Epidemiology

Food allergies pose a significant threat to human health. Bock and co-workers estimate that food allergies are the leading identifiable cause of anaphylactic reactions presenting to emergency departments in the United States. There are approximately 29,000 anaphylactic reactions per year, resulting in 150 deaths annually.²⁰ Hughes and Mills estimate that approximately 33% of anaphylactic reactions are caused by foods.⁸⁰ The actual incidence of anaphylaxis due to food allergies depends on the diagnostic criteria used. One study reported a 13% incidence among a sample of patients presenting with food-related allergic reactions,¹⁷⁰ whereas another reported an incidence of 51%.³⁸ In a study of patients presenting with food allergies to an allergy center in Singapore, 66% had a history of anaphylactic reaction to a food allergen.¹⁹⁷

Food allergies are common. It is estimated that approximately 4% of adults and 6% of children younger than age 3 years in the United States have a food allergy, with 2.2% of the population having an isolated seafood allergy.^184,185 Unlike many food allergies, seafood allergies appear to be more common in adults than in children. Similar to peanut allergy, patients with fish and shellfish allergies generally remain clinically reactive lifelong. A 2002 telephone survey conducted in the United States determined that fish allergies afflicted 0.1% and 0.4% of U.S. children and adults, respectively, whereas shellfish afflicted 0.1% of children and 2% of adults. Shellfish rank as the leading cause of IgE-mediated food allergies in the U.S. adult population.¹⁸⁴ Another analysis of persons with food allergies presenting to emergency departments in the United States estimated that shellfish are the number one cause of food allergies among individuals older than age 6 years.¹⁷⁰ Overall, seafood allergies have been identified in 2.3% of the U.S. population, with 5.9% of U.S. households reporting at least one seafood allergy.¹⁸⁴

Although the specific etiologies of food allergies vary in different countries according to regional dietary patterns, seafood allergies appear to be one of the leading causes of food allergies worldwide. In a study of patients with food allergies in Singapore, crustacea accounted for 34%, mollusks 19%, and fish 4% of the food allergies.¹⁹⁷ In a case series of children in Spain, fish and shellfish allergies accounted for 30% and 6.8% of reported food allergies, respectively.⁴¹ In several studies of food-induced anaphylaxis, fish allergy was implicated in 30% of cases in a series involving children in Italy,¹⁵² and 29% of cases in a study of children in Philadelphia.⁵¹

Biologic Classification of Seafood

Seafood can generally be classified into four categories of organisms, including fish, crustacea, mollusks, and echinoderms, with each belonging to a different phylum. Because most individuals with a seafood allergy are not allergic to all types of seafood, a basic understanding of the biologic classification of fish and shellfish can be helpful in guiding patients on selective avoidance diets. Table 73-3 provides an overview of the taxonomic relationships among seafoods.

TABLE 73-3 Taxonomic Relationships Among Seafoods

Data from Myers P, Espinosa R, Parr CS, et al: The animal diversity web, 2008. http://www.animaldiversity.org.

Fish belong to the phylum Chordata, with most edible fish belonging to the class of bony, ray-finned fish, Actinopterygii (super-class Osteichthyes). Sharks (including dogfish), rays, and skates are the exception, belonging to the class of cartilaginous fish Chondrichthyes. The most frequently consumed fish in the United States fall into several orders: Salmoniformes (salmon, trout, whitefish), Siluriformes (catfish), Pleuronectiformes (flounder, halibut, sole, flatfish), Perciformes (bass, perch, snapper, tuna, mackerel, tilapia, swordfish), Gadiformes (codfish, pollock), and Clupeiformes (herring, sardines, anchovies).¹⁴¹ Table 73-4 describes the taxonomic relationships among edible fish species.

TABLE 73-4 Taxonomic Relationships Among the Edible Fishes

From Myers P, Espinosa R, Parr CS, et al: The animal diversity web, 2008. http://www.animaldiversity.org.

Shellfish can be broken down into two distinct phyla. Crustacea, which include shrimp, prawns, crab, lobster, barnacles, krill, and crayfish, are classified as arthropods, sharing the Arthropoda phylum with spiders, centipedes, and insects. The Mollusca phylum includes eight classes, three of which are important for human consumption: Gastropoda (snails, abalone), Bivalvia (mussels, oysters, scallops, clams), and Cephalopoda (squid, octopus, cuttlefish).^141,195

Sea cucumbers and sea urchins and their products, including uni, or sea urchin coral, and roe, or sea urchin ovaries, comprise a very small category of marine organisms consumed by humans. Sea urchins and sea cucumbers belong to the phylum Echinodermata, with sea urchins belonging to the class Echinoidea, and sea cucumbers belonging to the class Holothuroidea.¹⁴¹

Immunologic Mechanisms

Although nonimmunologic reactions to fish and shellfish occur, true seafood allergies are immunoglobulin E (IgE)–mediated reactions that represent a failure of the body’s oral tolerance mechanisms. Oral tolerance can be defined as “an active non-response to antigens delivered via the oral route.”¹²⁴ It involves both prevention of uptake of allergenic proteins from the gut into the bloodstream and suppression of the immune system’s allergenic response to such proteins that enter the system.

