylaxis, and allergy to foods or latex. Severe Hyme­ noptera-induced anaphylaxis (generally with prominent hypotension) is the most common initial presentation for patients with underlying systemic mastocytosis. For this reason, it is important to check a base­ line tryptase (a reflection of mast cell burden) in patients who present with sting-induced anaphylaxis to screen for this condition. Hyme­ noptera allergy is also more likely in patients whose occupations (i.e., beekeepers, trash haulers, and landscape workers) place them in regu­ lar proximity to stinging insects. Most commonly, allergen-induced cross-linking of IgE-bound FcεRI receptors on mast cells and basophils initiates the signal transduction events leading to hypersensitivity syndromes, including anaphylaxis. The generation of allergen-specific IgE is the end result of sensitization via the adaptive immune system. While the mechanisms underlying sensitization are beyond the scope of this chapter, environmental factors, innate immune responses, and cytokines are among the many variables leading to antigen-specific IgE production by B cells and plasma cells. IgE-mediated drug allergies are most common with antibiotics and certain chemotherapy drugs, though theoretically, they can occur with almost any medication. As is the case with environmental allergies, repeated exposure to the allergy-causing antigen is an important risk factor to keep in mind when evaluating patients with anaphylaxis. In the case of allergy to carboplatin, the incidence of hypersensitivity is 27% in patients who have had ≥7 lifetime infusions and as high as 46% in patients who have had ≥15 lifetime infusions. Similarly, patients with cystic fibrosis have a relatively high incidence of allergic reactions to IV antibiotics, particularly beta-lactams, that they receive periodically for intermittent “clean-outs” to maintain airway clearance. Drugs can also function as haptens that form immunogenic conjugates with host proteins. The conjugating hapten may be the parent compound, a nonenzymatically derived storage product, or a metabolite formed in the host. Recom­ binant biologics in some cases can also induce the formation of IgE against the proteins or against glycosylated structures that serve as immunogens. Outbreaks of anaphylaxis to the epidermal growth factor receptor (EGFR) antibody, cetuximab, have been reported in associa­ tion with elevated titers of serum IgE to alpha-1,3-galactose (alphagal), an oligosaccharide found in nonprimate mammals. Cetuximab is derived from a mouse cell line expressing a transferase that tags the Fab′ portion of the cetuximab heavy chain with alpha-gal. Interestingly, patients with a history of multiple bites from Amblyomma americanum ticks commonly found in the Carolinas, Arkansas, and Tennessee are more likely to have anti-alpha-gal IgE as compared to patients living outside those states. A subset of individuals with anti-alpha-gal IgE

can develop episodes of delayed-onset anaphylaxis about 3–6 h after consuming mammalian meat (beef, lamb, or pork) in a condition now known as alpha-gal syndrome (AGS). The mechanisms behind AGS are not yet well understood. It is also important to remember that allergic reactions caused by the effector cells and mediators described previously can be triggered by a variety of mechanisms that may not require the presence of sensitizing IgE. Non-IgE-mediated mast cell activation secondary to certain drugs is clinically indistinguishable from classical IgE-mediated hypersensi­ tivity reactions but can occur with first known exposure since there is no prior need for mast cell sensitization by IgE. MRGPRX2, a G protein–coupled receptor that is highly expressed in skin mast cells, has been shown in mouse models and in vitro studies using human cells to induce mast cell activation and mediator release secondary to neuromuscular blocking drugs (NMBDs), quinolones, and icatibant. These findings are clinically significant since NMBDs are needed for procedures done under general anesthesia while quinolones are a commonly used antibiotic family. Icatibant, a bradykinin-2 receptor antagonist administered by subcutaneous injection for the treatment of acute attacks of hereditary angioedema, is known to frequently result in local injection site reactions. Another example of non-IgE-mediated anaphylaxis is demonstrated with paclitaxel, a chemotherapy agent most commonly used in combination with carboplatin to treat ovar­ ian cancer. It is derived from yew tree bark and needles that require polyethoxylated castor oil (Cremophor) to be solubilized into aqueous solution. Cremophor has been shown in vitro to activate the comple­ ment cascade, resulting in complement-dependent histamine release from mast cells and basophils. A version of paclitaxel that is solubilized by being bound to albumin nanoparticles, Abraxane, has a far lower rate of hypersensitivity, especially for patients who have had infusion reactions to Cremophor-solubilized paclitaxel. Reactions such as flush­ ing, hives, angioedema, and/or anaphylaxis to radiocontrast, opiates, vancomycin, and nonsteroidal anti-inflammatory drugs (NSAIDs) are other examples of non-IgE-mediated hypersensitivity. An example of non-IgE-mediated food anaphylaxis is scombroid poisoning, caused by the ingestion of a pharmacologically significant dose of histamine from contaminated fish. This is most commonly associated with fish that are rich in histidine, such as mahi-mahi, mackerel, and tuna. If improperly stored, surface contaminant bacteria expressing histidine decarboxylase convert histidine into histamine, which is not broken down by baking or broiling. Scombroid poison­ ing leads to symptoms including flushing, oropharyngeal