QUESTIONS FOR GROUP DISCUSSION

1. Tissue rejection is of concern for any transplant patient. Explain this patient’s workup to investigate whether his symptoms are caused by hyperacute/ acute rejection.

2. Review the immunology of acute rejection and consider whether the kinetics suggest this is a likely cause of the clinical presentation. How is acute rejection generally treated? Would a biopsy help here? Discuss the 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. Early chronic rejection is a (less likely) possibility. How would the pathophysiology of chronic rejection help us understand a presentation of acute respiratory failure?

4. If a diagnosis of “rejection” is not supported by the results obtained, what other considerations come to mind in patients on potent immunosuppressive therapy?

5. Malignancies and drug toxicity are important considerations. Are these likely to account for the predominant symptoms seen at this time after transplantation? How might this patient develop such an early appearing malignancy (consider donor origin)?

6. Direct drug toxicity reactions are certainly a consideration. Often an idiosyncratic drug (hypersensitivity) reaction, independent of common drug toxicities, will lead to respiratory complications. Is this likely with a patient on high doses of corticosteroids?

7. You should consider (early) the likelihood of infectious complications. Discuss the type of infections to which this patient is susceptible and the potential source of these infections.

8. Transplant patients are at increased risk of death from severe acute respiratory syndrome (SARS) compared with the normal population. Explain. Also, why is SARS of particular concern for this particular patient?

RECOMMENDED APPROACH

Implications/Analysis of Family History

We are not provided with any family history for the patient.

Implications/Analysis of Clinical History

The myocarditis as the cause of his cardiac failure is a potential issue. Could this infection have recurred causing failure of the transplanted organ with resultant respiratory failure (secondary to cardiac failure)? History regarding possible CMV (cytomegalovirus/ human herpes virus 5) status before the transplant is worth knowing, as is the patient’s drug history (any risk factors for HIV [human immunodeficiency virus] or other unsuspected pathogens?).

Acute and Chronic Rejection

Acute rejection is certainly the most likely initial explanation readily correlated with symptoms and presentation. However a biopsy failed to find any evidence for this: there were no signs of lymphocyte infiltration into the organ, no biochemical markers of cardiac cell death (elevated cardiac enzymes), and no changes in the electrocardiogram.

Chronic rejection occurs with release of a variety of mediators, including fibroblast growth factor and endothelial growth factor, which can cause an insidious fibrosing/proliferative reaction relatively refractory to immunosuppressive treatment. This could affect the heart, causing secondary lung failure (and the respiratory distress). However, the kinetic picture (<4 weeks after transplant) does not suggest this as a likely explanation.

Organ-Specific Damage

The most likely organ-specific damage to be seen in this patient (4 weeks after transplant) is the heart. However, all markers of cardiac biochemistry/function look normal. The organ affected is the lung (not transplanted). Moreover, this patient has a fever not yet explained.

While we treat symptoms (urgent provision of respiratory support; workup of infectious causes) it is time to “expand our net” to include other diagnoses.

Implications/Analysis of Laboratory Investigation

Routine blood work, physical examination, electrocardiogram, and serum levels of cardiac enzymes should be initiated at this time. As noted, a number of cardiac enzymes (e.g., troponin I, creatine phosphokinase, creatine kinase) are released when heart tissue is damaged. Measurement of cardiac muscle enzymes was normal, as was the electrocardiogram, ruling out killing (lysis) of heart cells as the cause of this patient’s problem. You were unable to maintain this patient’s oxygen saturation above 90% without providing artificial breathing support (intubation and ventilation). A chest radiograph shows “patchy” infiltrates throughout the lung fields.

Side Effects of Drug Therapy

Could this disorder represent one of a possible number of side effects of the treatment he received for the transplant? In general, we know that chronically immunosuppressed populations show an increased frequency of malignancy, drug toxicity, and infections (Fig. 44-1).

