Case 15

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 15

A 23-year-old woman, LL, is seen in your office complaining of flu-like symptoms that had persisted for several weeks. A physician at a local walk-in clinic gave her an antibiotic 2 weeks ago. She does not remember the name of it, but she finished the course of medications 3 days before coming to your office. She has noticed progressive pain in her hands and feet, and this morning on arising she noticed tender small bluish red spots on her fingertips. Your routine physical examination reveals nothing else of note. She is not a smoker, and she is currently afebrile. You order routine blood work and are called by the laboratory director when he noted the results indicated that she was profoundly anemic (see Appendix for reference values). At this stage you need to consider possible explanations for these findings; how might you investigate further?

QUESTIONS FOR GROUP DISCUSSION

1. LL is profoundly anemic. Explain why (a) newly discovered lung cancer and (b) iron deficiency would not be high on your list of considerations given the information provided.

2. Under what conditions can young females “normally” become iron deficient?

3. This young woman’s condition appears to be linked with an infection and the administration of antibiotics. Describe the mechanism by which a drug (antibiotic) can lead to hemolytic anemia.

4. The classic tests to detect the presence of anti-drug antibodies are the direct and indirect Coombs’ tests. Compare and contrast these two tests.

5. The results of both Coombs’ tests were negative. Yet, as LL’s physician you are convinced that the cause of her anemia is related to her recent infection and so you request an assay for cold agglutinins. Provide the rationale for this approach.

6. The cross-reacting IgM antibodies described in question 5 are referred to as “cold agglutinins.” Explain why they are so named.

7. Describe the etiology of cold agglutinin disease and why it manifests as small bluish red spots on fingertips (or outer extremities).

8. What would you recommend for therapy?

RECOMMENDED APPROACH

Implications/Analysis of Family History

No family history is provided.

Implications/Analysis of Clinical History

A prolonged infection that does not resolve with antibiotics could indicate an infection with a drug-resistant strain of bacteria. However, this would not explain the progressive pain in her hands and feet nor the tender small bluish red spots on her fingertips.

Implications/Analysis of Laboratory Investigation

A hemoglobin count of 86 g/L is of concern, and it is important to get to the root of the problem. A number of conditions can manifest as severe anemia, one of the most common being iron deficiency in young women who bleed heavily during menstruation. However, there is nothing in the clinical history to indicate this. Furthermore, this would not be associated with an infection.

A drug-induced hemolytic anemia would certainly be high on the list of possibilities here in that she has just completed a course of antibiotic medication. In drug-induced anemia, red cells bind a drug (nonspecifically) and act as a “carrier” for presentation of a hapten (the drug) to the immune system. Anti-drug antibodies are generated and bind to the drug on the red blood cell surface. The resulting immune complexes engage the classical complement pathway, resulting in red cell lysis and anemia.

Additional Laboratory Tests

Further laboratory investigation using the direct and indirect Coombs’ tests can be used to confirm (or rule out) drug-induced anemia as the cause of LL’s clinical presentation.

Coombs’ Tests

In the direct and indirect Coombs’ tests, a positive result is the visible manifestation of agglutination, resulting from aggregation and sedimentation of particulate antigen-antibody complexes (Fig. 15-1). In this case, the direct Coombs’ test was used to determine whether anti-drug IgG antibodies had formed and attached to drug/red blood cell complexes (Fig. 15-1A). The bound IgG antibodies are identified using anti-Fcγ antibodies generated in another species. When the anti-Fcγ antibodies crosslink anti-drug IgG antibodies, agglutination is observed and the sample is “positive.”

FIGURE 15-1 Testing for a type II hypersensitivity reaction. A, In the direct Coombs’ test, IgG antibodies that are bound to red blood cells are identified using anti-Fcγ antibodies generated in another species. When the anti-Fcγ antibodies crosslink anti-drug IgG antibodies, agglutination is observed and the sample is “positive.” B, In the indirect Coombs’ test we are testing for the presence of circulating anti-drug IgG antibodies in serum. Therefore, an additional step is required before agglutination can be observed. This step is the incubation of LL’s serum with the red blood cells, (to which the drug has bound) to allow LL’s anti-drug antibodies (if present) to bind to the red blood cell complex. Thereafter, the test is the same as that described for the direct Coombs’ test.

Indirect Coombs’ Tests

In contrast, in the indirect Coombs’ test we are testing for the presence of circulating anti-drug IgG antibodies in serum (see Fig. 15-1B). Therefore, an additional step is required before agglutination can be observed. This step is the incubation of LL’s serum with the red blood cells (to which we are assuming the drug has bound) to allow LL’s anti-drug antibodies (if present) to bind to the red blood cell complex. Thereafter, the test is the same as that described for the direct Coombs’ test. To determine the antibody titer, LL’s serum is serially diluted and the test is repeated. As the antibody concentration increases, agglutination will occur at higher and higher dilutions. Somewhat surprisingly to you, this test is negative!

Cold Agglutinins

At this point, you have to consider the fact that LL’s symptoms are coincident with an infection. In a number of patients, some viral and bacterial infections, particularly Mycoplasma pneumoniae, lead to the production of IgM antibodies that cross react with glycophorin (Ii), a protein present on the surface of red blood cells. A number of viral infections can also induce the production of these anti-Ii antibodies. These antibodies are referred to as cold agglutinins because they only bind to the red blood cells and engage the classical pathway of complement (causing red blood cell hemolysis) at temperatures below 30°C. These temperatures could occur in peripheral tissues (the cooler parts of the body) at night (lower overall temperatures), explaining the progressive pain in her hands/feet and tender small bluish red spots on her fingertips. The assay for cold agglutinins was positive.

DIAGNOSIS

LL was diagnosed with autoimmune hemolytic anemia, also known as cold agglutinin disease.

THERAPY

For acute cold agglutinin disease, a good (conservative) treatment is simply to keep the periphery warm! For chronic conditions, pharmacologic intervention (rituximab: anti-CD20 antibody) may be an option for specific immunosuppression.

ETIOLOGY: COLD AGGLUTININ DISEASE

Cold agglutinins preferentially bind to red blood cells at lower temperatures with subsequent hemolysis (by complement), phagocytosis, or often simply aggregation of red blood cells, resulting in capillary damage and microthrombi. The net effect is the accumulation of blood in the extravascular space that manifests as small bluish red spots (as appeared on LL’s fingertips).

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