Case 43

Published on 18/02/2015 by admin

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Last modified 18/02/2015

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CASE 43

Ms. Bell received cardiac transplantation approximately 6 years earlier for a cardiomyopathy that developed after she received chemotherapy (doxorubicin [Adriamycin]) for breast cancer. She has had routine endomyocardial biopsies each year, the last being 1 year ago. At that time the pathologist read the biopsy as normal, with no signs of rejection. The only change in her anti-rejection therapy over the past 2 years was a reduction in the prednisone dose (now 7.5 mg/day) and replacement of cyclosporine (which she had received for nearly 5 years since the time of transplantation) with tacrolimus. You (her son) were told that the advantage of tacrolimus was a slightly improved toxicity profile. You arrived home for a visit this afternoon to find your mother confused and with a droop on the left side of her face/mouth. You immediately call an ambulance and arrange transport to the local hospital.

QUESTIONS FOR GROUP DISCUSSION

1. Tissue rejection is of concern for any transplant patient. Explain why this patient’s symptoms are unlikely to be caused by hyperacute rejection.
2. Review the immunology of acute rejection and why this is unlikely the cause of the clinical presentation. In general terms how is acute rejection treated? Provide a rationale for the use of each of the following as therapy for acute rejection: (a) intravenous anti-CD3 antibodies and (b) anti-CD25 antibodies.
3. Explain how you would determine whether the clinical symptoms are the result of tissue (heart) damage.
4. Chronic rejection is still a possibility. What is the underlying cause of chronic rejection? Describe how (a) numerous, but minor, acute rejection episodes and (b) chronic immunostimulation against minor antigens in the graft could lead to chronic rejection. Discuss how this would affect heart function and how it might lead to generalized neurologic deficits. What aspect of this patient’s clinical presentation cannot be explained by a diagnosis of chronic rejection?
5. A diagnosis of “rejection” seems unlikely in this patient as discussed in the previous questions. What three potential problems should we consider given that this patient is on immunosuppressive therapy?
6. Discuss the three types of malignancies to which this patient may be susceptible and how these could account for the neurologic symptoms.
7. Why would you want to include Ms. Bell’s original breast cancer as a risk, in addition to the three that you have just described? What is the proposed mechanism underlying this increased risk of malignancies?
8. How would you rule out a new immune response in a patient known to be (a) infected with a virus prior to the transplant and (b) uninfected before the transplant?
9. Direct drug toxicity reactions are also a major consideration. Discuss how toxicity reactions secondary to therapy with tacrolimus and cyclosporine would manifest in (a) the kidney and (b) nervous tissue?
10. Discuss the possible complications of prednisone therapy. Explain how this would account for this patient’s clinical symptoms.

RECOMMENDED APPROACH

Implications/Analysis of Family History

At this stage we are not provided with any family history. Family history regarding cardiac problems is likely irrelevant in that Ms. Bell’s heart problems were related to chemotherapy after she was diagnosed with breast cancer.

Implications/Analysis of Clinical History

Ms. Bell received a cardiac transplant 6 years ago, and all the evidence we are provided with indicates that this was a successful graft in that the yearly endomyocardial biopsies have all been normal. In fact, the only change in her anti-rejection therapy has been a reduction in immunosuppressive therapy and change from cyclosporine to tacrolimus, which is slightly less toxic.

Chronic Rejection

Chronic rejection, most readily correlated with release of nonspecific “growth factor”-like mediators (e.g., fibroblast growth factor, endothelial growth factor) tends to take the form of an insidious fibrosing/proliferative reaction, which is relatively refractory to immunosuppressive treatment. (Fibrosis refers to the excessive accumulation of connective tissue in an organ.) Note that a fibrotic (noncompliant) heart would not pump as efficiently. Therefore, the resulting inability to oxygenate the tissues might cause some generalized neurologic deficits (e.g., the confusion referred to in the case description). Thus, one might consider the neurologic deficits as one possible manifestation of chronic rejection. However, the history suggests a more sudden onset, which does not fit this picture.

Organ-Specific Damage

Organ-specific damage is high on the list of possible diagnoses. Whenever we look for organ-specific damage (from T cell-mediated “attack”) we think of organ-specific “markers” for the damage. Thus, in kidney grafts, you would measure creatinine. For the heart you can look at the electrocardiogram and also measure specific cardiac muscle enzymes in the blood (see Implications/Analysis of Laboratory Investigation).

Implications/Analysis of Laboratory Investigation

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