The Internal Medicine Casebook: Real Patients, Real Answers

Editors: Schrier, Robert W.

Title: Internal Medicine Casebook, The: Real Patients, Real Answers, 3rd Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Chapter 1 - Allergy and Clinical Immunology

Chapter 1

Allergy and Clinical Immunology

Stephen C. Dreskin

Henry N. Claman

Anaphylaxis

• What is the clinical presentation in a typical case of anaphylaxis?

• What is the underlying pathophysiologic process?

• What conditions should be considered in the differential diagnosis?

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Discussion

• What is the clinical presentation in a typical case of anaphylaxis?

  In the most severe cases, the clinical presentation consists of sudden hypotension with or without cutaneous signs, bronchospasm, or laryngeal obstruction. Patients occasionally report a sense of impending doom. This may occur within minutes of the ingestion of a specific food, injection of an antigen (e.g., an antibiotic), or an insect sting, and may be fatal. A less rapid onset can begin with urticaria, angioedema, shortness of breath, hoarseness, and moderate hypotension. If the offending substance has been ingested, there can be abdominal cramps, vomiting, and diarrhea. The diagnosis of anaphylaxis should be easily made if the symptoms described appear over the course of minutes up to an hour. The blood pressure need not drop that is, there can be anaphylaxis without shock.

• What is the underlying pathophysiologic process?

  Mast cells and basophils are activated when an antigen (e.g., penicillin) combines with the antigen-combining site of immunoglobulin E (IgE) antibodies that are bound to Fc RI, the high affinity receptor for IgE. Vasoactive mediators such as histamine, leukotriene C4 (LTC4), and prostaglandin D₂ (PGD₂) rapidly enter the circulation. In some circumstances, mast cells are activated by non-IgE mechanisms, such as may be triggered by radiocontrast dye injections or by nonsteroidal antiinflammatory drugs (NSAIDs); this is called an anaphylactoid reaction, but the basic physiologic characteristics and treatment are otherwise similar to those of IgE-mediated anaphylaxis.

• What conditions should be considered in the differential diagnosis?

  The differential diagnosis list is not long. Collapse due to septic shock, cardiac arrhythmia, or asystole must be considered. The most common source of error is failing to recognize vasovagal. In such a situation, the patient's pulse is slow and there is no urticaria, edema, or dyspnea. The pulse is always rapid in the setting of anaphylaxis unless the patient is taking a -adrenergic blocker or there is an underlying conduction defect. Patients with hyperventilation do not wheeze or have hypotension. However, determining the cause of the anaphylactic episode can be difficult because antecedent events are not always clear and some episodes will remain idiopathic.

Case

An 18-year-old woman is seen in a local Emergency department (ED) complaining of acute shortness of breath, swelling, and a pruritic rash. Three hours before her symptoms began, she had a stir fry containing tofu which she had never eaten before. Thirty minutes before her arrival in the ED, she was at the gym where she undertook her usual brief (1 minute) warm-up and began running. Within 10 minutes she felt flushed, itchy, and short of breath, and noted the sensation of an enlarging lump in her throat. Her boyfriend drove her to the ED where she was examined immediately. She reports that she has never experienced similar symptoms. She appears anxious and diaphoretic; her vital signs are remarkable for a respiratory rate of 32 per minute, a pulse rate of 108 per minute, and a blood pressure of 85/50 mm Hg. She is noted to be diffusely flushed,

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• What might be the cause or causes of her reaction?

• How should she be treated?

• What follow-up should be recommended?

Case Discussion

• What might be the cause or causes of her reaction?

  There are a number of factors that might have triggered this reaction. Although the list of potential causes of IgE-mediated anaphylaxis is long and continues to expand, agents that deserve special mention include venomous insect stings, foods, injection of allergy extracts (allergy shots), latex, and medications of any type but particularly antibiotics and heterologous proteins. Non IgE-mediated anaphylaxis is most often caused by radiocontrast media, opioids, NSAIDs, and physical stimuli such as exercise-induced and food-related anaphylaxis.

  IgE-mediated allergies to venoms or foods are common causes of anaphylaxis in all age-groups. In the absence of a known sting or injection of allergen, foods and medications should be immediately considered. The foods most commonly implicated in children are milk, eggs, and peanuts and in adults are peanuts, tree nuts, shellfish, and fin fish but virtually any food is a potential cause in a sensitized person. Typical reactions begin within minutes but may occur after several hours.

