Case 41

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 41

Geoffrey is a 14-month-old child born with biliary atresia (absence of the biliary tree). His parents are advised that the only possibility of cure and a normal life is a liver transplant. Given the shortage of donors, the surgeon discusses the risk/benefit of living related transplants. Both parents are eager to consent, although the best match is deemed to be the father. Surgery involves transplantation of the left lobe of the father’s liver to his son. Both surgeries go well, and both patients make excellent recoveries, returning home within a week after surgery. There are no further complications of the father’s care. Some 4 weeks after the transplant, Geoffrey develops a desquamating, erythematous rash over his trunk, legs, and arms, a low-grade fever, and some diarrhea. His parents return him to the transplant center and are very concerned.

There has been no dramatic change in Geoffrey’s post-transplant immunosuppressive regimen. Blood work looks relatively normal, with some moderate elevation of liver function tests. The diarrhea is quite profuse, although stool cultures are negative for infectious organisms. In fact, blood cultures, urine, induced sputum, and even a lumbar puncture fail to identify an infectious cause of disease, despite evidence for a continuing low-grade fever. During the third hospitalization day he actually becomes quite tachypneic (short of breath), although again a chest radiograph fails to document any obvious pathologic process. He is holding reasonable oxygen saturation only when receiving high-flow 100% oxygen. Of particular concern, you have not been able to discern the cause of the rash, and he is only maintaining normal urine output with vigorous fluid resuscitation. The nurse in the intensive care unit comments that only in burn patients has she seen a rash this bad.

QUESTIONS FOR GROUP DISCUSSION

1. Acute and chronic rejection of a graft by a host is referred to as host-versus-graft disease (HvGD). Compare these two types of HvGD with respect to effector cells, time of onset, and treatment (see Case 42).
2. Explain why immunosuppressive therapy is essential for all transplants except for those from an identical twin.
3. Patients on immunosuppressive therapy have risk factors that are unrelated to the graft itself. Discuss these factors.
4. None of the risk factors (see question 3) will present as a desquamating rash (shedding of the outer layer of skin/epidermis). Furthermore, this complication occurs only with intestinal, bone marrow, and liver transplants. What do these tissues have in common?
5. Graft versus host disease (GvHD), as the term implies, refers to the immunologic assault of the host tissues by the graft. Given that one of the prominent features of GvHD is the desquamating rash, to what host antigens is this immunologic response directed?
6. Immunologic responses in HvGD and GvHD involve the same components of the immune system. In HvGD the host is targeting the graft, whereas in GvHD the graft is targeting the host tissues. In both these scenarios, CD4+ Th1 cells play a significant role. Review immunologic responses that require Th1-derived cytokines. (Begin by listing the type 1 cytokines.)
7. With reference to question 6, how would you treat GvHD?
8. For liver transplants, GvHD is a recognized complication; but once this is overcome, graft acceptance by the host occurs more readily than for other types of graft. One explanation is that the liver establishes microchimerism. Explain the term microchimerism and discuss how this might contribute to tolerance of a foreign tissue.
9. Assuming that the microchimerism model proposed is indeed the mechanism by which liver allograft tolerance is induced, explain why vigorous immunosuppression immediately after transplantation would condemn a patient to life-long immunosuppressive therapy.
10. Acceptance of a liver graft can itself facilitate acceptance of a later (different) organ allograft from the same donor. Discuss the potential implications of this for organ transplantation.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Biliary atresia is a disorder characterized by the absence or obstruction of bile ducts that normally transport bile to the small intestine or to the gallbladder for storage. The retention of bile within the liver leads to cell damage and subsequent scarring that can lead to cirrhosis.

No family history is provided, and for a clinical presentation of biliary atresia this is not critical in that there is no evidence of a genetic link for this disorder. Therefore, this disorder usually presents in only one child in a family or in only one child of a pair of twins. The incidence of this disorder is low, occurring in only 1:1500 to 1:2000 members of the general population. Interestingly, Asians and African Americans are more likely to be affected than whites.

