Case 33

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 33

A 22-year-old man is admitted to the intensive care unit (ICU) in severe respiratory distress. This unfortunate fellow was diagnosed with chronic myelogenous leukemia (CML) 6 months ago. His doctors advised both him and his family that a bone marrow transplant offered the only chance of cure. Extensive searching of relatives who were prepared to donate marrow failed to find a good match. However, searching the bone marrow transplant registry revealed one donor matched for all class I and II disparities. Transplant was performed 5 months earlier, after pretreatment with cyclophosphamide. He has had three episodes of graft-versus-host disease (GvHD), all of which resolved with pulses of anti-CD3 antibodies and corticosteroids. His current medications include cyclosporine, methotrexate, and prednisone. He has had hematuria for 10 days and watery diarrhea for 5. While in the ICU his respiratory distress worsens and there is an urgent intubation to allow for adequate oxygenation. All cultures are negative. At this stage you are not sure of what might be going on but are aware of a number of possibilities.

QUESTIONS FOR GROUP DISCUSSION

1. Explain why it is technically more difficult to closely match a solid organ compared with matching for bone marrow transplant.
2. Matching is generally done using restriction fragment length polymorphism (RFLP) or allele-specific polymerase chain reaction (PCR) to match for MHC antigens. Despite this, vigorous rejection may occur. Explain.
3. It is of interest that in the early years of clinical transplantation, concern was voiced that from our knowledge of how the T cell immune system developed one might predict that bone marrow transplant recipients might become immunologic cripples.
4. T cells expressing T cell receptors that can interact with self MHC (on thymic epithelium) with appropriate avidity are positively selected to leave the thymus. How do you reconcile the fact that in a bone marrow transplant, the antigen-presenting cells in the periphery would express donor MHC, yet the donor T cells have been educated on host thymic epithelial cells expressing host MHC (that is, how do T cells recognize these antigen complexes?)?
5. Patients who receive bone marrow transplants must receive immunosuppressive therapy to reduce the risk of HvGD and GvHD (host versus graft disease; graft versus host disease). To what type of infections are these patients particularly prone? How might these present?
6. GvHD itself presents often as a multisystemic disease with gastrointestinal, lung, genitourinary, and skin involvement. However, an alternative cause of these complaints could be that the patient has an infection (see question 5). Why is it important to rule out infection as the cause of these symptoms?
7. Why is it very important that you do not ignore GvHD as an unlikely cause of the symptoms while you investigate a possible viral infection? Discuss how you would proceed to “cover” both possibilities.
8. Within 2 days, the patient died of multiple organ failure. Blood culture showed gram-negative sepsis and disseminated cytomegalovirus (CMV) infection. CMV (human herpesvirus 6) has evolved strategies by which to hinder the immune response. Discuss these strategies.
9. With reference to question 8, one would expect that a decrease in class I MHC expression would hinder CD8+ T cells but a decrease in class I MHC should lead to NK cell activation. What cytokines are required to enhance NK cell cytotoxicity? What cell secretes these cytokines?
10. What cell population is the target of anti-CD3 therapy? Of cyclosporine therapy?

RECOMMENDED APPROACH

Implications/Analysis of Family History

CML is a clonal disorder of hematopoietic progenitor cells. Consequently, all cell types arising from that progenitor cell will be affected and increased in cell number. This would include granulocytes, monocytes, and platelets. Although the average age at which patients are diagnosed is 53, this disorder also occurs in young adults and children. White males are more likely to get CML than white women or African-American males. Hereditary factors are not known and may not play a role in disease susceptibility because an identical twin does not show greater susceptibility than a sibling when one twin has been diagnosed with CML.

Implications/Analysis of Clinical History

Nearly half of CML patients are asymptomatic, whereas others will present with fatigue, bleeding, abdominal fullness, and weight loss. Splenomegaly is the most common abnormality observed during the physical examination. Asymptomatic patients are often diagnosed after an abnormal blood test, which was requested for other reasons, including simply a physical checkup.

Implications/Analysis of Laboratory Investigations

In general, CML patients have an elevated white blood cell count (see Appendix for reference value) as well as an elevated platelet count (increase of ∼ 40%), in the absence of infection or an inflammatory response.

Additional Laboratory Tests

When the clinical picture, physical diagnosis, and blood tests are suggestive of CML, cytogenetic tests are used to confirm the diagnosis. Diagnosis is typically based on the detection of the Philadelphia (Ph) chromosome, which is present in 90% of the patients. The Ph chromosome is a modified version of chromosome 22, secondary to a reciprocal translocation with chromosome 9. The net effect of this translocation is the creation of a unique fusion gene, termed BCR-ABL. The BCR gene (N-terminal) fuses with the ABL gene, which is the catalytic domain of the tyrosine kinase gene (ABL). This chimeric gene product is key to the development of CML in that it leads to uncontrolled proliferation of cells expressing this gene. These mutated cells predominate in the bone marrow and the circulation. The BCR-ABL transcripts are detected using reverse transcriptase polymerase chain reaction (RT-PCR).

DIAGNOSIS

Diagnosis of chronic myelogenous leukemia is generally made based on the detection of the Ph chromosome.