Under physiologic conditions, luminal barriers within the gastrointestinal (GI) tract prevent the uptake of the majority of potential food allergens that enter the gut. Potentially allergenic proteins are degraded into nonimmunogenic forms by gastric acid and digestive enzymes, whereas IgA antibodies secreted by B cells in the gut bind foreign proteins and prevent their uptake. However, even under physiologic conditions, approximately 2% of ingested proteins cross the protective epithelium of the GI tract intact and are absorbed into the bloodstream as immunologically active antigens.^81,208 Usually these antigens do not elicit allergic reactions because of the body’s innate mechanisms that suppress the immune response to food allergens. This process of immune suppression begins when an intact antigen escapes the protective barriers of the gut and is then taken up and presented by antigen-presenting cells (APCs), including B cells, dendritic cells, and macrophages. APCs then activate regulatory and suppressor T cells, which secrete the suppressive cytokines, transforming growth factor β (TGF-β) and interleukin (IL)-10. Through this series of steps, a state of oral tolerance is achieved whereby the immune system essentially “ignores” the food antigen. In the case of high-dose oral antigen exposure, tolerance is mediated by a different mechanism, specifically, lymphocyte clonal anergy and/or deletion.^25,32

When oral tolerance mechanisms fail to inhibit the body’s immune response to ingested food antigens, food allergies can develop. True seafood allergies are type I immediate hypersensitivity IgE-mediated reactions that result from a chain of molecular and cellular interactions involving APCs, T cells, and B cells (Figure 73-1). Production of allergen-specific IgE (sensitization) antibodies forms the underlying basis of immediate hypersensitivity; atopy is defined as the genetic predisposition to developing allergen-specific IgE antibodies. The sensitization process requires a cooperative effort between CD4 T lymphocytes and B lymphocytes. It begins with presentation of an allergen to CD4 T lymphocytes by APCs in the context of a major histocompatibility complex. Cytokines released from CD4 T lymphocytes as a result of this interaction cause differentiation of B lymphocytes into immunoglobulin-secreting plasma cells. This differentiation leads to isotype switching (production of specific antibody types) within the plasma cells. For example, release of cytokines IL-4 or IL-13 from T lymphocytes promotes IgE switching.⁴⁹ Once allergen-specific IgE antibodies are produced, subsequent exposure and binding of the allergens to IgE molecules on the surface of mast cells results in cross-linking of the IgE molecules. Consequently, mast cells or basophils degranulate and release preformed and newly synthesized mediators. The prototype preformed mediator is histamine, and the newly synthesized mediators include those of the arachidonic acid pathway (leukotrienes, prostaglandins, and platelet-activating factor), neuropeptides (e.g., substance P), and cytokines (e.g., IL-4, IL-5).

FIGURE 73-1 The natural history of IgE-mediated allergic reaction (a simplified schematic). During Phase 1, the individual becomes sensitized to an allergen. During Phase 2, clinical disease develops. An overwhelming majority of individuals have an early response on reexposure to the allergen. The activation of mast cells and release of mediators dominate the early response. After the early response, most individuals have an influx of inflammatory cells, causing late inflammatory events, including spontaneous recurrence of release of mediators (late-phase reaction) and increased responsiveness to the allergen on reexposure (priming). Circles indicate the heterogeneity of these late inflammatory events.

(Modified from Naclerio R: Allergic rhinitis, N Engl J Med 325:860, 1991.)

The release of chemical mediators has various pathologic consequences that can cause both local and systemic clinical manifestations. Histamine causes vasodilation and increased vascular permeability, smooth muscle contraction, stimulation of sensory nerve endings, and glandular secretions, with clinical effects including nasal congestion, rhinorrhea, urticaria, angioedema, laryngospasm, cough, wheezing, and shock. Products of the arachidonic acid pathway have similar effects.

It is now known that allergic reactions consist of an early phase characterized by mast cell or basophil degranulation, and a late phase, which occurs 4 to 6 hours after the early phase. The hallmark of the late-phase reaction is an influx of inflammatory cells, such as eosinophils, basophils, and T lymphocytes.¹⁵ For example, basophils cause further histamine release, and T lymphocytes release additional cytokines that enhance IgE production (via IL-4) and eosinophil activation (via IL-5). As a result of further inflammatory activity by these cells, there is recrudescence of symptoms many hours after the initial allergen exposure. Leukotrienes, prostaglandins, and cytokines released in the early-phase reaction play an important role in recruiting the late-phase cellular components to the inflammatory site.

In theory, prior exposure and sensitization to a food allergen must occur before development of a clinically significant allergic reaction. The exposure may occur through cutaneous or inhalational routes, cross-sensitization via similar antigens, placental transfer, or as a result of hidden ingredients or contaminants in other foods. Risk factors for the development of food allergies include early age of antigen exposure, family history of atopy, presence of asthma or other atopic disease, and medications (e.g., antacids) or medical conditions that reduce the acidity of the gut and allow more potential allergens to escape the natural protective barriers of the GI tract.^25,201 In one study, more than half of patients with food allergy had concomitant allergic rhinitis, asthma, and/or atopic dermatitis.¹⁹⁷ In another study, codfish-allergic individuals were orally challenged with fish digested with gastric enzymes at pH 2.0 and 3.0. Subjects experienced allergic symptoms sooner or at a lower dose when the codfish was predigested at pH 3.0 compared to pH 2.0, underscoring the role of gastric digestion in the process of food allergen tolerance.²⁰¹