  Most cases of drug-induced anaphylaxis are IgE-mediated and are often due to penicillin antibiotics, although almost any drug can be etiologic. In the surgical setting, anaphylactic reactions are most often due to muscle relaxants and latex but can also be due to hypnotics, antibiotics, opioids, colloids, and other agents. Aspirin and NSAIDs are potent inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism, reportedly causing serious reactions in up to 10% of individuals with asthma and in 1% of the general population. In asthmatic patients, the reaction consists of severe bronchospasm; individuals who do not have asthma may have urticaria, angioedema, and anaphylaxis. Reactions to these drugs are usually not mediated by IgE. The mechanism responsible for causing them is poorly understood, but is possibly related to the inhibition of cyclooxygenase and the shifting of arachidonate metabolism to the lipoxygenase pathway. There are no immunologic tests that can detect this sensitivity, and challenge tests, which require the use of strict precautions, remain the only reliable method to identify aspirin- and NSAID-sensitive patients. However, as with any drug, IgE-mediated reactions can also occur.

  Exercise can cause a limited array of systemic reactions, particularly a type of urticaria (hives) called cholinergic urticaria, and rarely exercise-induced anaphylaxis. An unusual syndrome of exercise-induced and food-related anaphylaxis is not uncommon wherein the patient can eat a specific food and exercise without problems. But if the food is eaten within as many as several hours before exercise,

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  the patient will experience anaphylaxis. Systemic mastocytosis is a rare disease characterized by a gain of function mutation in the receptor for stem cell factor and a resultant overgrowth of mast cells. Typically, these patients have frequent manifestations of mast cell degranulation such as flushing and hives but can present with isolated anaphylaxis. Finally, a few patients have idiopathic anaphylaxis, that is, they have one or more episodes of anaphylaxis that remain unexplained after a thorough evaluation.

  In this particular case, there was no history of ingestion of a medication and no exposure to a venomous insect. However, many of the other diagnoses mentioned are possible explanations for the patient's episode and the true etiology may only become apparent over time. It is important to consider an allergic reaction to soy because tofu was ingested shortly before the anaphylactic episode, was a new food for her, and there is adequate opportunity to become sensitized to soy through a number of common foods. Of course a stir fry contains many foods in addition to the tofu and any of these are potential culprits. In the event that the results of all diagnostic evaluations are negative, this episode may indeed be idiopathic.

• How should she be treated?

  There is a generally accepted protocol for treating anaphylactic syndromes. Epinephrine is the mainstay of treatment in anaphylaxis; it acts by inhibiting mediator release from mast cells and basophils, relaxing bronchial smooth muscle, and bolstering blood pressure. Often, all of the signs and symptoms of anaphylaxis resolve completely within minutes of a single injection of epinephrine but the underlying pathophysiologic events persist and symptoms recur after the epinephrine is metabolized. As soon as the diagnosis of anaphylaxis is strongly entertained, starting dose of 0.3mL of a 1:1,000 solution of epinephrine should be given intramuscularly, preferably in the thigh, for an adult and 0.01 mg/kg for a child. If no untoward side effects occur, the patient may receive repeated doses every 10 minutes until the symptoms improve. Rarely, 1 to 2 mL of a 1:10,000 dilution of epinephrine is given by intravenous (IV) route but this should be avoided if possible because it may cause potentially fatal cardiac arrhythmias. In a patient whose primary site of involvement is the upper airway (such as the one described here), inhaled 2% racemic epinephrine is a valuable adjunct to parenteral therapy (at a dose of 0.5 mL). In addition, an H₁ antagonist (e.g., diphenhydramine, 50 mg) should be given slowly by the IV route. Recent evidence shows that the addition of an H₂ blocker, such as ranitidine 150 mg by slow IV infusion leads to more rapid resolution of acute allergic events. If the patient has severe airway obstruction at presentation (cyanosis) or the obstruction worsens despite the prompt use of epinephrine, endotracheal intubation should be performed promptly using a small-bore tube (no. 4 or 5). If this is not possible because of the degree of edema, cricothyrotomy should be performed. In the example given, semielective intubation was chosen by a skilled ED physician to avoid the complications associated with emergency intubation of patients with swelling of the airway. The patient was extubated after 8 hours without sequelae.

  Anaphylaxis in patients who are taking -adrenergic antagonists may be particularly difficult to treat. If wheezing does not respond to initial epinephrine or inhaled

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  -agonist therapy, glucagon should be administered. Patients with hypotension refractory to treatment with subcutaneous epinephrine, antihistamines, and parenter-al fluids may require parenteral dopamine, norepinephrine, and glucagon therapy.

  In patients who have significant symptoms affecting any target organ system, IV corticosteroids (Solu-Medrol, 1 mg/kg) should be given immediately, followed by an oral dose 6 hours later. Patients who have a prolonged clinical course should continue to receive corticosteroids every 6 hours.

  Initial therapy consisting of the interventions just described brings about complete and sustained relief of the signs and symptoms of anaphylaxis in 50% of patients. However, one fourth of the patients remain partially resistant to therapy for several hours and occasionally for several days (protracted anaphylaxis). The remaining 25% of the patients respond to initial therapy, but after a variable interval (up to 8 hours) without signs or symptoms, they experience recurrence of life-threatening complications (biphasic anaphylaxis). There is no reliable way to predict which patients will have such a relapse. Therefore, all patients with anaphylaxis should be observed by medical personnel for at least 8 hours after the onset of the episode.

