PBL Sessions: Immunologic Diseases


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Page 10

Final Discussion of Case:

The stable where Heather works had changed to a different supplier of feed for the horses, including hay bales instead of hay cubes, the month before. Heather wants to know if further episodes of her illness can occur, and if there is a way to deal with them - cheaply. She has no other place to go.

Review the diagnoses in this case.

Tasks

  • Discuss the cause(s) for immunologic manifestations in this patient.

  • Review the clinical findings and explain how they occur.

  • Discuss the cause(s) for this patient's episodic edema.

  • Discuss the laboratory findings which help to explain the findings.

  • Prepare for the case wrap up session.

Immunologic Diseases PBL - Summary

James initially visited the physician for a temporary condition, contact dermatitis, which probably resulted from his home gardening activities. Contact dermatitis is a form of type IV hypersensitivity.

The theme in this case for Jack is a neoplastic disease. The non-tender lymphadenopathy and weight loss in his initial presentation are highly suggestive that a malignancy is present. This should be in the hypothesis list, but it is not addressed formally until page 6. The biopsy shows a low-grade B cell lymphoma, which is CD20 positive.

Biotherapy for malignancies is becoming more common. In the case of low-grade B cell lymphomas, there is a monoclonal antibody known as rituximab that is directed at CD20 antigen. The antibody kills the CD20 positive B cells by a variety of mechanism, one of which is a form of type II hypersensitivity known as antibody-dependent cell-mediated cytotoxicity (ADCC).

Madge has features of systemic lupus erythematosus, including myalgias, arthralgias, pericarditis, skin rash, and renal disease. This autoimmune disease is often mediated by formation of antigen-antibody complexes, a form of type III hypersensitivity.

Heather has hay fever. The use of the baled hay releases more dusts with allergens into the air. There may also have been a different type of grass in the new product to which she was sensitive. Regardless, she can use antihistaminic agents to treat episodes of hay fever, and these can be over-the-counter drugs.

Sarah's illness is the most complex. Her C1-INH deficiency is likely inherited. Whether interited or acquired, it is rare. The inherited form is responsible for the condition hereditary angioedema (HAE).

Hereditary Angioedema

Hereditary angioedema (HAE) is an autosomal dominant disorder with a prevalence of 1:50,000 worldwide and a spontaneous new mutation rate of about 25%. There have been more than 100 different C1 inhibitor gene mutations identified. Different mutations yield different degrees of severity (phenotype), and there is clinical variability, even amongst persons who have the same mutation (genotype).

In about 85% of cases of HAE, there is deficiency in circulating C1 INH. Though it would be predicted that levels should be 50% with one mutated gene, laboratory studies show levels that vary from 5 to 30% of normal, probably due to abnormalities in secretion, transport, and catabolism as well as production. In about 15% of cases of HAE, their are adequate levels of C1 INH, but the C1 INH is not fully functional. High plasma concentrations of dysfunctional C1 INH can be found because the mutant protein is secreted normally and it is unable to form complexes with proteases, which increases its half-life in the circulation.

Persons with C1 INH inhibitor deficiency have recurrent episodes of non-pruritic, non-pitting edema, typically involving extremities. Sometimes there may be erythema of overlying skin, but not urticaria. Peripheral pain is not usually a feature, unless swelling occurs on pressure bearing areas or where subcutaneous tissue is limited. The onset of edema gradually occurs over several hours, increases slowly for 12 to 36 hours, and then diminishes over 2 to 5 days. Episodes may occur weekly in some patients and infrequently in others. When edema involves the upper respiratory tract, there is a 15-33% risk for mortality from acute airway obstruction. In about a fourth of patients, the most significant findings are abdominal pain with nausea and vomiting, which is the result of intestinal and mesenteric edema, and the onset of abdominal involvement may be rapid, with findings that suggest an acute surgical abdomen. Risks for episodes can include local trauma, infections, drugs containing estrogen, ACE inhibitors, and stress.

Complement C1 inhibitor (C1 INH) is the principle protein that controls early activation of the classic complement pathway by immune complexes. CI INH is mainly synthesized in the liver, but smaller amounts may be produced by monocyte-macrophages. In addition, C1 INH controls activation of kallikrein, plasmin, and coagulation factors XI and XIIa. The inappropriate activation of the classic pathway generates vasoactive proteins, including C3a and C5a, that lead to inflammatory cell chemotaxis and to vascular exudation. Deficient C1 INH results in excessive kallikrein production that increases generation of bradykinin that promotes vascular permeability.

Abdominal CT imaging can reveal edema involving bowel and soft tissues. When surgery is performed and tissue resected, microscopic examination shows only edema and mild to moderate inflammatory cell infiltrates. These findings are relatively non-specific and response to treatment with C1 INH concentrate may be the only way to differentiate a surgical condition from an acute attack of C1 INH deficiency. The diagnosis with laboratory testing is suggested by decreased activity of whole complement, C4, and C2. Serum C4 level is a good screening test for C1 INH deficiency, since the C4 is usually low in untreated HAE. The diagnosis is confirmed by direct assay of the C1 INH, since symptomatic persons will have levels below 30%.

Stress reduction may help to avoid episodes of HAE. Prevention and treatment of infections should be done to try and eliminate potential triggers for HAE episodes. For women, avoidance of oral contraceptives and hormone replacement therapy may be contraindicated. For persons with hypertension, ACE inhibitors should not be used and angiotensin II receptor agonists should be avoided. The usual treatments for allergic reactions, including epinephrine, corticosteroids, and antihistamines, are not effective in treating HAE.

Long-term prophylaxis may be needed if patients are bothered by freqent or severe episodes. Occasional episodes of peripheral edema may be bothersome, but not life-threatening. Prophylaxis consists of antifibrinolytic agents, including tranexamic acid or epsilon aminocaproic acid, which inhibit plasminogen activation. Androgens, including danazol or stanozolol, which increase hepatic synthesis of C1 INH, may be used, and though are more effective at reducing the number and severity of attacks, have more side effects. Long-term prophylaxis with C1 INH may be needed if antifibrinolytics or androgens do not work or are not tolerated.

Short-term prophylaxis with antifibrinolytics, androgens, or C1 INH may be used for patients undergoing surgical or dental procedures. C1 INH is preferred for this purpose because of its more immediate effect.

Treatment for severe acute attacks of HAE consists of infusion of C1 INH concentrate. Patients with HAE may consider having their own supply of C1 INH for emergencies. However, these patients need to be trained to properly infuse this product and to properly refrigerate it.

Acquired angioedema (AAE) has clinical features identical to HAE, but has an onset later in life. There are a variety of mechanisms for development of AAE, but usually a lymphoproliferative disease is present. Antibodies against C1-Inh may play a role. Treatment of the underlying disease often is accompanied by disappearaance of AAE. If not, it can be treated similarly to HAE.