Clinical Manifestations

Clinical manifestations of fish and shellfish allergies are similar to other IgE-mediated food allergy reactions, ranging from mild urticaria to life-threatening anaphylaxis. In the U.S. telephone survey discussed earlier, 55% of finfish reactions and 40% of shellfish reactions were severe enough that evaluation by a physician was sought.¹⁸⁴ IgE-mediated reactions are generally rapid in onset, with allergic symptoms developing within minutes to an hour of exposure and most reactions occurring within 30 minutes.^{1,27,28,46,74} However, delayed onset of symptoms may occur (3 to 24 hours after exposure) and have been noted with, among other seafood, dogfish,^136,168 cuttlefish,¹⁸¹ abalone,¹¹⁹ and limpets.¹³⁶ In 25% to 30% of cases, a biphasic reaction occurs whereby the patient will appear to recover and then experience a late-phase reaction with a recrudescence of symptoms after an asymptomatic period of 1 to 72 hours.^99,176

Symptoms of seafood allergy are often, but not always, related to the method of exposure and can occur after ingestion, cutaneous contact, and inhalation. Following ingestion of an offending seafood, the most commonly reported signs and symptoms include: generalized itching and urticaria; angioedema—particularly swelling of the lips and tongue; pulmonary manifestations including dyspnea, wheezing, and chest tightness; gastrointestinal complaints such as nausea, vomiting, diarrhea, and abdominal cramping; and shock.^101,184 It is the direct contact of the allergenic food with the oral mucosa that causes pruritus and angioedema of the lips, tongue, throat, and palate—a constellation of symptoms known as oral allergy syndrome (OAS).^36,53 In patients with underlying atopic disease, exposure to fish and shellfish allergens can cause exacerbations of eczema¹⁷³ and, less commonly, asthma symptoms.⁸⁵ Because ongoing exposure to a food allergen may cause chronic urticaria, the presence of an undiagnosed food allergy should be sought in patients with chronic urticaria.⁵³

In general, ingestion of the allergic seafood leads to gastrointestinal symptoms, urticaria, and possible vascular compromise, whereas skin contact results in mainly dermatologic symptoms, and inhalational exposure typically causes respiratory symptoms. For example, there are documented cases of patients allergic to fish presenting with skin reactions after handling raw fish^138,162 as well as symptoms of asthma in fish-allergic children after inhalation of aerosolized fish.¹⁶⁶ However, this is by no means the rule, and systemic reactions after cutaneous and inhalational exposure may occur. In one case study, a 2-year-old fish-allergic child experienced facial urticaria and angioedema after her grandfather, who had eaten fish 2 hours earlier, kissed her.¹³² In another report, a shellfish-allergic patient experienced anaphylaxis after kissing her boyfriend who had recently ingested shrimp.¹⁸⁹ In one survey, in 8.6% of fish and 10% of shellfish allergic individuals, more severe reactions occurred following inhalational or dermal exposure rather than ingestion. These allergic individuals were able to consume the offending antigen without significant sequelae.¹⁸⁴

Vascular involvement is not uncommon in patients with seafood allergies. In one review of patients with seafood allergies, 8% of subjects with fish allergy and 13% of subjects with shrimp allergy developed anaphylactic shock after seafood challenge.¹⁰¹ Manifestations of vascular involvement may include hypotension, a subjective “sense of doom,” respiratory distress progressing to asphyxia, dysrhythmias, and myocardial infarction. Near-fatal and fatal reactions may start with only mild symptoms, such as OAS, before rapidly progressing to cardiovascular collapse. Risk factors for severe anaphylactic reactions are the presence of other atopic disease(s), inadvertent ingestion of the offending food, rapid onset of symptoms, failure to promptly treat with epinephrine, and history of prior anaphylaxis to the causative food.⁵³

One form of anaphylaxis that occurs in the setting of seafood allergy is food-associated, exercise-induced anaphylaxis. Affected patients develop anaphylaxis if they exercise within 2 to 6 hours of ingesting an allergic food, but remain asymptomatic if the same food is ingested without exercise. Although the mechanism is poorly understood, shellfish and wheat flour are the most common causes of food-associated, exercise-induced anaphylaxis.^17,216 Shrimp and mollusks are among the most commonly implicated seafoods.^90,123

Occupational Seafood Allergy

Just as is the case on the consumer side, hypersensitivity reactions secondary to occupational exposure to fish and shellfish in the seafood processing industry are increasingly recognized. Rather than ingestion, most reactions are associated with direct contact or inhalational exposure during cutting, cleaning, cooking, or drying of seafood.¹⁰⁰ Occupational reactions have been reported in a variety of seafood workers, including fishermen, seafood processing workers, canners, restaurant cooks, delivery persons, and other workers associated with the seafood industry.^{29,30,50,105,179} Occupational seafood allergy can manifest as rhinitis, conjunctivitis, asthma, urticaria, contact dermatitis, or OAS.^3,87 Studies performed on snow crab workers demonstrated a 33% incidence of asthma, 24% incidence of skin rash, and 18% rate of rhinitis or conjunctivitis related to inhalational exposure or skin contact with snow crab meat or by-products.²⁹ In a survey of occupational allergies in seafood workers in Australia and South Africa, skin reactions accounted for 78% to 81% of reported problems, followed by asthmatic symptoms (7% to 10%) and nonspecific allergic symptoms (9% to 15%).¹¹⁷ Although rare, vascular involvement related to occupational seafood exposure has been reported.¹⁷⁹

