Case 42

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 42

Elizabeth is a 19-year-old girl with severe Crohn’s disease. In the course of this disease characterized by diarrhea, pain, loss of appetite, and weight loss, the associated inflammatory processes led to bowel obstruction that necessitated resection of a large portion of the intestine. Unfortunately, so much of the small intestine was removed that the remaining segment could no longer absorb the required nutrients. Consequently, Elizabeth began receiving total parenteral nutrition, which is intravenous feeding. As such, she was an ideal candidate for a pilot intestinal transplant program and had received a small intestinal transplant 1 month earlier. In this procedure, the surgeon transplants a segment of a cadaver’s small intestine into the patient. The patient was also prescribed a regimen of immunosuppressive drugs to overcome the rejection, but this also increases the risk of infection.

After 27 days, Elizabeth returned to the hospital showing evidence of weight gain, but with a diffuse “weeping” rash covering her body, abdominal cramps, and a fever of 5 days’ duration. As you begin to consider this problem, think of issues related to transplantation in general, of the side effects of transplantation, and of small intestinal transplantation in particular.

QUESTIONS FOR GROUP DISCUSSION

1. What is Crohn’s disease? Families of patients with Crohn’s disease have shown a strong association with mutations in the NOD2 gene. What is NOD2?
2. Ex vivo studies have repeatedly shown that macrophages isolated from diseased intestinal segments of Crohn’s disease patients produce more interleukin (IL)-12 compared with macrophages isolated from control patients. Explain how IL-12 production would lead to an increase in interferon gamma (IFNγ), tumor necrosis factor (TNF), and IL-2 but a decrease in IL-4.
3. IFNγ, TNF, and IL-2 play a significant role in various aspects of the immune system. Discuss these and how each might play a role in destruction of the intestine.
4. T cells isolated from Crohn’s disease patients also produce more IFNγ and decreased amounts of IL-4. Both IL-12 and IFNγ play an important role in inflammation, and this is supported by studies in which Crohn’s disease patients treated with antibodies that block the IL-12 receptor showed a significant decrease in inflammation.
5. Acute graft rejection by the host’s immune system is the most frequent early complication of transplantation. What is acute graft rejection, and what is the primary underlying cause? How do we try to avoid this problem clinically?
6. Evidence for acute rejection would be nonspecific (e.g., fever) as well as physiologic “failure” of the graft. Explain the role of cytokines in nonspecific graft rejection and how cytokines play a role in the induction of fever.
7. Rejection of an intestinal graft would manifest as a loss of weight with cramping. Explain what is causing the cramping.
8. Acute rejection episodes are best treated by increasing nonspecific immunosuppression. However, the side effects of immunosuppression itself are often the cause of the patient’s main complaints. CD4+ T cells are usually the target for immunosuppression. Review the role of CD4+ T cells in immune responses and in acute rejection.
9. What organs and tissues are particularly susceptible to drug (cyclosporine and tacrolimus) toxicity? In addition to the drug toxicity, to what malignancies and types of infections are immunosuppressed patients particularly prone?
10. A peculiarity to intestinal transplantation is that we generally transplant donor lymphoid tissue here (as well as the intestinal graft itself). In fact, the intestine is a source of some 50% of the total body lymphoid pool and can lead to graft versus host disease (GvHD). Discuss how a diagnosis of GvHD would explain the cramps, fever, and weeping rash.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Crohn’s disease is a disorder that develops from an unregulated mucosal immune response in the gastrointestinal tract. This disease is, in part, genetically determined because studies with identical twins indicate that there is a 58% to 67% concordance. Whole genome screens of families of patients with Crohn’s disease have shown a strong association with mutations in the NOD2 gene, also known as CARD15. NOD2, an intracellular receptor for peptidoglycan present in various bacteria, is expressed by epithelial cells as well as by phagocytes and antigen-presenting cells. Several hypotheses have been put forward regarding the mechanism by which NOD2 mutations could contribute to unregulated mucosal immunity; however, more studies are required to provide a solution to this problem. No specific pathogen from the normal resident flora has been identified as a stimulus for the inflammatory process.

Implication/Analysis of Clinical History

Elizabeth’s clinical presentation includes a weekend-long fever, abdominal cramps, and a diffuse “weeping” rash covering her body. In a patient who is 1 month post transplant, the first considerations are acute rejection and infection to account for a fever of 5 days’ duration.

Infection

Infection could certainly be a cause of the fever. Viral infections, particularly cytomegalovirus (CMV), are particularly prominent early after transplantation because the primary target of immunosuppressive therapy is the T cell. T cells play a key role in many aspects of the immune system, including activation of the cytotoxic T cell, a key player in viral immunity.

In intestinal transplant patients, immunosuppressive drugs and/or graft rejection may disrupt the mucosal barrier such that bacteria can enter the lamina propria and from there access the mesenteric lymphatics and, ultimately, the circulation. Sepsis is a common cause of death after an intestinal transplant.

Acute Rejection

The most frequent early complication of transplantation is acute graft rejection by the host immune system. This is a function of, among other things, the degree of MHC incompatibility between donor and host. Pretransplant MHC “matching” of donor and recipient is an attempt to minimize acute rejection.

