Case 38

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 38

FG is a 62-year-old man who had received a renal transplant 12 years earlier after a period of 5 years during which he had undergone both peritoneal dialysis and later hemodialysis. The underlying cause of his chronic renal failure was believed to be a combination of diabetes (he had been insulin dependent since the age of 16) and long-standing hypertension (>25 years), which had been refractory to simple therapy and required triple therapy for adequate control. He has been on maintenance therapy (rapamycin and azathioprine) for immunosuppression, having been weaned from an earlier regimen of cyclosporine and prednisone at the suggestion of his transplant team, who thought this would be a simpler regimen for him.

FG lives at home with a daughter and son-in-law. He was referred by his general practitioner for admission to the hospital to investigate both a progressive jaundice of some 4 to 6 weeks’ duration, along with a scaling erythematous rash on both legs, which his physician had initially thought to be a simple cellulitis but that has failed completely to respond to oral antibiotics (he has received both cloxacillin and later ciprofloxacin without any significant impact on his symptoms).

QUESTIONS FOR GROUP DISCUSSION

1. In the early post-engraftment phase, the most frequent early complication is acute graft rejection. Given that 10 years have passed since transplantation, the likelihood that we are dealing with a manifestation of an acute rejection response is low. Review the etiology of acute graft rejection. Explain the rationale for immunosuppressive therapy (and cell target) in this therapeutic intervention.
2. Chronic graft failure, which is more insidious than acute rejection and more difficult to treat, is not a likely possibility. How would you rule out chronic rejection in the case of kidney transplants?
3. Infection is a leading cause of death in immunosuppressed patients. Cytomegalovirus (CMV/ human herpesvirus 6) and Epstein-Barr virus (EBV/human herpesvirus 4) are common infections in post-transplant patients. These patients may present with hepatitis, elevated liver enzymes, but rarely jaundice. Yet, these may not be de novo infections. Explain.
4. Explain why hepatitis C infection would be high on your list of considerations for this patient.
5. CMV and EBV have evolved immunoevasive strategies that allow them to remain in a latent phase even in the presence of a healthy immune system. Describe these immunoevasive strategies.
6. Virally infected cells are destroyed by natural killer (NK) cells and cytotoxic T cells. Despite this, patients develop anti-CMV and anti-EBV antibodies when infected. Explain.
7. A number of infectious agents (e.g., hepatitis C) and some malignancies induce the production of cryoglobulins, abnormal antibodies that precipitate at temperatures below 98.6°F (37°C) and become soluble again at normal body temperatures. Discuss how the production of cryoglobulins could be the stimulus for processes that cause the rash.
8. Although there is some evidence that complement activation can lead to lysis of enveloped viruses, this is not considered one of the main effector mechanisms in host immunity to viral infections. Therefore, it is unlikely that this would lead to a low C4 level in serum as observed in this patient. Provide a rationale for the low levels of C4 (and C3) complement proteins.
9. In this patient, polymerase chain reaction (PCR) detected high levels of hepatitis C in the blood, indicative of active viral infection. Given this information, what would you expect to be the cause of the rash on this patient’s legs? Explain how this would manifest. How would you treat the hepatitis C infection?
10. Discuss other possible causes of the leukocytoclastic vasculitis and how you would treat this even in the absence of confirmation that this was the cause of the rash.

RECOMMENDED APPROACH

Implications/Analysis of Family History

Although we are not provided with any family history, this patient has had insulin-dependent diabetes and hypertension for decades. Disease susceptibility for type 1 diabetes mellitus depends on the degree of genetic similarity that an individual has with the proband (see Case 24). Hypertension is known to have a strong genetic association, but the genes have not been identified. There are a number of risk factors for development of hypertension, one of which is diabetes.

Implications/Analysis of Clinical History

There is a case history of multiple medical problems, along with the specific ones potentially related to engraftment and immunosuppression.

Complications Associated with Graft Rejection

Note that in the early phases after engraftment the most frequent early complication seen is acute graft rejection. Given that this patient’s problems started 10 years after transplantation the likelihood that we are dealing with a manifestation of an acute rejection response is unlikely. Even chronic rejection, which is more insidious and results in chronic graft failure, is doubtful. In this case, a hint that this was a problem would appear in the form of a slow and inexorable increase in serum creatinine levels over time, an indication that the kidney was slowly losing its major filtration functional capacity. If, indeed, the disease processes we are seeing are related to the transplant itself, they are more subtly related than these two obvious scenarios.