In most studies, occupational asthma appears to be the most prominent clinical presentation of seafood allergy, with a reported prevalence of 7% to 36%.⁸⁷ Seafood implicated in occupational asthma include all the major seafood groupings: oysters,¹⁴³ clams,⁵⁰ shrimp,^50,105 prawns,⁶² fish,^42,52 snow and king crabs,^29,155 lobsters,^105,159 sea squirts,⁹¹ abalone,³⁹ powdered marine sponges,¹⁴ cuttlefish,¹⁹⁸ and clam liver extract.⁹³ In one case study, shark cartilage powder caused a fatal occupational asthma attack.¹⁵⁸ Hypersensitivity pneumonitis may also result from occupational exposure to seafood allergens and has been documented secondary to mollusk shell dust inhalation.^156,157 Clinical manifestations of hypersensitivity pneumonitis include dyspnea, fever, chills, cough, and malaise. With chronic low-level allergen exposure, fever and chills may be absent, with symptoms of exertional dyspnea, fatigue, and weight loss predominating.¹⁰⁴

Dermatologic occupational seafood allergy has been less well studied but generally takes the forms of contact urticaria and a chronic recurrent dermatitis known as protein contact dermatitis (PCD).^3,78,140 The estimated prevalence of occupational PCD ranges from 3% to 11%.⁸⁷ The most frequent clinical presentation is chronic or recurrent eczema that may be limited to the fingertips or extend to the wrists and arms. Initial manifestations include itchy, erythematous, and vesicular lesions, which usually progress to chronic eczema, with episodic acute exacerbations after repeated contact with the culprit allergen.^3,78 Some cases of chronic paronychia (after handling the allergic food) may also be a variant of PCD, with redness and swelling of the proximal nail fold.²⁰⁰ In some cases, percutaneous sensitization to seafood allergens may occur via direct skin contact in the workplace, as may occur with seafood packers or delivery persons. If ongoing exposure occurs, the individual may develop allergic symptoms and even anaphylaxis following ingestion of the offending seafood.¹⁷⁹ Risk factors for sensitization and development of clinical allergy in seafood workers include the presence of atopy, as well as duration and intensity of exposure to the potential allergen.^92,186

Differential Diagnosis

Diagnosing a seafood allergy can range from simple to extremely complex. There are a number of hidden allergens in foods, as well as seafood allergy mimics (such as seafood toxins and allergens present in seafood parasites), that can easily go unrecognized. When evaluating a patient with a suspected seafood allergy or a patient with an apparent allergic reaction to an unknown allergen, it is important to obtain a careful history and consider a broad differential diagnosis.

Many non-seafood products contain fish and shellfish, often unbeknownst to the consumer. For example, imitation crab meat is usually made of pollock or monkfish. Surimi, which is processed fish meat usually derived from Alaskan pollock in the United States, is commonly used for seafood-flavored snacks, sauces, flavors, “meatless” hot dogs, sausages, pepperoni sticks, imitation crab, and pizza toppings.²¹⁰ Anchovies are a routine ingredient in Caesar salad dressing and Worcestershire sauce. Many pills and medications contain chitin, a component of the outer skeleton of crustacea and other arthropods. Additionally, many products, although not purposefully containing seafood products, may be contaminated with seafood because they are processed in a facility that also handles seafood. Although the allergenic potential of some of these products has not been well studied, it is important to consider them as a potential allergenic source in patients presenting with allergic symptoms. A thorough history may help to identify these accidental ingestions, especially in patients with a known seafood allergy who present with an allergic reaction of unknown etiology.

Apparent seafood allergies can also be due to seafood parasites, rather than to the particular fish or shellfish that is consumed. The parasite Anisakis simplex, for example, is gaining increasing recognition as a cause of allergic reactions in individuals after consuming parasitized seafood.^9,10,94 A. simplex is a nematode that infects fish worldwide and can cause health issues in humans, either via transient infection after consuming raw or undercooked flesh of infected fish or via Anisakis allergy. The allergic reaction is a typical IgE-mediated reaction, presenting as acute urticaria, angioedema, or anaphylaxis following ingestion of infected fish.¹⁰ To date, nine different Anisakis allergens have been characterized.¹¹⁸ One of the responsible allergens, Ani s 3, is the invertebrate pan-allergen, tropomyosin, which is capable of cross-reacting with shellfish tropomyosins, adding to the diagnostic dilemma when faced with a patient with a potential seafood allergy.^{8,10,68,122,209} In one study, Anisakis allergy was demonstrated in 23 individuals who experienced allergic reactions following ingestion of seafood. All of the subjects had negative skin tests to the actual seafood consumed, and all of them demonstrated sensitization to Anisakis by either positive skin-prick test (SPT) or serum-specific IgE.¹³³ In another study of patients with a history of food allergy, Kimura and colleagues found IgE-reactivity against A. simplex to be higher than that against any specific fish tested, suggesting that sensitization to Anisakis allergen is more common than sensitization to any fish allergens.⁹⁶