• What follow-up should be recommended?

  All patients with a history of anaphylactic reaction, no matter what the cause, should be given preloaded syringes containing epinephrine for self-administration (e.g., EpiPen 0.3 mg or EpiPen Jr 0.15 mg Auto-injector, Dey Inc., Napa, California) and also diphenhydramine (25 mg capsules). Before they leave the ED, the patient and family members should be trained on how to administer the epinephrine and diphenhydramine and told to call 911 or proceed immediately to a nearby ED. Another important general measure to be implemented is the replacement of -blocking drugs with a suitable alternative medication if possible in those individuals who are at possible risk for further episodes of anaphylaxis.

  After acute treatment of the anaphylactic episode, the most likely cause of the reaction should be determined so that recommendations on future avoidance can be made. In the patient described here, food skin tests to all the ingredients in the meal preceding her reaction should be performed by an allergist/immunologist. Soy is particularly suspicious as a possible cause of her anaphylaxis. If the skin test results are positive to one or more foods, carefully monitored, graded, double-blinded, placebo-controlled (DBPC) food challenges can be performed to identify the etiologic agent. In the event that the food challenge results are negative, it is not necessary for the patient to avoid soy or any of the other implicated foods. In practice, most patients just avoid the suspect food or foods. This is suboptimal because there may be unnecessary changes in lifestyle and nutrition may be compromised. Patients with a history of food-induced anaphylaxis should always carry epinephrine and diphenhydramine (Benadryl) because of the possibility of inadvertent exposure. Patients with recurrent episodes of idiopathic anaphylaxis have been shown to benefit from daily administration of antihistamine and oral corticosteroid therapy. This type of therapy, however, is unwarranted in patients who have known avoidable causes of anaphylaxis.

  The patient described here had a positive skin test to celery and a negative test to soy. The most likely diagnosis in her case is exercise-induced and food-related

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  anaphylaxis. So, she was advised to avoid exercising for 6 hours after eating celery, to carry her epinephrine and diphenhydramine, to never exercise alone, and to never exercise in remote settings.

Suggested Readings

Canter LM. Anaphylactoid reactions to contrast media. Allergy Asthma Proc 2005;26:199.

Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol 2005;95:217.

Lieberman P. Anaphylaxis. Med Clin North Am 2006;90:77.

Sicherer SH, Sampson HA. Food allergy. J Allergy Clin Immunol 2006;117:S470.

Simons FE. Anaphylaxis, killer allergy: long-term management in the community. J Allergy Clin Immunol 2006;117:367.

Wiener ES, Bajaj L. Diagnosis and emergent management of anaphylaxis in children. Adv Pediatr 2005;52:195.

Angioedema

• What are the clinical pictures associated with angioedema?

• What pathophysiologic processes underlie angioedema?

• How is hereditary angioedema (HAE) diagnosed?

Discussion

• What are the clinical pictures associated with angioedema?

  Angioedema can present with several different clinical pictures. It can include an exaggerated form of urticaria, with itching and swelling of soft tissues that can arise anywhere in the body and appear within a few minutes or over the course of hours. Alternatively, it may involve the bronchial mucosa or the vocal cords, leading to airway obstruction. Other forms of angioedema do not include itching or urticaria. They may be local or may result from trauma. In these cases, the swollen tissues may hurt, but do not itch.

• What pathophysiologic processes underlie angioedema?

  In angioedema that coexists with urticaria, the underlying mechanism is the same as that in anaphylaxis the activation of mast cells with the release of mast cell mediators, such as histamine. In the setting of angioedema without urticaria, the mechanism may involve mast cells or may be the unbridled activation of the complement and kinin systems because of lack of a major complement control protein, C1 inhibitor(C1 INH).

• How is HAE diagnosed?

  The clinical clue to HAE is a history of repeated bouts of angioedema without urticaria arising anywhere in the body, such as the face, tongue, and extremities. The airway can be compromised. Some patients experience diffuse abdominal pain and may have had laparotomies at which only bowel edema is found. These lesions do not itch and may be painful. HAE is transmitted as an autosomal dominant trait. Nevertheless, the family history is negative

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  in 50% of the patients and these cases are either due to new mutations or mistaken paternity. The laboratory clues point to the complement system, with a deficiency of complement control proteins at fault.