FIGURE 44-1 Vascular sheathing, edema, necrosis, and hemorrhage of the retina, characteristic of cytomegalovirus retinitis.

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

Malignancy is unlikely (too early post transplant), unless the tumor was “transferred” with the donor organ. Drug toxicity (particularly idiosyncratic hypersensitivity reactions to drugs) are a consideration. You should certainly be considering the risk of infection, both common (community acquired), opportunistic (e.g., Pneumocystis carinii (jiroveci), CMV), and others that are more individual specific (e.g., transferred with the transplant).

Additional Laboratory Tests

Impaired tumor immunosurveillance, as a result of immunosuppression, would be unlikely to cause fulminant growth of an endogenous tumor so early but could result in rapid proliferation of one inadvertently transferred from the donor. A biopsy (lung) would be helpful. At this stage you might consider contacting UNOS to find out about the status of other recipients (from this donor) and more about the donor’s history.

The chest radiograph was consistent with an infiltrate, but biopsy showed no signs of malignancy.

Drug toxicity (or idiosyncratic drug effects) remains a possible explanation of this patient’s clinical presentation. Tacrolimus has been associated with fibrotic reactions, but this is very early for such an effect. Moreover, checking his file, you find he is not on tacrolimus as immunosuppressant!

There is no eosinophilia, which is often seen in the case of hypersensitivity reactions.

You request viral antibody titers (IgM and IgG) for herpes simplex virus (human herpesviruses 1 and 2), CMV, and influenza viruses (asking whether this might be a primary infection or recurrence). You should begin treatment with broad-spectrum antibiotics.

DIAGNOSIS

UNOS reports back that all of the recipients of this donor’s organs are in intensive care units, with the exception of the lung recipient who died 2 days ago. All have a fever, with marked respiratory distress. There is no evidence of opportunistic malignant cell transfer in any case.

The donor was a businessman who had recently traveled to Southern China and Hong Kong on a sales mission. UNOS tells you that his wife was also recently admitted to the local hospital with respiratory distress and fever of unknown origin, although she seems to be recovering. Serologic tests from his wife have just become available, showing evidence for SARS coronavirus infection.

THERAPY

Transplant patients are at a highly increased risk of death from SARS compared with the normal population. Exact figures are still quite preliminary, but an estimate of a 10-fold increased mortality rate seems reasonable. Transplant patients have an enormous viral load compared with nontransplant patients (>10⁵ more) and shed virus at high levels, putting care workers at increased risk. Viral polymerase chain reaction (PCR) and serology can be used to confirm infection. Therapy is in its infancy. There is evidence that combination use of corticosteroids (anti-inflammatory) and interferon alpha (IFNα) can be an effective treatment, although use of other antiviral agents (e.g., ribavirin) has been ineffective to date.

ETIOLOGY: TRANSPLANTATION COMPLICATIONS

The transplant cohort is at increased risk of infection as a result of immunosuppression through endogenous reactivation, transfusion, community-acquired infection, and transplant-related infection (from organ), with a resulting marked elevation in mortality. Although we have become cognizant of the risk of Epstein-Barr virus infection (lymphoproliferative disease in transplant patients) and polyomavirus infection (especially in renal cohorts, since this virus is endogenous to the urinary tract) with resultant increased graft loss (and often distant disease, e.g., leukoencephalopathy in some patients), emerging infectious complications of equal importance are related to CMV, HIV, hepatitis C and B, West Nile virus, and SARS. All can also be transferred by transfusion, with marked decrease in risk by screening the blood pool (HIV and hepatitis C, <1 in 10⁶; West Nile [pre 2003] 1 in 10³; now with screened blood, 1 in 10⁵), but it is important to note that even a screened blood pool does not detect the infection from a recent mosquito bite (hence we should ask blood donors about recent history). PCR (on a transplanted organ) is a sensitive assay for virus but again will not detect low copy numbers (from recent infection). If there is a risk, the organ should be declined.