Evidence also suggests that Anisakis allergy contributes to occupational respiratory and skin allergies in seafood workers. Armentia and colleagues found A. simplex to be the cause of occupational asthma in two seafood workers by in vitro and in vivo studies.⁴ In a case report by Scala and co-workers, Anisakis was found to be the allergen responsible for contact urticaria and inhalational asthma in a seafood factory worker.¹⁷⁸ In one study looking at the prevalence of Anisakis sensitization and related symptoms in fish-processing factories, the prevalence of sensitization to Anisakis was found to be higher than that for the fish being processed and was associated with a higher risk of allergic reactions.¹⁴⁸ These findings underscore the importance of considering Anisakis allergy in patients presenting with first-time allergic symptoms following consumption of seafood, especially if that seafood has been tolerated in the past. Unfortunately, studies suggest that ingestion of frozen or cooked seafood, which is recommended for anisakiasis prophylaxis, does not prevent IgE-mediated allergic reactions to Anisakis. Given the prevalence of parasitism of fish and shellfish by Anisakis, for patients diagnosed with Anisakis allergy, a seafood-free diet is recommended.¹³³

A common mimicker of IgE-mediated seafood allergy is scombroid poisoning (see Chapter 72). Scombroid intoxication results from the ingestion of some dark-meat fish (tuna, salmon, marlin, mahi-mahi, bluefish, mackerel, and others) that contain high levels of free histamine produced by bacteria in the fish flesh during spoilage.³¹ Usually within 10 to 30 minutes of ingestion, the histamine produces symptoms that mimic IgE-mediated allergy, including perioral tingling and burning sensations, flushing, urticaria, gastrointestinal complaints, and possibly progressing to bronchospasm, tachycardia, and hypotension. Symptoms that suggest scombroid intoxication include headache, dizziness, perioral tingling and burning, as well as a history of consuming fish that tasted peppery or bitter.³¹

Other types of seafood poisoning (ciguatoxin, diarrheic shellfish poisoning, and others) may result in a variety of physical complaints, but these are usually clinically distinct from IgE-mediated allergic reactions. Similarly, seafood-associated illness may occur secondary to bacterial and viral etiologies, such as poisoning due to toxins (botulism, Staphylococcus) or gastroenteritis from bacterial or viral infection.³¹ These illnesses also tend to be clinically distinct from IgE-mediated reactions.

Diagnosis

A critical step in diagnosing seafood allergy, or any other food allergy, is obtaining a thorough and accurate history, including specific symptoms, food(s) ingested around the time of symptom onset, timing of the reaction, prior history of similar reactions, presence of known food allergies, and any exacerbating factors such as exercise. Patients should also be questioned about possible contaminants or hidden allergenic ingredients in ingested food(s), particularly if the inciting allergen is unknown. Although taking a good history is of utmost importance, research suggests that medical history alone is insufficient in diagnosing food allergy. In one study of children with a self-reported food allergy, the allergic reaction was reproducible in only 40% by double-blind, placebo-controlled food challenge.¹⁹

In patients with suspected seafood allergy, SPTs are a relatively safe, inexpensive, and useful screening tool. Commercial extracts are not available for every seafood species; therefore, mixed extracts are often used. Additionally, actual raw or cooked food itself can be used for skin testing. SPT may be contraindicated in patients with a history of severe anaphylactic reaction to the seafood being tested or in patients with significant skin disease. Given the fact that SPTs measure sensitization to a particular allergen, and sensitization is not equivalent to allergic disease, caution must be taken in interpreting SPT results. Multiple studies comparing SPTs with double-blind, placebo-controlled food challenges have found that a positive SPT does not always correlate with symptomatic fish allergy.^18,19,73 Thus, SPTs have a high sensitivity and excellent negative predictive value, but a low specificity and poor positive predictive value.⁵³ Specifically, patients with positive results on SPT may not necessarily have clinically significant allergic disease. However, a study using mean wheal diameters to predict positive food challenges with shrimp suggested that skin testing for seafood allergy may not be as problematic as was once thought.⁸⁹ A mean wheal diameter of 30 mm (1.2 inches) after SPT provided an 80% and 95% predictive probability for positive food challenge in subjects with allergies to black tiger prawn and giant freshwater prawn, respectively. This study suggested that the predictive probability of SPT can be helpful in cases where food challenge cannot be performed.⁸⁹

In vitro diagnostic methods, such as measurement of serum food-specific IgE by radioallergosorbent test, such as the Pharmacia CAP-RAST FEIA, can also be useful screening tools, particularly for patients in whom skin testing is contraindicated. RAST testing is fraught with the same diagnostic dilemmas as is skin testing, in that in vitro reactivity, like cutaneous sensitization, does not necessarily correlate with clinical allergy.¹³¹ Thus, many patients with positive RAST testing may not have allergic disease when exposed to the allergen in question.^18,73 Studies by Sampson and colleagues, however, suggest that quantitative measurement of food-specific IgE antibodies may be a useful predictive tool in identifying patients with clinical reactivity.^174,175 In one study, the CAP System FEIA was used to establish diagnostic levels of IgE—called “decision points”—that could predict clinical reactivity with greater than 95% certainty to a variety of allergic foods, including fish, egg, peanut, and milk. Diagnostic IgE levels were identified at 20 kU (A)/L or greater for fish allergy.¹⁷⁵ The predictive value of using diagnostic IgE levels to substantiate clinical reactivity was confirmed in a prospective study in which greater than 95% of clinical food allergies, including fish allergy, were correctly identified using quantitative serum food-specific IgE concentrations.¹⁷⁴ These findings suggest that the CAP-RAST FEIA may be a safe alternative to oral challenge in patients suspected of having IgE-mediated food allergy. Of note, the diagnostic levels of IgE for predicting crustacean allergy have not yet been determined.