Case

A 25-year-old woman presents to the ED with complaints of severe facial swelling resulting in difficulty swallowing beginning on the day after she had undergone an endoscopic procedure. She noted mild facial swelling on awakening in the morning. Throughout the ensuing day, the swelling has worsened to involve her left cheek, upper and lower lips, and tongue. Approximately 6 hours before coming to the ED, she noted she was becoming hoarse. She had undergone the endoscopy as part of an evaluation for intermittent abdominal pain. Previous investigations include a barium swallow and enema, and the results of both were negative. Since 19 years of age she has had abdominal pain, which she describes as crampy and occasionally associated with nausea, vomiting, or diarrhea. These symptoms usually resolve within 3 to 4 days with no specific medical intervention and are not associated with her menstrual periods. The symptoms began when she started using birth control pills. She has had one other episode of facial swelling 3 years before, after a tooth extraction (although it was much less intense and not associated with difficulty swallowing). The swelling resolved spontaneously after approximately 3 days. There is no family history of similar syndromes.

• What is the most likely diagnosis in this woman?

• What laboratory tests for complement are useful in making a diagnosis of HAE?

• How should an acute attack of HAE be treated?

• What prophylactic measures are available for HAE?

Case Discussion

• What is the most likely diagnosis in this woman?

  The most likely diagnosis is HAE. Although exposure to latex gloves can cause an allergic reaction that includes angioedema, a diagnosis of HAE is much more consistent with this patient's case history. Local anesthetics, like any medication, can cause angioedema but this is rare. HAE characteristically presents as a swelling of the submucosal and subcutaneous tissues. Although virtually any body part can be involved, usually the face and extremities are affected. Mucosal edema may occur. This can cause abdominal pain when the small bowel is affected, or a change in voice or even stridor when the larynx is affected. This patient had both of these symptoms. Urticaria is not a part of the HAE syndrome.

  The angioedema associated with HAE frequently occurs after local trauma (including dental procedures and endoscopy), illness, or emotional stress, but can also arise in the absence of a specific trigger. HAE episodes usually begin during childhood, but the onset can occur at virtually any age. Attacks vary greatly in intensity and frequency. Most patients experience self-limited facial or extremity swelling, but others can have life-threatening laryngeal edema. Attacks usually last for 1 to 4 days. They may increase in the premenstrual or postpartum periods. This

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  disease exhibits an autosomal dominant hereditary pattern, but the family history is negative in 50% of patients.

• What laboratory tests for complement are useful in making a diagnosis of HAE?

  A serum C4 level represents the best screen for this disease because it is low even when the patient is asymptomatic and is very low when the patient is experiencing swelling. Measurement of serum C1 INH is a laboratory test that can be performed to establish the diagnosis. HAE is caused by a decrease in the level and/or the function of C1 INH, which is the inhibitor of the activated first component of complement (C1 which contains a critical esterase activity called C1s) and is also an inhibitor of kallikrein, which generates bradykinin from kininogen. When the level of this inhibitor is low or absent, the early classic complement pathway is activated and various complement components are then used up faster than they can be synthesized. In addition, excess bradykinin, a very potent vasoactive peptide, is generated in excess. In 85% of patients, the level of the C1 INH protein is decreased, whereas in 15% of the patients the protein is present but dysfunctional. Therefore, in a subgroup of these patients the C1 INH level is normal and the nature of the disease cannot be detected unless the C1 INH function is assessed. Although we make the diagnosis by monitoring the complement system, the actual cause of the symptoms appears to be edema generated by the formation of bradykinin. Histamine release is not part of this condition.

• How should an acute attack of HAE be treated?

  Neither antihistamines nor corticosteroids have a role in the treatment of an acute attack of HAE, whereas they are effective in the treatment of allergic urticaria that includes angioedema. Because the medical treatment of HAE is not always effective, and if upper airway compromise is present or pending, stat otolaryngology and anesthesiology consultations should be obtained because a tracheostomy may be required to prevent airway closure. The only alternative to tracheostomy is nasotracheal intubation, which should be performed only in an operating room with a surgeon present in the event an emergent tracheostomy is required. Treatment with fresh frozen plasma is somewhat controversial because this substance provides further proteins that, when activated secondary to a decrease in C1 INH, might worsen the angioedema. Nevertheless, many physicians routinely administer two units of fresh frozen plasma. As mentioned earlier, these diseases can present as crampy abdominal pain, sometimes misinterpreted as an acute abdominal condition, but this disease can be differentiated from an acute abdominal condition by the lack of abdominal rigidity and fever and absence of an elevated white blood cell count with a leftward shift. This abdominal pain can be relieved by narcotics such as meperidine. Some experienced physicians treat the abdominal or extremity pain associated with these angioedema attacks (which, in general, are self-limited) using meperidine. They reserve fresh frozen plasma (which supplies C1 INH) and, of course, tracheostomy for threatened airway closure. Purified C1 INH and a bradykinin receptor antagonist may soon be available for treatment of acute attacks.

• What prophylactic measures are available for HAE?