pruritis/ angioedema, nausea/vomiting, and lightheadedness. Symptoms are often self-limited but still treatable with antihistamines and, if needed, epinephrine. Because the source of histamine is exogenous, tryptase levels are not elevated. A final example of non-IgE-mediated anaphylaxis occurred in clustered cases of anaphylaxis to IV unfractionated heparin in Europe and North America in 2008. Cases were attributable to specific lots of heparin found to be enriched in a contaminant, oversulfated chon­ droitin sulfate (OSCS). OSCS is able to activate the contact activation system, leading to the generation of bradykinin and the anaphylatoxins C3a and C5a, which led to the anaphylactic symptoms. Heparin is now routinely screened for this contaminant to prevent further outbreaks. ■ ■DIAGNOSIS The diagnosis of an anaphylactic reaction depends primarily on a his­ tory revealing the onset of symptoms and signs within seconds to min­ utes after the putative trigger is encountered. An exception is delayed anaphylaxis to mammalian meats in patients with AGS. Table 364-1 lists other possibilities to consider on the differential for IgE-mediated anaphylaxis. Every attempt to identify the specific cause or causes should be made to minimize the risk of recurrent anaphylaxis. If a particular drug or food is suspected, skin or serum-specific IgE testing can be useful to confirm clinical suspicions. If a specific trigger cannot be identified by history or testing, a workup of underlying baseline atopic diatheses may be useful to identify risk factors that could play potential contributory roles alone or in concert. In the acute setting, laboratory biomarkers of mast cell degranulation may be useful to

TABLE 364-1  Differential Diagnoses for IgE-Mediated Anaphylaxis CONDITION DISTINGUISHED BY Mastocytosis Elevated baseline tryptase, spindleshaped mast cells (MCs) on bone marrow CHAPTER 364 Pheochromocytoma Elevated urine metanephrines Carcinoid syndrome Elevated urine 5-hydroxyindoleacetic acid Hereditary angioedema Decreased C4 during attacks Acquired angioedema Decreased C1q Anaphylaxis Systemic capillary leak syndrome Severe hypotension on presentation with lack of response to firstline hypersensitivity medications (epinephrine, antihistamines) Scombroid poisoning Tryptase not elevated; negative skin test and oral challenge to fish Drugs (opiates, neuromuscular blocking agents, vancomycin), computed tomography radiocontrast Direct MC degranulation triggered through MRGPRX2 receptor or other as-yet-undetermined mechanism document the severity of an anaphylactic episode. The most obvious serum biomarker to assay, histamine, has an extremely short serum half-life with a measurable time-window that expires <1 h from the onset of anaphylaxis. A more practical and reliable biomarker is serum tryptase, which is released from mast cells, peaks 60–90 min after the onset of anaphylaxis, and can be measured as long as 5 h after the onset of anaphylaxis. It may be useful to follow up an elevated tryptase mea­ surement in the acute setting with another measurement when the patient is clinically stable to establish a baseline reference since there is considerable variability of baseline serum tryptase (BST) within the general population. For example, ~6% of Western populations have hereditary alpha-tryptasemia (HAT), a mostly benign condition featuring elevated BST due to expression of an extra allele of TPSAB1, the gene that encodes alpha-tryptase. Some studies suggest that HAT may be a risk factor for severe anaphylaxis and is also overrepresented in patients with indolent mastocytosis. Another cause for temporarily elevated BST is high environmental allergen exposure, something that can occur, for example, in regions with distinct pollen seasons. A work­ ing group on mast cell disorders in 2010 came up with a formula to better interpret tryptase levels since (1) the range of “normal” BST is wide within the general population and (2) an acutely elevated tryptase for a given patient may still fall within normal parameters if their BST is low. The “20% + 2” rule stipulates that a tryptase level drawn in the setting of possible anaphylaxis that is 20% above the patient’s baseline plus 2 ng/mL is diagnostic for an acute event involving a clinically significant degree of mast cell activation. ■ ■TREATMENT Early recognition of an anaphylactic reaction and appropriate interven­ tion are critically important because severe, even fatal, complications can occur within minutes after symptoms first appear. The treatment of first choice is intramuscular administration of 0.3–0.5 mL of 1:1000 (1 mg/mL) epinephrine, with repeated doses at 5- to 20-min intervals as needed for a severe reaction. The failure to use epinephrine within the first 20 min of symptoms is a risk factor for poor clinical outcomes in various studies of anaphylaxis. IV fluids and vasopressor agents may be administered in the acute medical setting if intractable hypoten­ sion occurs. Epinephrine provides both α- and β-adrenergic effects, resulting in vasoconstriction, bronchial smooth-muscle relaxation, and attenuation of enhanced venular permeability. Beta blockers may attenuate this response; therefore, an alternative antihypertensive may be considered in patients at high risk of needing emergency epineph­ rine. Oxygen alone via a nasal catheter or with nebulized albuterol may be helpful; however, either endotracheal intubation or a tracheostomy is mandatory for oxygen delivery if progressive hypoxia develops. Ancillary agents such as antihistamines, glucocorticoids, and broncho­ dilators are also useful therapeutics to treat urticaria/angioedema and bronchospasm once the patient is hemodynamically stable.