THERAPY

Treatment consists of high-dose chemotherapy that destroys proliferating cells, which includes both the leukemic cells and the normal hematopoietic cells. Such treatment necessitates allogeneic bone marrow transplantation. As mentioned earlier, the mean age of CML at diagnosis is 53 years, but bone marrow transplantation has a significant mortality risk for patients older than 40 years of age. In this case, the patient is only 22 years old and so this is the best option for him. Irrespective of the age of the patient, bone marrow transplants have a high risk of GvHD.

New Approaches to Treatment

Some patients can be treated and cured with allogeneic bone marrow transplants. For the elderly, GvHD obviates this as a treatment. Treatment of these patients has in recent years included interferon alpha (IFNα) as adjunctive therapy. IFNα is a cytokine that is known to have antiviral and antiproliferative effects. Not everyone can tolerate the side effects of this treatment. A promising new therapy is imatinib (Gleevec), an inhibitor of the BCR-ABL kinase.

ETIOLOGY: GRAFT VERSUS HOST DISEASE

GvHD is not uncommon after allogeneic bone marrow transplantation. This patient was closely matched for all MHC class I/II mismatches (technically easier to do for marrow transplants when time is on your side). In contrast, when a solid organ becomes available the ischemic time (for the potential graft) limits the time available to match carefully for all incompatibilities). Matching would generally be using RFLP and/or allele-specific PCR. However, note that even after careful complete matching for MHC incompatibilities, multiple minor histologic incompatibilities are likely to be present, and often immune responses to these can generate as vigorous a rejection response as that to MHC antigens.

MHC Restriction in Allogeneic Bone Marrow Transplantation

It is of interest that in the early years of clinical transplantation concern was voiced that, from our knowledge of how the T cell immune system developed, one might predict that bone marrow transplant recipients might become immunologic cripples. Thus, their T cells would become MHC restricted (in the host thymus) to MHC alleles (e.g., peptide/HLA-DR3) of host origin (expressed on drug-resistant and/or radioresistant persistent host epithelial cells) whereas antigen in the periphery would be presented to them in the context of donor MHC (e.g., peptide/HLA-DR4 on antigen-presenting cells developing from myeloid precursors in the marrow transplant). Some data in the animal literature supported this theoretical position. In practice, human transplants are performed in general across closely matched (MHC) alleles, and, perhaps for this reason, this problem has not, in general, been seen in practice.

Graft Versus Leukemia Effect

A potential benefit from bone marrow transplantation in cases of patients suffering from myeloid malignancies has been realized with the observation that lymphocytes differentiating in such transplanted individuals often develop a repertoire of cells capable of recognizing the tumor cells (graft versus leukemia T cells [GvL]), which are distinct from those recognizing host (graft versus host cells [GvH]) and could thus potentially be harnessed to assist clearance of the tumor. An early concern was that in fact the specificities of GvH T cells were not distinguishable from those of GvL. However, it has become increasingly apparent that the (multiple minor) histoincompatibility differences responsible for each reactivity are distinct, and thus therapies aimed at eliminating GvH do not necessarily eliminate the beneficial GvL effect.

Clinical Presentation: GvHD or Infection?

GvHD itself presents often as a multisystem disease with gastrointestinal, lung, genitourinary, and skin involvement. Treatment of GvHD would involve a pulse of increased immunosuppressive drugs. However, an alternative cause of the presenting complaints may itself be an infectious episode, secondary to the immunosuppression to which the patient has been exposed already to allow engraftment (prevent rejection) of the bone marrow graft. This immunosuppression exposes the patient to multiple opportunistic infections (somewhat analogous to HIV infection or patients treated for autoimmune disorders), among which lung pathogens (CMV, Pneumocystis) would rank high on the list (Fig. 33-1). In addition, some of the immunosuppressive drugs used (methotrexate, in particular) can often induce hepatic and/or lung toxicity on their own accord.

image

FIGURE 33-1 Lung tissue of bone marrow transplant patient with opportunistic infection by Pneumocystis jiroveci. Alveoli are filled with aggregates of Pneumocystis whereas alveolar septa are widened and infiltrated with mononuclear cells. (Schiff stain, ×400.)

Consequence of Misdiagnosis

It is important, before beginning a treatment plan, to at least have a working hypothesis concerning what you are treating and a backup plan should that hypothesis not be borne out by future events. If it is believed that the primary problem is infectious, more immunosuppression would obviously be to such a patient’s detriment! Further administration of more toxic drugs would also not be useful if that is deemed to be the problem. However, if the problem really is GvHD and we do not treat it—that, too, could be fatal.

Therapy

A reasonable plan might be to treat the most likely pathogens (assuming infection), while at the same time trying to generate data (cultures of serum/urine/blood/cerebrospinal fluid) that would support that hypothesis and attempt to investigate further for signs of GvHD (biopsy of available tissue from affected organs [e.g., liver/bronchoscopy of the lung]) before beginning increased immunosuppressive therapy to treat that option.

Outcome

Within 2 days the patient became anuric (renal functioning ceased) and he required vasopressors to maintain his blood pressure. His lungs showed opacities throughout (on chest radiograph) that were read as evidence of acute respiratory distress syndrome by the radiologist. Taken together this multiple organ failure was thought likely to be due to terminal systemic sepsis. He died 12 hours later. Blood cultures showed gram-negative sepsis and disseminated CMV infection.

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