Implications/Analysis of Family History

Other than the fact that his friend is unaware of any other family member presenting with similar conditions, we have no information regarding family history. A first time presentation in a 19-year-old, with no apparent family history, suggests that an inherited immune defect is unlikely (e.g., anaphylatoxins of the complement cascade). The absence of the medic-alert bracelet signifies that this is not a condition that has been previously diagnosed.

Implications/Analysis of Clinical History

Pale, cool, and clammy are the cardinal signs of impending shock and indicate that the patient is not perfusing the peripheral tissues with blood, hence pale and cool skin. A number of conditions can induce these symptoms, particularly blood loss during trauma, as the peripheral vasculature constricts to conserve remaining blood flow to the central key organs (e.g., brain/heart). However, even in the absence of severe blood loss, release of inflammatory mediators that induce vasodilatation and increase vascular (capillary) permeability can lead to a reduction in blood volume and cessation of blood flow to the periphery, with a concomitant drop in blood pressure (see Etiology). The low blood pressure triggers an increase in sympathetic nervous system activity and release of catecholamines from the adrenal medulla.

A number of nontrauma conditions can manifest in this manner. For example, patients experiencing septic shock as a result of gram-negative bacterial infection, dehydration, or heart damage may also present with similar symptoms. Josh’s illness, however, occurred suddenly while eating at an Italian restaurant, and this should steer us away from these causes. The acute presentation of Josh’s symptoms while eating is a strong indication that something this patient ate is most likely the precipitating factor. Ingested toxins (poisons) or a protein to which Josh had been previously sensitized are both in the realm of possibilities because these stimuli can induce the observed clinical “picture.”

Italian restaurants (and other exotic restaurants) are environments where nuts and shellfish are commonly on the menu. These are two of the most potent mediators of food allergies. Reaction depends on re-exposure of a previously sensitized individual, so your patient must have (at least once) eaten similar foods without a response (see Etiology). Drug or food allergies present like this more commonly than do toxins or poisons.

In addition to the signs of impending shock, Josh is wheezing and has poor air intake, suggesting the bronchi and bronchioles of the respiratory “tree” are constricting, which is consistent with an allergen-induced anaphylaxis.

Implications/Analysis of Laboratory Investigation

Up to this point, no laboratory tests have been requested, first, because we have been dealing with a life-threatening situation, and, second, because this is essentially a clinical diagnosis (made based on history and physical examination).

Additional Laboratory Tests

Pharmacologic Intervention

Long-Term Care

Many allergic reactions are inconvenient but not life threatening. Welts after insect bites (local histamine release to insect saliva) and orbital edema on exposure to cat/animal dander are two such examples (Fig. 14-1). Other allergies kill people! These life-threatening allergies include some food allergies (nuts/shellfish) and some allergies to insect stings (yellow jackets). Therefore, Josh should be advised to carry an epinephrine-containing pen (Epi-Pen) to deliver immediate epinephrine in the event of re-exposure, as well as diphenhydramine (Benadryl) (to be taken after epinephrine, as the patient is en route to the hospital). A medic-alert bracelet (in case a patient is ever unable to communicate significant medical history to caregivers) is essential.

FIGURE 14-1 Typical wheal and erythema of allergic urticaria in a patient with peanut allergy.

Note that it would be well to advise this person that allergies tend to generalize over time. For example, if Josh’s reaction was in response to peanuts (or peanut oil), he may, over time, be unable to tolerate any nuts. A shrimp allergy will often generalize to all shellfish (lobster, oysters, crab). The forewarning of this generalization may be merely the stomach cramps and diarrhea, but a patient may be unlucky and the only warning may be a full-blown systemic anaphylactic reaction carrying the risk of death.

Sensitization Phase

In the initial response to the allergen, IgE antibodies do not appear for at least 7 to 10 days after protein ingestion because of the length of time required for B cells to undergo antigen-induced differentiation and isotype switching to IgE. By this time, the allergen has long been removed from the system, so there is no antigen available to bind the newly generated IgE. Consequently, IgE antibodies bind to Fcε receptors present on mast cells and basophils (Fig. 14-2A). Although circulating IgE antibodies have a very short half-life, antibodies bound to mast cells can persist for months. Because these IgE antibodies are bound via their Fc regions, the antigen-binding sites are readily available to bind the allergen should it enter the system again. An absolute requirement for a type I hypersensitivity reaction is the localization of IgE antibodies on mast cells and basophils, and so the effector phase/clinical manifestation cannot occur in the absence of previous exposure to the allergen.

FIGURE 14-2 Sensitization (A) and effector (B) phases of type I hypersensitivity reactions. A, In the initial response to the allergen, IgE antibodies are generated, but by this time the allergen has long been removed from the system, so there is no antigen available to bind the newly generated IgE. Consequently, IgE antibodies bind to Fcε receptors present on mast cells and basophils. B, The effector phase is initiated when allergens (e.g., food allergen) enter the circulation and crosslink two IgE antibodies bound via their Fc regions to Fcε receptors on mast cells or basophils, which leads to the release of primary mediators and, subsequently, secondary mediators of inflammation.