  Chronic prophylaxis for this life-threatening disease is important. We use an attenuated androgen (such as danazol). These impeded androgenic steroids cause

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  an increase in synthesis of C1 INH. High doses bring about correction of both the C1 INH and C4 levels. Unfortunately, unacceptable side effects may arise at these doses, including weight gain, headaches, muscle cramping, menometrorrhagia, androgenic effects, and mild increases in the serum aspartate and alanine aminotransferase levels. HAE can usually be controlled with lower doses of these androgens, which do not entirely correct these laboratory abnormalities, but produce fewer side effects. Therefore, the androgen dose is adjusted to achieve symptomatic relief, not to correct the laboratory abnormalities. Androgens are not helpful in managing acute exacerbations of this disease, and neither corticosteroids nor antihistamines have a prophylactic effect.

  Women with HAE frequently note a worsening of their disease when they start taking birth control pills. This is possibly due to the antiandrogenic effect of the pills. Pregnant women with HAE, however, do well in late pregnancy and delivery.

Suggested Readings

Bracho FA. Hereditary angioedema. Curr Opin Hematol 2005;12:493.

Cicardi M, Zingale L, Zanicherlli A, etal. C1 inhibitor: molecular and clinical aspects. Springer Semin Immunopathol 2005;27:286.

Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol 2005;53:373.

Chronic Urticaria

• What is the definition of chronic urticaria?

• What is the pathogenesis of chronic urticaria?

Discussion

• What is the definition of chronic urticaria?

  Chronic urticaria is defined as urticaria that persists for 6 weeks or more.

• What is the pathogenesis of chronic urticaria?

  The pathogenesis of chronic urticaria includes a spectrum of events. Commonly, there is simple local edema and itching caused by the release of histamine from mast cells. Other more severe cases have an inflammatory component, such as vasculitis that is revealed by biopsy specimens. In these cases, the responsible mechanism may be either tumor necrosis factor -leased from activated mast cells, or antigen antibody complexes, which in turn activate the complement and lead to the production of anaphylatoxins. These substances trigger local mast cell activation, with subsequent itching, erythema, and wheal formation.

Case

A 25-year-old woman is seen because of a pruritic rash characterized by multiple, circumscribed, raised areas of erythema varying in size from 2 mm to 3 cm and occurring

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• What causes of urticaria should be considered in this woman?

• What diagnostic approach should be taken in this patient?

• What therapeutic approach is desirable?

• What is the prognosis in this patient if no specific allergen is identified?

Case Discussion

• What causes of urticaria should be considered in this woman?

  The most common cause of acute urticaria is an allergic reaction to a food or drug. By contrast, usually no external cause is found in 80% to 90% of the patients with chronic urticaria. As a group, these patients are not atopic; that is, the prevalence of eczema, allergic rhinitis, or asthma is not increased. The presence of dermatographism indicates a general increase in the sensitivity of the mast cells and blood vessels in the skin, but the cause of dermatographism is unknown. Nevertheless, it is important to take a careful history to uncover any underlying cause, if present. Almost any medication can cause urticaria. Birth control pills as well as over-the-counter preparations such as aspirin, vitamins, and cold tablets should be considered as possible culprits. Foods sometimes cause chronic urticaria and should be considered if indicated by the patient's history.

  Urticaria can also be associated with underlying systemic illnesses such as systemic lupus erythematosus, Sj gren's syndrome, rheumatoid arthritis, and hyperthyroidism or hypothyroidism. These patients often have elevated ESRs, and skin biopsy specimens may reveal the presence of true vasculitis with polymorphonuclear infiltrates and the deposition of immunoglobulins and complement. Infections are also rare causes of urticaria, including viral infections such as prodromal infectious hepatitis or infectious mononucleosis, as well as helminthic infections.

  Certainly, any symptoms or signs of infection should be pursued and treated; however, it is not worthwhile to do specific workups in pursuit of cryptic infections.

• What diagnostic approach should be taken in this patient?

  In diagnosing the cause of the urticaria in this patient, a good medical history and complete physical examination are important to exclude any underlying systemic disease. Some special tests may be done to investigate any clues revealed by the history. These might include food skin tests for a suspected food sensitivity or an

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  ice-cube test of the skin if cold urticaria is suspected. If no cause is apparent, any underlying systemic disease can be ruled out by a CBC, urinalysis, ESR, and blood chemistry profile. Antibodies to Fc RI have been described in up to 40%, defining a subgroup with autoimmune urticaria.

  If the presence of an elevated ESR suggests the possibility of vasculitis, the following tests should be considered: CH₅₀ (total hemolytic complement), C₃ (third component of complement), C₄ (fourth component of complement), skin biopsy with immunofluorescent staining, hepatitis B surface antigen and antibody (HBsAg and HBsAb), cryoglobulins, antinuclear antibody, and circulating immune complexes.

  In this patient, it is not unreasonable to obtain stool sample to test for ova and parasites because of her recent trip to Nepal.

  If none of these approaches is successful in revealing a cause, have the patient stop taking birth control pills for a month and observe the urticaria, untreated.

• What therapeutic approach is desirable?