Atopy patch tests (APTs) have also been evaluated as useful tools in the diagnosis of food allergy. In the classic patch test, the suspected allergen is applied to a piece of cloth or paper, which is then placed on intact skin and covered with an impermeable barrier for 24 to 48 hours. The patch is then removed and the skin examined.¹⁰⁴ However, recent studies have found that APTs add little predictive value to the standard SPT and IgE measurements in the diagnostic workup of suspected food allergies and thus cannot be routinely recommended.¹²⁶

The gold standard test in verifying a particular food allergen is the double-blind, placebo-controlled food challenge (DBPCFC).²¹ This should not be performed in persons who have experienced life-threatening reactions and should be undertaken only under close physician supervision. Dried or freeze-dried foods are encapsulated in opaque, dye-free capsules; alternatively, the food of interest can be hidden in a food vehicle. Appropriate identical placebo-controls are prepared. Although such testing is time consuming and labor intensive, it permits precise diagnosis.

When a certain type of seafood is suspected of producing symptoms, a diagnostic elimination diet can support the diagnosis. Once the offending allergen is eliminated from the diet, the allergic reactions should not occur. The food is then reintroduced to determine if the allergic reaction is reelicited. Diagnostic elimination diets should only be used in persons who have experienced mild allergic symptoms.

Although the methods described previously are useful in diagnosing food allergies, diagnosis of occupational allergies often requires a different approach, especially in the case of occupational asthma due to inhalation of a seafood allergen. If the allergic individual notes the onset of asthma symptoms related to work exposure, and there is improvement during weekends or vacation, occupational asthma should be suspected. Asthma is verified by appropriate pulmonary function tests, such as spirometry with and without bronchodilators. If the history of asthma is suspected but not corroborated by physical examination or spirometry, it may be necessary to perform a provocation test with inhaled methacholine or histamine to document airway hyperreactivity. The diagnosis depends ultimately on the provocation of symptoms by a bronchial inhalation challenge with the suspected allergen to simulate industrial exposure.¹⁰⁴ Such evaluation can be performed at the workplace or in a controlled laboratory environment. If a workplace challenge is performed, the subject’s lung function is monitored during the workday with the idea that lung function will decline during the work period because of workplace exposure to the offending allergen. Laboratory challenge is the diagnostic method of choice for diagnosis of occupational asthma, as it allows for identification of a specific etiologic agent (unlike a workplace challenge, where many different allergens may confound the test).¹⁰⁴ Because of inherent dangers of exposing an allergic individual to high doses of allergen, laboratory challenge should occur under close observation in a hospital setting.

Occupational allergic contact dermatitis may also require a specialized approach. Approximately 90% of occupational dermatitis involves the hands, usually the palm and back of the wrist¹⁰⁴; therefore, dermatitis in a different distribution should raise doubt about the diagnosis. Additionally, location of the dermatitis and location of exposure to the allergen must be matched. Although routine atopy patch testing is not recommended as part of the diagnostic workup of food allergy, in the case of suspected occupational skin disease, patch testing may be useful in demonstrating allergic contact dermatitis to a suspected allergen.¹⁰⁴

Management

Treatment of acute allergic reaction due to seafood is the same as for any other allergic reaction and depends on the severity of the reaction and the specific symptoms. Treatment should begin with assessment and management of the ABCs. For only mild cutaneous reactions, antihistamines alone may be sufficient. In patients with severe reactions, epinephrine should be promptly administered either subcutaneously or, in refractory cases, intravenously. In addition to epinephrine, intravenous fluids and pressors should be used to manage hypotension. Respiratory symptoms, such as wheezing, can be treated with an aerosolized β₂-agonist. To decrease the risk of a delayed, or late-phase, reaction, glucocorticoids should also be given. Because of the risk of a recurrence of symptoms after initial recovery from the allergic event, patients should be observed for a period of several hours up to 24 hours, depending on the severity of the allergic reaction. If severe respiratory or cardiac compromise is present, the patient should be hospitalized.

Aftercare

All individuals at risk for anaphylaxis should carry a device for self-injection of epinephrine (e.g., EpiPen, Adrenaclick, Twinject) and should carry a medical information card or wear a medical information bracelet. Patients should be referred to an allergist for evaluation and testing to help determine the nature and extent of the seafood allergy.

Avoidance is the only treatment for seafood allergy. Because the allergens present in fish and shellfish are molecularly different (see Molecular Biology, later), patients with an allergy to fish generally do not need to avoid shellfish, and vice versa. Allergists generally recommend removing all edible fish from the diet when the patient has a demonstrated history of allergic reaction to any fish and/or if there is a positive skin test or RAST test to a fish extract. In patients with a history of severe anaphylactic reaction or allergic reactions to many types of seafood, avoidance of all fish and shellfish may be the safest strategy. However, in patients with a history of less severe allergic reaction to a particular seafood, research suggests that selective avoidance diets may be reasonable. Studies using double-blind, placebo-controlled fish challenges^18,73 and other tests⁴⁸ in fish-allergic children have shown that individuals are not uniformly sensitive to all fish species; hence, sensitivity to one species does not automatically warrant dietary elimination of all seafood. Studies of fish challenges are often negative in children with negative skin tests.¹⁸ Therefore, it seems reasonable to recommend dietary elimination of any seafood species for which there has been a demonstrated allergic reaction or a positive SPT or in vitro test. If a patient tests positive by SPT or in vitro testing to a particular seafood item, but has no history of clinical allergy to that seafood species, DBPCFC can be performed to determine whether true clinical allergy exists. Given the high negative predictive value of SPT, seafood species for which patients have no history of allergic reaction and have tested negative by SPT could be permitted in the diet after oral challenge. In the setting of a newly diagnosed seafood allergy to a particular fish or shellfish species, it is reasonable to allow patients to consume other seafood items that have not caused allergic symptoms before and that they have consumed previously.