Fever in Acute Rejection

Acute rejection triggers an inflammatory response as activated macrophages secrete tumor necrosis factor (TNF) and interleukin-1 (IL-1) that alter the vascular endothelium to facilitate the transmigration of leukocytes from the circulation to the tissue.

When host CD4+ T cells are activated, they release cytokines (e.g., IFNγ/TNF) that enhance the cytotoxicity of macrophages, as well as their secretion of IL-1 and TNF. At high concentrations, TNF and IL-1 act on the hypothalamus, which triggers a cascade of events that lead to a febrile response, associated with elevated endogenous production of prostaglandin E2. (Acute rejection also includes destruction of the graft as a result of CD8+ T cell activation.)

The abdominal cramping could be caused by histamine released from mast cells during an inflammatory response. Mast cell degranulation leads to the release of histamine, which can act on histamine receptors present on the mesenteric musculature, causing increased contractions with concomitant cramping.

Other Possibilities

Elizabeth has some, but not all, of these findings, which might serve to alert you to other possibilities!

Implication/Analysis of Laboratory Tests

How might you measure directly evidence for graft failure in this case? Various measures have been tried. Note: we need some specific assay for intestinal function (e.g., serum creatinine for the kidney). Accordingly, measuring the absorptive function of the intestine is currently the best approach.

Assessing Intestinal Absorption

The d-xylose absorption test may be used to assess absorption of carbohydrates. d-Xylose is a carbohydrate that is absorbed normally by the small intestine but is not utilized by the body. This test measures the amount of d-xylose in the blood or urine about 2 hours after swallowing a drink containing the sugar. Because d-xylose is normally absorbed by the intestine, this test can be used to assess absorption of carbohydrates.

Fat absorption can be assessed with the fecal fat test in which dietary intake of fat during a defined period (e.g., 3 days) is compared with the amount of fat in feces in the same period of time. The fat content in the feces will be higher than normal in patients who are unable to absorb fats.

Additional Laboratory Tests

There is one key feature that none of these explanations has addressed, however, namely the rash. Endoscopy and colonoscopy with tissue biopsy of the intestine are used to obtain tissue samples to establish an unequivocal answer. In general, pathologic and histologic assessment is more definitive than endoscopy (visual inspection alone), which only diagnoses rejection about two thirds of the time. The pathologic report indicates evidence for villous blunting, a significant mononuclear cell infiltrate with edema of the lamina propria, inflammation of crypts (cryptitis), and increased cell death (crypt cell apoptosis). All are findings consistent with intestinal GvHD.

DIAGNOSIS

A peculiarity in intestinal transplantation for Crohn’s disease is that we generally transplant donor lymphoid tissue here (as well as the intestinal graft itself). In fact, the intestine is a source of some 50% of the total body lymphoid pool. GvHD is thus a distinct problem in this form of transplantation. Massive cytokine production (now from both activated host and donor CD4 cells) often leads to the severity of the symptoms (a so-called cytokine storm). This would also account for the “weeping rash” (elevated permeability of vessels after cytokine release) and the cramps (and fever).

THERAPY

As in all cases, we have to weigh the pros and cons of different treatments. Acute rejection episodes are best treated by increasing nonspecific immunosuppression. Increased (or different) immunosuppression would be a first step. However, increased infection (a consequence of immunosuppression) and increased evidence of malignancy are two of the “big” side effects. Interestingly, the incidence of malignancy is relatively restricted to two problems: lymphomas and skin malignancies.

Another complication of immunosuppressive treatment is often the toxicity of the drugs themselves. Hypersensitivity reactions are included as possibilities but are rare because the drugs themselves are immunosuppressive. However, toxicity to other tissues is common, such as renal toxicity and neurotoxicity, which is particularly common with cyclosporine and tacrolimus.

Depending on the patient’s response to increased immunosuppression, graft removal may be the only remaining option.

ETIOLOGY: CROHN’S DISEASE

Crohn’s disease is a chronic inflammation of the intestine. For most patients, this disease requires extensive bowel resections and a need for total parenteral nutrition. Often patients are unable to maintain a satisfactory nutritional status or fluid and electrolyte balance. Consequently, weight loss becomes a problem.

Before bowel resection, inhibition of cytokines that play a role in an unregulated immune response may be successful. In recent years, monoclonal antibodies that bind TNF have been used for some patients with Crohn’s disease with varying degrees of relief. For this patient, blocking cytokine activity was not an option because a substantial length of the small intestine had already been removed and so intestinal transplantation had been her only remaining option.

Models for Unregulated Immune Response

Although no genetic susceptibility genes have been identified that would result in an unregulated immune response, two models have emerged. The first is that unregulated mucosal inflammatory response arises as a result of a predominance of inflammatory cytokines (e.g., IL-12, IFNγ, TNF); the other is that unregulated responses could occur if patients have a defect in the regulatory T cells that would normally dampen this response.

Ex vivo studies have repeatedly shown that macrophages isolated from diseased intestinal segments of patients with Crohn’s disease produce more IL-12 compared with macrophages isolated from control patients. Additionally, T cells isolated from patients with Crohn’s disease also produce more IFNγ and decreased amounts of IL-4. Both IL-12 and IFNγ play important roles in inflammation, and this is supported by studies in which patients with Crohn’s disease treated with antibodies that block the IL-12 receptor showed a significant decrease in inflammation.

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