  There is no known cure for urticaria unless the allergen is identified and eliminated. Otherwise, treatment is aimed at providing symptomatic relief. Type H₁ antihistamines such as diphenhydramine [Benadryl (Parke-Davis, Morris Plains, NJ)] or hydroxyzine [Atarax (Roerig, New York, NY)] are commonly used first. For longer-term treatment, four nonsedating antihistamines are available: fexofenadine [Allegra (Hoechst Marion Roussel, Kansas City, MO) and generic], loratadine [Claritin (Schering-Plough, Madison, NJ) and generic], cetirizine [Zyrtec (Pfizer, New York, NY)], and desloratadine/loratadine [Clarinex/Claritin (Schering-Plough, Madison, NJ)]. This form of treatment is based on the concept that mast cells release histamine, and histamine is the primary offender in urticaria.

  Combining H₁ and H₂ antihistamines has also been helpful in some patients. Short courses of corticosteroids may be used in severe, poorly controlled cases; however, the long-term use of steroids should be avoided, if possible, because of the severe side effects associated with these agents. Finally, some allergists may try out an elimination diet or a fast in severely affected patients to rule out a food or preservative allergy, even when no specific agent is suspected. Patients with severe disease may be treated with immunomodulatory drugs such as hydrochloroquin, sulphasalazine, or cyclosporin.

• What is the prognosis in this patient if no specific allergen is identified?

  Assuming that no cause has been found, and there is no autoimmune disease present, the prognosis is quite good. The signs and symptoms almost always-disappear within 2 years, but the reason for this is not known.

Suggested Readings

Baxi S, Dinakar C. Urticaria and angioedema. Immunol Allergy Clin North Am 2005;25:353.

Dibbern DA Jr. Urticaria: selected highlights and recent advances. Med Clin North Am 2006;90:187.

Varadarajulu S. Urticaria and angioedema. Controlling acute episodes, coping with chronic cases. Postgrad Med 2005;117:25.

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Monoclonal Gammopathy

• What is the definition of a monoclonal gammopathy?

• What clinical pictures are seen in patients with monoclonal gammopathies?

Discussion

• What is the definition of a monoclonal gammopathy?

  A monoclonal gammopathy is defined as the overproduction of a particular immunoglobulin protein by a single clone of overactive or malignant B cells. This clone can produce a whole immunoglobulin, composed of both heavy and light chains, or it can produce just heavy chains, just light chains, or a combination of whole immunoglobulin plus excess light chains. The monoclonal light chains are calledBence Jones protein.

• What clinical pictures are seen in patients with monoclonal gammopathies?

  Some monoclonal serum immunoglobulins are discovered incidentally. These are usually small (<2 g/dL) and there are no associated signs, symptoms, or laboratory abnormalities. Patients with plasma cell (multiple) myeloma usually present with back pain (vertebral fracture or compression), anemia, hypercalcemia, and often renal disease. The clinical picture of Waldenstrom's macroglobulinemia resembles that of a lymphoma, and consists of fever, lymphadenopathy, and sometimes hepatosplenomegaly. Hyperviscosity can be a component of this syndrome. Light chain disease can present as amyloidosis.

Case

A 62-year-old man is seen in the ED because of a right upper quadrant abdominal pain of 5 days' duration. The pain radiates around to his back and is worse with movement and coughing. He denies nausea, vomiting, or a change in his bowel habits but admits to having intermittent epigastric pain, frequent night sweats, a feeling of weakness, general malaise, and a 15-pound (6.75-kg) weight loss over the last year. His past medical history is remarkable for a back injury incurred from a motor vehicle accident 10 years before and the presence of mild hypertension. His physical examination findings are unremarkable, except for the following. His blood pressure is 150/110 mm Hg. He has a grade 2/6 systolic ejection murmur that can be heard along the left sternal border. Rectal examination reveals a 2+ prostate. His stool is heme negative. A slight kyphosis is noted and there is questionable decreased sensation to pinprick along the right lower rib cage (T9 distribution). A chest radiographic study, CBC, and chemistry panel are performed. The chest radiograph shows no infiltrates, but a compression fracture of undetermined age is noted at T9. His hemoglobin is 10 g/dL; hematocrit, 31%; and platelet count, 275,000. His chemistry panel shows serum creatinine, 2.2 mg/dL; blood urea nitrogen, 22 mg/dL; total protein, 10.2 mg/dL (normal, 6.8 to 8.4 mg/dL); albumin, 3.1 mg/dL (normal, 3.7 to 4.9 mg/dL); and calcium, 11.0 mg/dL (normal, 8.5 to 10.0 mg/dL). You conclude that his pain is most likely due to the T9 compression fracture. Because of concern about his renal insufficiency, you avoid prescribing NSAIDs but instead prescribe

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• If you were considering a diagnosis of a monoclonal gammopathy (which you should have), what screening test would you order?

• What further immunologic tests should be ordered?

• What further tests are important in this case?