Implications/Analysis of Clinical History

Patients with biliary atresia generally appear normal at birth and initially show normal weight gain. By the time they are 2 or 3 weeks of age, they develop jaundice, become irritable, and show weight loss. Urine samples are dark; stool samples become light colored. When a diagnosis of biliary atresia is made before the infant is 3 months of age, surgical intervention may reestablish bile flow. When this intervention is not successful, or if the infant is not diagnosed within the time frame that allows surgery, the only option is a liver transplant. Although we are not given the early clinical history, we are told that Geoffrey received a liver transplant when he was 14 months of age. This would necessitate immunosuppressive therapy even though we are not provided with this information. Four weeks after the liver transplant, Geoffrey was brought back to the transplantation center because he had developed a desquamating, erythematous rash over most of his body, a low-grade fever, and some diarrhea.

Given this clinical history, our immediate concern is acute rejection of the graft or a complication of immunosuppressive therapy that would include infection, malignancy, or drug toxicity.

Implications/Analysis of Laboratory Testing

Graft rejection (host versus graft disease [HvGD]) is our first concern. However, liver function tests revealed only moderate elevation of liver function tests. Whereas complications of immunosuppressive therapy include malignancy and drug toxicity, as well as infection, the fact that Geoffrey has a fever and profuse diarrhea puts infection at the top of this list. However, stool cultures, blood cultures, urine, induced sputum, and lumbar puncture were all negative for any infectious agent. Although a viral diagnosis could have explained the profuse diarrhea and fever, it would not account for the rash. An idiosyncratic drug hypersensitivity reaction could present as a desquamating rash, but this would not present as a fever and diarrhea.

We need to consider the fact that transplantation of liver, bone marrow, and intestinal grafts is unique in that these grafts contain major donor lymphoid elements. A complication of grafts that have major lymphoid donor cells is graft versus host disease (GvHD), which occurs when donor immune cells attack host tissues.

Additional Laboratory Tests

A biopsy of skin was examined histologically, and these findings were characteristic of changes occurring in GvHD. Consistent with such a diagnosis, there was evidence for lymphoid infiltration with death of basilar epidermal cells, vacuolization of more superficial epidermal cells, and eosinophilic bodies. Polymerase chain reaction was used to determine if the human leukocyte antigens present in the skin tissue and peripheral blood lymphocytes obtained by biopsy (phlebotomy) was predominantly of donor (father) or recipient origin.

DIAGNOSIS

On the basis of these laboratory results and the clinical presentation, Geoffrey was diagnosed with GvHD. In GvHD, donor cells of allograft origin target host antigen present on the epithelia of the gut, lung, and biliary tree. Inflammation, edema, and increased vascular permeability to both fluid and cells characterize these reactions.

THERAPY

Immunosuppression should be increased.

ETIOLOGY: TOLERANCE OF LIVER ALLOGRAFTS

Many different mechanisms have been put forward to explain the observation that allograft tolerance occurs more often with transplanted livers than with other organs. Some of the proposed mechanisms include production of soluble MHC class I proteins, generation of immunoregulatory suppressor T cells, induction of regulatory cells, and microchimerism. The concept of microchimerism is particularly interesting in that it suggests that patients with stable microchimerism may eventually be able to be withdrawn from all immunosuppression without loss of the graft (stable graft-specific tolerance).

Microchimerism

In the world of transplantation, an ideal scenario would be one in which the patient becomes tolerant to the allograft without the need for long-term immunosuppressive therapy. Although still uncommon, there are documented reports of allograft tolerance after liver transplantation. The explanation may lie in the ability of the liver to establish cellular microchimerism. Within this context, microchimerism refers to the seeding of peripheral tissues with blood cells present in the graft. In one model, tolerance is induced because donor cells attack the host cells (graft versus host), which would cause graft versus host disease; whereas if host cells attack the donor cells (host versus graft), that would cause host versus graft disease. Following their activation, both populations of cells undergo apoptosis, resulting in tolerance. Support for this model comes from studies that have shown that prior acceptance of a liver graft can itself facilitate subsequent acceptance of a later (different) organ allograft from the same donor.

Multiple attempts have been made to document evidence for such microchimerism in patients with long-standing grafts on minimal (or often no) immunosuppressive therapy. To date there has been no consistent evidence that microchimerism represents the common theme explaining tolerance in these cases, and this remains an intellectually attractive, although still unproven, explanation.

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