(Modified with permission from Gorczynski R, Stanley J: Clinical Immunology. Austin, Landes, 1999.)

Effector Phase

In cases of food allergies, there is a breakdown in oral tolerance such that allergen-specific IgE antibodies are generated and bind to mast cells/basophils. The effector phase is initiated when allergens (e.g., food allergen) enter the circulation and crosslink two IgE antibodies bound via their Fc regions to Fcε receptors on mast cells or basophils (see Fig. 14-2B). When the allergen crosslinks the IgE antibodies on these cells, tyrosine kinases are activated and numerous proteins are phosphorylated, including phospholipase Cγ1 and Cγ2. It is thought that this phosphorylation event triggers phospholipase C activation because inositol phospholipids are degraded and calcium is released from intracellular stores. Following these signal transduction events, mast cells degranulate, causing the release of histamine, proteases, and chemotactic factors. Crosslinking of IgE on the surface of mast cells/basophils also leads to the activation of phospholipase A₂. In some cases, this manifests as allergic urticaria.

Mast Cell–Derived Inflammatory Mediators

Inflammatory products released from mast cell/ basophil granules are referred to as primary mediators (e.g., histamine). In addition to degranulation, crosslinking of IgE on the surface of mast cells/ basophils leads to the activation of phospholipase A₂ and release of arachidonic acid from membrane lipids. Different products are derived from arachidonic acid, depending on the enzyme that oxygenates this fatty acid. Thromboxane A₂ (TXA₂) and prostaglandin D₂ (PGD₂) are produced when cyclooxygenase acts on arachidonic acid, but the action of lipoxygenase on this fatty acid leads to the generation of leukotrienes (LTC4, LTD4, and LTE4). Inflammatory products that are generated in this manner are referred to as secondary mediators.

Histamine Release from Mast Cells and Basophils

For the most part, mast cell/basophil degranulation occurs in response to cross linking of IgE or following binding of the complement anaphylatoxins (C3a, C4a, C5a) to cognate receptors. However, some compounds can stimulate histamine release from mast cells/basophils directly (e.g., wasp venom, bradykinin, intravenous injection of morphine). Ingestion of scombroid fish (e.g., tuna) infected with bacteria that have a high histidine content can produce symptoms similar to those discussed previously. These bacteria decarboxylate histidine to form histamine, which is a major cause of the just-described clinical presentation.

Role of Histamine in Vasodilation

Irrespective of the trigger for histamine release, a series of inflammatory events ensue after binding of histamine to H1 or H2 receptors on smooth muscles and glands. (H3 receptors are expressed on histaminergic neurons; H4 receptors are present on peripheral blood cells, spleen, and thymus.) In the cardiovascular system, histamine binds to both H1 receptors on vascular endothelial cells and H2 receptors on vascular smooth muscle cells. Although both of these signals leads to vasodilatation of small blood vessels, the responses vary in a number of ways, including the duration of response, which is more sustained after binding to H2 receptors.

Role of Histamine in Increased Vascular Permeability

Histamine binding to H1 receptors on arterioles leads to vasodilatation, but binding to H1 receptors on postcapillary venules leads to contraction of the endothelial cells and a widening of the interendothelial spaces such that the basement membrane is exposed. Because the basement membrane is permeable to serum, this leads to an increase in vascular permeability and edema. Laryngeal edema may cause obstruction of the upper airways.

Role of Histamine in the Gut

Contraction of the gut is mediated via stimulation of H1 receptors. It should not be surprising, therefore, that food allergy will often present as nausea, stomach cramps, and diarrhea, because histamine release in the gastrointestinal tract stimulates smooth muscle H1 receptors to cause contractions in the intestinal wall. Other mediators are also released that (transiently) alter membrane fluid exchanges and cause the watery diarrhea. (Acid secretion by parietal cells in the stomach is mediated by H2 receptors.)

Role of Histamine in Bronchi

Histamine binding to H1 receptors on smooth muscle that surrounds the bronchi and bronchioles leads to bronchoconstriction and difficulty in breathing.

Role of Leukotrienes and Prostaglandins

Leukotrienes and prostaglandins (inflammatory mediators) bind to their respective receptors on smooth muscle cells. LTE4, LTD4, and LTC4 are potent bronchoconstrictors and induce mucus secretion when they bind to recCysLT1 (receptor). Their action on the vasculature leads to an increase in vascular permeability. Thromboxane A₂ (TXA₂) is a potent vasoconstrictor and mediates its effects after binding to TXA₂ receptors. PGD₂/receptor interaction leads to increased mucus secretion and bronchoconstriction. Pulmonary obstruction is accentuated by hypersecretion of mucus. Both the leukotrienes and PGD₂ are more potent bronchoconstrictors than histamine.