• What is the immunologic capability of this patient who has excess gamma globulin?

• What is the current treatment for such a patient?

  While you are evaluating this patient, your colleague learns of your expertise in this field and asks you about a 61-year-old man with atopic dermatitis who had the incidental finding of a high protein-to-albumin ratio on a comprehensive chemistry panel. A screening (SPEP), has shown a monoclonal band, which has been identified as IgM k on immunofixation electrophoresis (IFE). The band was quantified at 2.0 g/dL.

• What course of action do you recommend in the 61-year-old patient?

• What is the diagnosis in the patient described in question 6, and what is the prognosis?

Case Discussion

• If you were considering a diagnosis of a monoclonal gammopathy (which you should have), what screening test would you order?

  The screening test that should be ordered in this patient is an SPEP, which shows a monoclonal spike in most cases. The clinical suspicion for myeloma should be high because he exhibits the classic triad of anemia, back pain, and renal insufficiency, which is associated with multiple myeloma. The most common presenting complaint is back pain. Multiple myeloma is the most common lymphoreticular neoplasm in nonwhite men and the third most common in whites. Its annual incidence is 3 in 100,000, and more than 90% of all affected patients are older than 40 years. Other factors that implicate multiple myeloma in this case are the elevated total serum protein content and the relatively decreased albumin level. These suggest that there is an increase in the globulin fraction.

• What further immunologic tests should be ordered?

  Further immunologic tests that should be done include an IFE, which can identify the heavy and light chains in the monoclonal protein. A urine electrophoresis can identify the spilling of light chains (Bence Jones protein) or, if the glomerulus is damaged, the presence of complete monoclonal protein.

• What further tests are important in this case?

  A skeletal survey is an important additional test to document the extent of bone disease. In this situation it is better than a bone scan. The skeletal survey should include the skull, complete spine (both anteroposterior and lateral views), the pelvis, and the chest. A computed tomographic scan of the abdomen would be useful only if a solitary extramedullary plasmacytoma is suspected.

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  A bone marrow aspiration is essential to confirm the diagnosis. In all but the rarest cases, clumps and sheets of plasma cells are seen.

  A serum calcium determination is needed because hypercalcemia can produce symptoms such as lethargy, nausea, and vomiting. Elevated values for -2 macro-globulin, C-reactive protein, and lactate dehydrogenase suggest a more dire prognosis.

• What is the immunologic capability of this patient who has excess gamma globulin?

  The immunologic capability in this patient is probably compromised, such that he is susceptible to high-grade bacterial pathogens. The excess immunoglobulin represented by the spike on SPEP is useless in fighting infection, and it is likely that he is severely depleted of normal polyclonal gamma globulins. In fact, these patients are functionally hypogammaglobulinemic. They are prone to infections with pyogenic organisms, and they do not produce adequate antibodies after prophylactic immunizations. They should be carefully watched for early signs of infection. Some physicians prescribe monthly IV gamma globulin.

• What is the current treatment for such a patient?

  Melphalan and prednisone constitute the chemotherapy most often used to treat myeloma. Bone marrow transplantation is being used more frequently. Thalidomide has also been shown to be effective.

• What course of action do you recommend in the 61-year-old patient?

  For the second patient, you recommend that a detailed examination be undertaken for lymphadenopathy, hepatosplenomegaly, anemia, hypercalcemia, lytic bone lesions, and Bence Jones protein. Everything returns normal. Since the monoclonal spike is IgM, a very large protein (850 kd) that predisposes to hyperviscosity, you recommend that the serum viscosity be determined. This too proves to be normal.

• What is the diagnosis in the patient described in question 6, and what is the prognosis?

  This is the clinical picture of monoclonal gammopathy of undetermined significance, which consists of a small monoclonal serum spike (generally less than 2.0 g/dL) without other signs, symptoms, or laboratory indications of myeloma or macroglobulinemia. The prognosis in these patients is unclear. Some patients progress to frank disease; others do not. The best plan is to observe the patient by performing a physical examination and screening SPEP every 6 to 12 months.

Suggested Readings

Hideshima T, Bergsagel PL, Kuehl WM, etal. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607 618.

Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351 (18):1860; [Erratum appears in N Engl J Med 2005;352(11):1163].

Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Bailliere's Best Pract Clin Haematol 2005;18:689.

Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol 2005;16:1223.

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Penicillin Allergy

• What are the clinical pictures that can result from an allergy to penicillin?

• What are the immunologic mechanisms responsible for the clinical syndromes associated with penicillin allergy?

Discussion

• What are the clinical pictures that can result from an allergy to penicillin?