Niggemann and colleagues have proposed an algorithmic approach to diagnosing food allergies, including seafood allergies (Figure 73-2).¹⁴⁹ In this algorithm, all patients with a suspected food allergy should undergo food-specific IgE or SPT. If negative, oral challenge can be conducted. If initial IgE or SPT is positive, previously established food-specific IgE or SPT “decision points” should be evaluated. If the patient’s quantitative IgE or SPT wheal diameter is above the previously established decision point, the food should be eliminated from the diet, but if it falls below the decision point, oral challenge can be conducted.¹⁴⁹

FIGURE 73-2 An algorithmic approach to diagnosing food allergies, including seafood allergies: proceeding from the suspicion of food-related symptoms to final recommendations on a specific elimination diet. *Diagnostic decision points appear to be population, age, and allergen dependent. SPT, Skin prick test.

(From Niggemann B, Beyer K: Diagnosis of food allergy in children: Toward a standardization of food challenge, J Pediatr Gastroenterol Nutr 45:400, 2007.)

Education is also crucial following an allergic reaction to seafood. Patients should be counseled to read all food labels for the possibility of hidden or unexpected allergenic ingredients as well as potential allergic contaminants. Since the passage of the United States Food Allergen Labeling and Consumer Protection Act of 2004, food labels have been required to clearly state the presence of eight specified food allergens, including fish and crustacean shellfish. Importantly, mollusks are not included in this labeling mandate.⁶¹ Patients should also be informed about the potential for allergic reaction after aerosolization of the offending allergen, such as may occur during cooking of seafood, either at home or in fish markets. Finally, patients should be cautioned about the potential for exposure to seafood allergens via inadvertent cross-contact, such as in restaurants where equipment is shared for seafood and nonseafood cooking, or during contact with contaminated saliva with kissing or utensil sharing.^132,189

Molecular Biology of Seafood Allergies

The major allergens responsible for IgE-mediated allergic reactions due to fish and shellfish are the parvalbumin and tropomyosin proteins, respectively.^{47,54,55,111,180} Since the original characterization of these allergens in codfish and shrimp models, researchers have continued to characterize these proteins and confirm their allergenicity in a wide variety of species of fish and shellfish, as well as identify new classes of proteins also implicated in the development of seafood allergies. Tables 73-5 and 73-6 list the allergens characterized in fish and shellfish to date.

Cross-Reactivity

Cross-reactivity may be defined as “the recognition of distinct antigens by the same IgE antibody, demonstrable by in vivo and in vitro tests, which clinically manifests as reactions caused by antigens that are homologous to different species.”²¹⁰ Individuals may also demonstrate sensitization by positive allergy testing to multiple species of fish and/or shellfish without demonstrating overt symptoms after consumption of that particular seafood, although the clinical significance of this observation is unclear. As discussed previously, the major allergens responsible for allergies due to fish and shellfish are parvalbumins and tropomyosins, respectively. It is the homology of the epitopes of these proteins across different types of seafood that is thought to produce cross-reactivity.

When looking at cross-reactivity within the class of bony fish, it is estimated that approximately 50% of individuals allergic to a particular fish species will be allergic to another fish species.¹⁹⁹ Among crustacea, cross-reactivity appears to be even higher, with approximately 75% of individuals allergic to a crustacean species being allergic to another type of crustacea, likely because of the greater degree of similarity among tropomyosins compared to parvalbumins.¹⁹⁹ Both clinical and serologic cross-reactivity among fish and shellfish have been well documented in the literature. However, some studies have produced conflicting results, suggesting that the mechanisms of cross-reactivity and the responsible allergens have not been completely elucidated. Furthermore, most studies have only looked at in vitro and serologic cross-reactivity, with few studies testing for actual clinical cross-reactivity.

Although some degree of cross-reactivity is common, species-specific allergies also occur and have been reported to sole, swordfish, tuna, and shrimp.^5,86,95,135 In studies on monospecific fish allergies, subjects with allergies to multiple fish species showed IgE binding to 12- to 13-kD bands (parvalbumins), whereas the monosensitive subjects showed IgE binding to unique bands at 40 kD in tuna,⁸⁶ 25 kD in swordfish,⁹⁵ and 6 to 7 kD and 40 kD in tropical sole.⁵ Such monospecific reactions are thought to be secondary to IgE antibodies to minor, species-specific antigens rather than to the major allergenic proteins, parvalbumins, and tropomyosins.

It is also noteworthy that because different antigens are responsible for causing allergic reactions to fish and shellfish, cross-reactivity between fish and shellfish does not occur. Allergy to both fish and shellfish in a single individual may occur, but it is not due to cross-reactivity. Nonetheless, in the American telephone survey previously discussed, it was estimated that 10% of individuals with a seafood allergy have an allergy to both fish and shellfish,¹⁸⁴ perhaps reflecting an atopic predisposition in this population.