Complications of Immunosuppressive Therapy

Complications of the immunosuppressive therapy used to ensure graft survival are unfortunately quite common and include malignancy (lymphoma and melanoma), infection, and drug toxicity. Recrudescence of earlier infections or opportunistic infections can also cause problems in immunosuppressed individuals. Opportunistic infections that could certainly be of concern include Pneumocystis carinii (jiroveci) pneumonia (PCP) and infection with Cryptosporidium, Mycobacterium tuberculosis, as well as the opportunistic species M. avium. Indeed, a variety of pathogens seen in another population of immunosuppressed individuals (e.g., acquired immunodeficiency syndrome; see Case 13) is of more than passing interest as we remember that this patient first came to attention with evidence of liver disease (jaundice).

A number of viral infections are also prevalent in immunosuppressed individuals. These include cytomegalovirus (CMV/human herpesvirus 6), hepatitis C, Epstein-Barr virus (EBV/human herpesvirus 4), and human herpes simplex virus (HSV/human herpesvirus 1/2), although the latter two are less likely to cause this hepatitis. Recrudescence of chickenpox (herpes zoster) may also occur in immunosuppressed individuals (Fig. 38-1).

image

FIGURE 38-1 Disseminated herpesvirus infection such as can occur in immunocompromised (post-transplantation) patients on chronic prednisone therapy.

(From Fireman P, Slavin R: Atlas of Allergies, 2nd ed. St. Louis, Mosby, 1996.)

Implications/Analysis of Laboratory Tests

To determine where to focus laboratory investigations we should keep in mind that the risk of malignancies is in fact quite restricted, with lymphomas and skin malignancies (especially epithelial cancers) quite common. Infections are more common. CMV can cause hepatitis, but jaundice is rare with infection with this virus. A more appropriate test to learn if infection is the cause of this patient’s symptoms is to determine if this patient is infected with hepatitis C.

Malignancy

Investigation for lymphomas (abdominal ultrasound/computed tomography [CT]; head CT) proved negative. Biopsy of the rash (see later) indicated this was not the cause of either difficulty.

Viral Infections

Serologic investigation to test for anti–hepatitis C antibodies using the enzyme-linked immunosorbent assay (ELISA) revealed a high anti–hepatitis C antibody titer. To further investigate this, a request was made for a viral load measure.

Additional Laboratory Tests

Polymerase Chain Reaction

PCR was used to access hepatitis C viral load. Results indicated high levels of hepatitis C in the blood, indicative of active viral proliferation.

Complement

Chronic antibody production to hepatitis C could lead to immune complex deposition disease and a vasculitis reaction (which may be what the skin lesion is all about!). To assess the role of immune complex–mediated activation of complement in the etiology of the vasculitis, serum levels of complement proteins C3 and C4 were measured. Both were decreased relative to controls.

Biopsy of the Skin

A biopsy of the skin (rash) on the legs showed marked infiltration with neutrophils and some lymphocytes, along with other activated monocytes. The picture was described by a pathologist as being typical of leukocytoclastic vasculitis, in which deposition of immune complexes plays an important role (e.g., hepatitis C/anti–hepatitis C antibody complexes). After immune complex deposition and complement activation, the subsequent inflammatory reaction results in impairment in the circulation in small vessels in the skin and damage to blood vessels, with resultant bleeding into the skin often manifesting as a rash.

Finally it is worth remembering that included among the potential complications of immunosuppression is toxicity of the drugs themselves, which can cause both hepatotoxicity reactions and hypersensitivity reactions. Therefore, the vasculitis could, in fact, be the result of a hypersensitivity reaction to the drugs, subsequent formation of antigen-antibody complexes, and associated inflammatory processes involving both complement and neutrophil activation.

Kidney Biopsy and Serum Creatinine

A renal biopsy suggested extensive immunoglobulin deposition in the glomerulus and parenchyma, with some mononuclear cell infiltration. Serum creatinine levels were mildly elevated, reflecting damage to the glomeruli as a result of immune complex–mediated activation of complement and neutrophils with associated inflammatory processes.

DIAGNOSIS

This patient is infected with the hepatitis C virus and should be treated accordingly (see Therapy). The rash, diagnosed as leukocytoclastic vasculitis, is the result of immune complex deposition and subsequent inflammatory processes. Whether the antigenantibody complexes are the result of a drug/anti-drug antibody interaction or hepatitis C/anti–hepatitis antibody interaction would require further testing.

THERAPY

In FG’s case, a prudent course of action would be to treat the acute hepatitis C infection (with interferon alpha [IFNα) and to modify further the rejection therapy FG is receiving, presuming that the relatively new addition of some drugs may be a cause of the hypersensitivity.

ETIOLOGY: ANTIBODIES IN CHRONIC GRAFT REJECTION

In the absence of hyperacute rejection, it is accepted that early after transplant there is little evidence for antibody-mediated rejection processes. There is, however, a growing realization that with time anti–donor-specific antibodies are present in graft recipients. What is not altogether clear is whether this has beneficial (blocking) effects or is a contributor to the pathology of rejection.

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