  There are two categories of clinical pictures that can result from penicillin allergy: acute and subacute. Penicillin allergies can be mediated by IgE or IgG antibodies. The acute allergic reaction can arise immediately or rapidly, within a matter of minutes to an hour or two. It can include sudden anaphylaxis with hypotension, or asthma, rhinitis, and urticaria (see question 1 under the section on Anaphylaxis). Continued penicillin administration can cause continued symptoms. A less dramatic picture may occur 7 to 10 days after penicillin treatment starts, or 1 to 2 days after repeat therapy. In this setting, the picture is subacute and can include urticaria, fever, and arthralgias or arthritis, and rarely nephritis or neuritis.

• What are the immunologic mechanisms responsible for the clinical syndromes associated with penicillin allergy?

  Acute reactions result from penicillin reacting with preformed IgE to penicillin, a result of previous penicillin treatment that may have produced no visible allergic reaction. The IgE is bound to Fc RI on mast cells and basophils. When the penicillin hapten binds to the IgE, the mast cells and basophils degranulate, releasing histamine and other mediators. These substances are responsible for producing the signs and symptoms. The subacute reaction is caused by preformed IgG to penicillin, also a result of previous penicillin treatment. The IgG fixes complement. The combination of penicillin and the IgG antibody form an immune complex. When this is deposited in the tissue, complement is activated and the complement breakdown products produce inflammation. The inflammation is responsible for the signs and symptoms in the organs where the immune complexes lodge, such as the skin, joints, and kidneys.

Case

A 26-year-old woman who has mitral stenosis requires extensive dental surgery. Penicillin prophylaxis against streptococci is indicated, but the patient is allergic to penicillin. She states that 15 years ago she had hives and wheezing 30 minutes after she had taken oral penicillin.

• How would you determine whether the patient is likely to have an allergic reaction if she is treated with penicillin now?

• What do you do if the skin test result to penicillin is positive?

• What is the prevalence of allergic cross-sensitivity between penicillin and cephalosporins?

• If the patient's skin test result to penicillin proves to be negative, how certain is it that she is not allergic?

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• If the skin test result to penicillin is positive, could you avoid a reaction by giving penicillin orally instead of by injection?

• If penicillin must be used because there is no acceptable alternative, can this patient be rapidly desensitized?

Case Discussion

• How would you determine whether the patient is likely to have an allergic reaction if she is treated with penicillin now?

  Skin testing for penicillin can be an extremely useful procedure for determining whether a patient, who has a history of penicillin allergy and in whom an IgE-mediated immunologic mechanism is suspected, is likely to have an allergic reaction to a later exposure to penicillin. If all of the reagents are available, the reliability of these tests has been as high as 96% in studies of patients who had a history of allergy, whose skin test results were negative, and who were subsequently challenged with penicillin. The testing should be done by a person familiar with the procedure. The reagents used include histamine (the positive control), saline (the negative control), penicilloyl polylysine (Pre-Pen), the minor determinant mix (MDM), and the penicillin that will be used for treatment. For the test result to be positive, the patient must show a positive reaction to histamine, a negative reaction to saline, and a positive reaction to Pre-Pen, MDM, and/or the native penicillin. The positive reaction consists of a wheal and flare that appears in 15 minutes. Unfortunately, because of the rare need for this test and extreme caution by the U.S. Food and Drug Administration (FDA), neither Pre-Pen nor the MDM is available. For this reason, we almost always use alternative drugs. If the history is not suggestive of a type I immediate hypersensitivity reaction and no alternative drugs are satisfactory, a test dose is given under controlled conditions. If the history is suggestive of a type I reaction and no alternative drug is available, we can desensitize the patient (see question 6 in following text).

• What do you do if the skin test result to penicillin is positive?

  First, you always look for an effective nonpenicillin drug substitute and use it. If one is not found, consider desensitizing the patient to penicillin.

• What is the prevalence of allergic cross-sensitivity between penicillin and cephalosporins?

  The cephalosporins resemble the penicillins chemically, but the true prevalence of cross-reactivity between semisynthetic penicillins and cephalosporins is not known because investigators cite discordant results. A reasonable estimate is that 5% of penicillin-allergic patients are sensitive to third-generation cephalosporins.

• If the patient's skin test result to penicillin proves to be negative, how certain is it that she is not allergic?

  Assuming that the entire panel of skin tests (including the controls) were done properly and the results interpreted correctly, a negative skin test result is a reliable

  P.17

  indicator that an acute IgE-mediated reaction will not occur. However, the skin test has no bearing on IgG-mediated reactions.

• If the skin test result to penicillin is positive, could you avoid a reaction by giving penicillin orally instead of by injection?

  No. Oral penicillin can also sensitize and elicit an acute reaction in already sensitized individuals.

• If penicillin must be used because there is no acceptable alternative, can this patient be rapidly desensitized?

  Yes. However, this is a potentially dangerous and always time-consuming procedure. It should be done in the intensive care unit by an experienced allergist using published protocols.

Suggested Readings

Gruchalla RS, Pirmohamed M. Clinical practice. Antibiot allergy. N Engl J Med 2006;354:601.

Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics 2005;115:1048.