Future Directions

The current standard of care for managing seafood allergies is avoidance diets and provision of a self-injectable epinephrine device. However, much research is underway to develop new strategies for treating and preventing seafood allergies. Some of the therapeutic modalities currently under investigation include sublingual and oral immunotherapy, anti-IgE therapy, peptide immunotherapy, traditional Chinese medicine, DNA immunization, and development of hypoallergenic seafood for human consumption.^26,56

Although traditional allergen-specific immunotherapy (SIT) was discovered nearly a century ago and has been used successfully in the treatment of peanut allergy, it is currently not recommended because of unacceptably high incidence of dangerous systemic allergic reactions during the treatment course.^147,154 Additionally, there appears to be a potential for developing hypersensitivity to cross-reacting food allergens, such as shrimp, as described in subjects undergoing house-dust mite immunotherapy.²⁰⁶ Given the high incidence of adverse reactions using traditional immunotherapy, alternatives are currently under investigation and promising new methods are being developed. For example, sublingual immunotherapy (SLIT), originally developed to treat allergic rhinoconjunctivitis and asthma, was used successfully and safely to treat hazelnut food allergy in hazelnut-allergic patients.⁵⁷ Along similar lines, studies looking at the efficacy of specific oral tolerance induction (SOTI) or oral immunotherapy (OIT) in inducing desensitization to food allergens have yielded some promising results, although the long-term effects of such therapy have not been rigorously investigated.^{23,26,125,150,160} In one study including patients with fish allergy, a standardized OIT protocol induced desensitization, as evidenced by conversion from skin test positive to skin test negative, following treatment in 78% of subjects who completed the OIT protocol.¹⁶⁰

Another promising modality currently in clinical trials is recombinant humanized monoclonal anti-IgE antibodies. These IgG antibodies directed against the IgE molecule bind to freely circulating IgE, creating antigen–antibody complexes that are then cleared from the circulation. Use of anti-IgE appears to decrease levels of circulating free IgE, inhibit early- and late-phase responses to allergens, suppress inflammation, and improve the control of allergic diseases.^56,128 Although not yet tested for use in seafood allergies, a recent clinical trial using anti-IgE in the treatment of peanut allergy found that a significant number of patients had a significant decrease in clinical symptoms in response to peanut challenge following treatment.¹⁰⁶

Peptide immunotherapy is another novel therapy currently under investigation that uses peptide fragments containing reactive epitopes rather than the complete protein allergen, with the idea that these peptide fragments are immunogenic but are theoretically unable to cross-link IgE molecules, activate mast cells, and cause clinical allergic symptoms.^22,26 Use of these peptide fragments for immunotherapy would thus render T cells unresponsive to subsequent allergen exposure without causing dangerous systemic allergic reactions during the course of therapy. Thus far, clinical studies using peptide immunotherapy for bee venom sensitivity and cat allergy have demonstrated promising results, with subjects experiencing a significant decrease in allergic symptoms after allergen exposure following therapy.^{22,139,151,153,194} Although peptide immunotherapy for food allergy has not yet reached clinical trials, studies underway using peanut allergen peptides suggest that peptide immunotherapy may have a future role in the treatment of food allergies, including seafood allergy.^65,79

Traditional Chinese medicine and the use of herbal remedies have recently gained attention as potential modalities for treating allergic diseases, including food allergies. In studies on peanut allergy using murine models, the Food Allergy Herbal Formula-1 (FAHF-1) and the simplified FAHF-2 significantly reduced IgE levels and blocked anaphylactic reactions to peanut for up to 5 weeks following therapy.^112,188 Although Chinese herbal remedies hold some promise, only studies with murine models have been conducted and the active ingredients and mechanism of action of these remedies remains to be delineated.

Another new approach in the treatment of food allergy is DNA immunization.¹⁸⁷ With this strategy, a plasmid DNA (pDNA) vector encoding a specific food allergenic protein would be injected subcutaneously or delivered orally. The pDNA sequence would then be taken up by APCs, the DNA would be transcribed and translated, and the allergenic protein would then be presented on the surface of the APC as an endogenously produced protein. This endogenous protein would induce a Th1 response (rather than Th2 as occurs in allergic disease) with suppression of allergen-specific IgE production, thus producing desensitization to the specific food allergen.^26,171 Although promising, allergen DNA immunization is likely years away from practical use.

Genetic alteration of epitopes on food allergens to suppress their allergenicity is also currently under investigation as a means of producing safer allergens for immunotherapy. Hypoallergenic foods could also be developed for consumption by individuals with food allergies. For example, studies on shrimp tropomyosin (Pen a 1) have demonstrated that substitution of critical amino acids in Pen a 1 epitopes results in significant reduction of IgE binding while still preserving immunogenicity.¹⁰² Such a mutated molecule could be used safely and effectively for immunotherapy without the risk of allergic reaction during treatment, or the mutant could be incorporated into the genome to create a hypoallergenic organism.¹⁰² A recombinant hypoallergenic carp parvalbumin mutant has been constructed that has 95% reduced IgE reactivity and diminished allergenicity as demonstrated by in vitro assays and in vivo SPT, but has preserved immunogenicity, making it a candidate for immunotherapy.¹⁹¹ Studies using genetic transformation technology to modify the allergic structure in shrimp are also underway,^36,164 with the eventual goal of producing nonallergenic transgenic seafood that is safe for consumption by individuals with seafood allergy.